KR20220122701A - 폴리뉴클레오티드 및 의약 조성물 - Google Patents

폴리뉴클레오티드 및 의약 조성물 Download PDF

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KR20220122701A
KR20220122701A KR1020227025851A KR20227025851A KR20220122701A KR 20220122701 A KR20220122701 A KR 20220122701A KR 1020227025851 A KR1020227025851 A KR 1020227025851A KR 20227025851 A KR20227025851 A KR 20227025851A KR 20220122701 A KR20220122701 A KR 20220122701A
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히로시 아베
히로토 이와이
마사카즈 홈마
가나 아사노
겐지 하라다
준이치로 야마모토
후미카즈 시노하라
게이이치 모토사와
야스아키 기무라
고스케 나카모토
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내셔널 유니버시티 코포레이션 토카이 내셔널 하이어 에듀케이션 앤드 리서치 시스템
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Abstract

본 발명은, 번역 영역에 수식 부위를 가지면서도 번역 활성을 유지하고 있는 폴리뉴클레오티드를 제공하는 것을 과제로 한다. 상기 과제는, 개시 코돈에서부터 종지 코돈까지의 번역 영역을 포함하고, 상기 번역 영역이 n개의 코돈을 포함하며, 상기 n이 2 이상의 양의 정수이고, 상기 n개의 코돈이 각각 1번째, 2번째 및 3번째의 뉴클레오티드를 포함하고, 상기 n개의 코돈 중 적어도 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드에 의해서 해결할 수 있다.

Description

폴리뉴클레오티드 및 의약 조성물
본 발명은 폴리뉴클레오티드 및 이 폴리뉴클레오티드를 포함하는 의약 조성물에 관한 것이다.
세포에 있어서의 유전 정보는, DNA를 주형으로 하여 RNA 합성 효소에 의해서 전령 RNA(이하, 「mRNA」라고 하는 경우가 있다)가 전사되고, 전사된 1본쇄 mRNA에 리보솜이 결합하여 번역에 의해서 단백질이 합성됨으로써 전달되고 있다. 이 전달 형식은 분자생물학에 있어서 「센트럴 도그마」라고 불리며, 원핵생물 및 진핵생물 양쪽에 공통된 기본 원리이다.
유전 정보 전달의 중간 물질인 mRNA는, 리보솜에 직접 인식되어 단백질로 번역되기 위한 염기 서열 정보와 구조를 갖고 있다.
핵산 의약은 차세대 의약으로서의 기대가 최근 높아지고 있다. mRNA로서의 폴리뉴클레오티드(이하, 「인공 mRNA」라고도 부른다)는, 발현 증강 혹은 발현 항진에 의한 단백질 보충 요법형의 핵산 의약 또는 펩티드 발현에 의한 백신 요법형의 핵산 의약으로서 이용할 수 있다.
그러나, 천연 염기만으로 구성되는 인공 mRNA를 밖에서 세포 안으로 도입하면, 세포 안의 Toll 모양 리셉터(TLR3, TLR7, TLR8, RIG-I 등)에 결합함으로써 빠르게 면역 응답이 야기되어, 염증 반응 및 단백질 번역량의 저하가 야기된다는 것이 알려져 있다(비특허문헌 1). 세포 내에서 단백질을 발현시키기 위해서는, 어떠한 형태로 인공 mRNA 자체의 면역 반응성을 저감하면서 또한 번역량을 저하시키지 않게 강구할 필요가 있다. 또한, 천연 염기만으로 구성되는 RNA는 핵산 분해 효소에 대하여 취약하므로, 안정성 부여의 관점에서도 수식 뉴클레오티드의 도입이 필요하게 되고 있다(비특허문헌 2). 수식 뉴클레오티드 중에서도 2'-O1-메틸화 RNA, 2'-F화 RNA나 가교형 핵산 등의 당부 수식(sugar-modified) 뉴클레오티드를 포함하는 폴리뉴클레오티드는, 핵산 의약의 면역 반응성의 저감이나 핵산 분해 효소에 대한 내성 부여의 어디에나 유효하다는 것이 나와 있다(비특허문헌 3).
최근, in vitro 전사법(in vitro transcription, 이하, 「IVT」라고 한다)에 의해서 시험관 내에서 인공적으로 합성한 mRNA를 의약품으로서 이용하는 움직임이 활발히 진행되고 있다(비특허문헌 4).
예컨대 비특허문헌 5에, 멜라노마 환자를 대상으로 한 인공 mRNA 암 백신의 임상 시험에서는, 암 백신의 투여가 시작되고 나서 전이 발증율이 대폭 감소하는 것이 보고되어 있는 것과 같이, 일정한 성과도 보고되고 있다.
그러나, 이들 임상 응용되고 있는 인공 mRNA는 IVT에 의해서 제작된 것이다. IVT로 제조되는 인공 mRNA는 이하의 두 가지 과제를 갖는다. 첫째로, 면역 반응성의 저감이나 핵산 분해 효소에 대한 안정성 부여를 목적으로 하여 도입되는 수식 뉴클레오티드의 도입 위치는 제어할 수 없다. 2'-F화 수식 RNA를 IVT에 의해 도입한 인공 mRNA에서는, 펩티드 번역능이 감약·소실하는 사례가 특허문헌 1에 개시되어 있다. 둘째로, IVT에서 이용되는 RNA 합성 효소에 기질로서 인식되는 수식 뉴클레오티드 이외에는 도입이 불가능하다. 마찬가지로 특허문헌 1에는, 2'-O-메틸화 수식 RNA를 포함하는 인공 mRNA는, 일반적인 RNA 폴리메라아제를 이용한 IVT 반응으로는 조제가 곤란하다는 것이 개시되어 있다.
따라서, IVT에 의해 수식 뉴클레오티드를 도입하여 제작된 인공 mRNA에서는, 수식 뉴클레오티드의 위치 및 종류에 관해서 충분한 검토가 이루어졌다고 말하기 어렵다.
복수의 RNA를 화학적으로 연결하는 기술을 이용하여 mRNA를 인공적으로 합성하는 방법이 보고되어 있다(비특허문헌 6, 7). 이 방법을 이용하면, 코딩 시퀀스(Coding Sequence, 이하, 「CDS」라고 하는 경우가 있다)를 포함하는 인공 mRNA의 임의의 위치에 당부 수식을 포함하는 수식 뉴클레오티드를 도입하는 것이 가능하다. 실제로 비특허문헌 6 및 7에서, mRNA의 CDS 중 한 곳에 2'-O-메틸화 수식 RNA를 도입한 인공 mRNA를 제작하여, 그 펩티드 번역능이 확인된 것이 개시되어 있다. 한편, 당부 수식 뉴클레오티드의 도입 위치에 따라서는 펩티드 번역능이 현저히 감약하는 것이 개시되어 있으므로, 핵산 의약으로서 충분히 낮은 면역 반응성이나 높은 안정성을 실현하기 위해서는, 수식 뉴클레오티드의 수식률, 위치 및 종류에 관한 추가적인 지견이 필요한다.
특허문헌 1: 국제공개 제2014/093574호
비특허문헌 1: 네이쳐 리뷰즈 드러그 디스커버리(Nature Reviews Drug Discovery), 제13권, 759-780 페이지(2014) 비특허문헌 2: 네이쳐 바이오테크놀로지(Nature Biotechnology), 제35권, 제3호, 238-248 페이지(2017) 비특허문헌 3: 드러그 디스커버리 투데이(Drug Discovery Today), 제13권, 제19/20호, 842-855 페이지(2008) 비특허문헌 4: 네이쳐 바이오테크놀로지(Nature Biotechnology), 제35권, 제3호, 193-197 페이지(2017) 비특허문헌 5: 네이쳐(Nature), 제547권, 제7662호, 222-226 페이지(2017) 비특허문헌 6: 뉴클레익 애시즈 리서치(Nucleic Acids Research), 제44권, 제2호, 852-862 페이지(2015) 비특허문헌 7: 진즈(Genes), 제10권, 제2호, 84 페이지(2019)
본 발명은, 번역 영역에 수식 부위를 가지면서도 번역 활성을 유지하고 있는 폴리뉴클레오티드를 제공하는 것을 목적으로 한다.
본 발명자들이 예의 검토한 결과, 번역 영역을 구성하는 복수의 코돈이 각각 포함하는 1번째, 2번째 및 3번째의 뉴클레오티드 중, 1번째의 뉴클레오티드의 당부를 수식하여도 번역 활성이 유지되는 것을 알아냈다.
본 발명은 이하의 실시형태를 포함한다.
[1]
개시 코돈에서부터 종지 코돈까지의 번역 영역을 포함하고,
상기 번역 영역이 n개의 코돈을 포함하며, 상기 n이 2 이상의 양의 정수이고,
상기 n개의 코돈이 각각 1번째, 2번째 및 3번째의 뉴클레오티드를 포함하고,
상기 n개의 코돈 중 적어도 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
[2]
상기 당부 수식 뉴클레오티드가 적어도 2' 위치가 수식된 당부를 포함하는 [1]에 기재한 폴리뉴클레오티드.
[3]
상기 적어도 2' 위치가 수식된 당부가 이하에서 선택되는 [2]에 기재한 폴리뉴클레오티드.
Figure pct00001
[4]
상기 당부 수식 뉴클레오티드가 아데닌, 구아닌, 시토신 및 우라실로 이루어지는 군에서 선택되는 염기에 대응하는 염기부를 포함하고,
상기 염기의 종류가 적어도 2종류인 [1]∼[3] 중 어느 하나에 기재한 폴리뉴클레오티드.
[5]
상기 당부 수식 뉴클레오티드의 적어도 1개가 수식 염기부를 포함하는 [1]∼[4] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6]
상기 n개의 코돈 전부에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-1]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 5% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-2]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 10% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-3]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 15% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-4]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 20% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-5]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 25% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-6]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 30% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-7]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 35% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-8]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 40% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-9]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 45% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-10]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 50% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-11]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 55% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-12]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 60% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-13]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 65% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-14]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 70% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-15]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 75% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-16]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 80% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-17]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 90% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[6-18]
상기 n개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 95% 이상인 [1]∼[5] 중 어느 하나에 기재한 폴리뉴클레오티드.
[7]
상기 종지 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [1]∼[6-18] 중 어느 하나에 기재한 폴리뉴클레오티드.
[8]
상기 개시 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [1]∼[7] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9]
상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [1]∼[8] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-1]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 50% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-2]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 45% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-3]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 40% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-4]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 35% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-5]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 30% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-6]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 25% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-7]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 20% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-8]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 15% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-9]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 10% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-10]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 5% 이하인 [1]∼[9] 중 어느 하나에 기재한 폴리뉴클레오티드.
[9-11]
상기 n개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 0%인 [1]∼[6-18] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10]
상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [1]∼[9-11] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-1]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 100%인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-2]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 90% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-3]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 80% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-4]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 70% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-5]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 60% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-6]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 50% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-7]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 45% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-8]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 40% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-9]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 35% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-10]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 30% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-11]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 25% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-12]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 20% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-13]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 15% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-14]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 10% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-15]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 5% 이하인 [1]∼[10] 중 어느 하나에 기재한 폴리뉴클레오티드.
[10-16]
상기 n개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율이 0%인 [1]∼[6-18] 및 [9]∼[9-11] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11]
상기 n이 2∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-1]
상기 n이 2∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-2]
상기 n이 2∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-3]
상기 n이 2∼500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-4]
상기 n이 5∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-5]
상기 n이 5∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-6]
상기 n이 5∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-7]
상기 n이 5∼500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-8]
상기 n이 10∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-9]
상기 n이 10∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-10]
상기 n이 10∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-11]
상기 n이 10∼500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-12]
상기 n이 50∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-13]
상기 n이 50∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-14]
상기 n이 50∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-15]
상기 n이 50∼500의 정수인 [1]∼[10-16] 중 어느 하나13에 기재한 폴리뉴클레오티드.
[11-16]
상기 n이 100∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-17]
상기 n이 100∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-18]
상기 n이 100∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-19]
상기 n이 100∼500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-20]
상기 n이 200∼2000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-21]
상기 n이 200∼1500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-22]
상기 n이 200∼1000의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[11-23]
상기 n이 200∼500의 정수인 [1]∼[10-16] 중 어느 하나에 기재한 폴리뉴클레오티드.
[12]
5' 측 비번역 영역을 더 포함하는 [1]∼[11-23] 중 어느 하나에 기재한 폴리뉴클레오티드.
[13]
상기 5' 측 비번역 영역이 이하의 염기부를 포함하는 염기부 수식 뉴클레오티드를 포함하는 [12]에 기재한 폴리뉴클레오티드.
Figure pct00002
[식 중, R은 탄소수 1∼6의 알킬기이다]
[14]
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [12] 또는 [13]에 기재한 폴리뉴클레오티드.
[15]
5' 캡 구조를 더 포함하는 [12]∼[14] 중 어느 하나에 기재한 폴리뉴클레오티드.
[16]
3' 측 비번역 영역을 더 포함하는 [1]∼[15] 중 어느 하나에 기재한 폴리뉴클레오티드.
[17]
상기 3' 측 비번역 영역이 폴리A쇄를 포함하는 [16]에 기재한 폴리뉴클레오티드.
[18]
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 [16] 또는 [17]에 기재한 폴리뉴클레오티드.
[19]
5' 측 비번역 영역 및/또는 3' 측 비번역 영역이 당부 수식 뉴클레오티드를 포함하는 [12]∼[18] 중 어느 하나에 기재한 폴리뉴클레오티드.
[20]
이하의 구조를 포함하는 [1]∼[19] 중 어느 하나에 기재한 폴리뉴클레오티드.
Figure pct00003
[식 중, R1 및 R2는 각각 독립적으로 H, OH, F 또는 OCH3을 나타내고,
B1 및 B2는 각각 독립적으로 염기부를 나타내고,
X1은 O, S 또는 NH를 나타내고,
X2는 O, S, NH 또는 이하의 구조를 나타내고,
Figure pct00004
X3은 OH, SH 또는 이들의 염을 나타내며,
단, X1 및 X2는 동시에 O이 아니다]
[21]
포스포로티오에이트 구조를 포함하는 [1]∼[20] 중 어느 하나에 기재한 폴리뉴클레오티드.
[22]
상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 1번째의 뉴클레오티드와 2번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 [1]∼[21] 중 어느 하나에 기재한 폴리뉴클레오티드.
[23]
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 [1]∼[22] 중 어느 하나에 기재한 폴리뉴클레오티드.
[24]
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 [1]∼[23] 중 어느 하나에 기재한 폴리뉴클레오티드.
[25]
[1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드를 포함하는 의약 조성물.
본 발명은 이하의 실시형태를 더 포함한다.
[1A]
질환의 치료에 사용하기 위한 [1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드 또는 [25]에 기재한 의약 조성물.
[1B]
질환을 치료하는 방법으로서, 그 필요가 있는 환자에게 치료 유효량의 [1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드 또는 [25]에 기재한 의약 조성물을 투여하는 것을 포함하는 방법.
[1C]
질환을 치료하기 위한 [1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드 또는 [25]에 기재한 의약 조성물의 사용.
[1D]
질환을 치료하기 위한 의약의 제조에 있어서의 [1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드의 사용.
[1E]
질환을 치료하기 위한 의약의 제조에 사용하기 위한 [1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드.
[1F]
[1]∼[24] 중 어느 하나에 기재한 폴리뉴클레오티드 또는 [25]에 기재한 의약 조성물 및 사용설명서를 포함하는 질환의 치료에 사용하기 위한 키트.
본 발명은 이하의 실시형태를 더 포함한다.
[2A]
번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
[2B]
번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
[2C]
번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
[2D]
번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
[2E]
번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
[2F]
번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
[2G]
번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
[2H]
번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
[2I]
번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드.
본 발명에 의하면, 번역 영역에 수식 부위를 가지면서도 번역 활성을 유지하고 있는 폴리뉴클레오티드를 제공할 수 있다.
[도 1] 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 번역 영역의 개략도.
[도 2] 모든 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 번역 영역의 개략도.
[도 3] 모든 코돈에 있어서의 1번째의 뉴클레오티드 및 종지 코돈에 포함되는 3개의 뉴클레오티드 전부가 당부 수식 뉴클레오티드인 번역 영역의 개략도.
[도 4] 화합물 R1 및 화합물 R17을 기질로 하고, PURExpress(등록상표)를 이용하여 행한 번역 반응의 웨스턴 블롯 해석 결과를 도시한다. 각 레인은 이하와 같다(1-3: 화합물 R17)(각각 반응액 중의 농도가 1, 3, 5 μM), 4-6: 화합물 R1(각각 반응액 중의 농도가 1, 3, 5 μM), 7: RNA 없음, M: 프로테인 사이즈 마커(Precision Plus Protein Dual Extra Standards(BIORAD사))). 도면 좌측의 숫자는 단백질의 분자량을 나타내고, 화살표는 생성된 번역 산물을 나타내고 있다.
[도 5] 화합물 R2 및 화합물 R18을 기질로 하고, RRL을 이용하여 행한 번역 반응의 웨스턴 블롯 해석 결과를 도시한다. 각 레인은 이하와 같다(1: RNA 없음, 2: 화합물 R18(5 μg), 3: 화합물 R2(5 μg), M: 프로테인 사이즈 마커(Precision Plus Protein Dual Extra Standards(BIORAD사))). 도면 좌측의 숫자는 단백질의 분자량을 나타내고, 화살표는 생성된 번역 산물을 나타내고 있다.
<폴리뉴클레오티드>
본 발명의 일 실시형태는, 개시 코돈에서부터 종지 코돈까지의 번역 영역을 포함하고, 상기 번역 영역이 n개의 코돈을 포함하며, 상기 n이 2 이상의 양의 정수이고, 상기 n개의 코돈이 각각 1번째, 2번째 및 3번째의 뉴클레오티드를 포함하고, 상기 n개의 코돈 중 적어도 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드에 관한 것이다.
도 1에, 임의의 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 번역 영역의 개략도를 도시한다.
번역 영역을 구성하는 복수 코돈에 있어서의 1번째의 뉴클레오티드의 당부를 수식하여도 번역 활성이 유지되기 때문에, 본 실시형태의 폴리뉴클레오티드는 번역 영역에 수식 부위를 가지면서도 번역 활성을 유지하고 있다. 본 명세서에 있어서 「번역 활성」이란, mRNA가 번역되어 폴리펩티드가 합성되는 활성을 의미한다(본 명세서에서의 「폴리펩티드」는 단백질을 포함한다). 또한, 본 실시형태의 폴리뉴클레오티드는 효소(예컨대 핵산 분해 효소(뉴클레아제))에 대한 우수한 안정성도 갖는다.
본 명세서에서 「번역 활성이 유지된다」란, 복수 코돈에 있어서의 1번째의 뉴클레오티드의 당부를 수식한 폴리뉴클레오티드가, 수식하지 않은 폴리뉴클레오티드와 비교하여, 60% 이상의 번역 활성이 있다는 것을 가리킨다. 수식 폴리뉴클레오티드의 번역 활성이, 미수식 폴리뉴클레오티드와 비교하여, 70% 이상, 80% 이상, 90% 이상 또는 100% 이상인 것이 바람직하다.
본 실시형태의 폴리뉴클레오티드는, 번역 영역이 폴리펩티드로 번역된다고 하는 점에서, 예컨대 mRNA, small open reading frame(smORF), non-canonical open reading frame, long noncoding RNA(lncRNA), pri-microRNA(pri-miRNA)와 동등한 기능을 갖는 폴리뉴클레오티드로 이해된다.
(번역 영역)
본 실시형태의 폴리뉴클레오티드는 번역 영역을 포함한다. 번역 영역은 코딩 서열(CDS)이라고도 불린다. 하나의 폴리뉴클레오티드가 복수의 번역 영역을 포함하고 있어도 좋다. 번역 영역은, 개시 코돈에서부터 종지 코돈(또는 종결 코돈이라고 한다)까지의 복수의 코돈으로 구성되며 또한 번역되어 폴리펩티드가 합성되는 영역이다. 코돈은 폴리펩티드를 구성하는 각 아미노산을 코드하는 단위이며, 상기 단위는 3개의 뉴클레오티드로 구성된다.
천연의 코돈표에 한정되는 것은 아니지만, 천연의 코돈표에 기초하면, 개시 코돈으로서는 예컨대 메티오닌을 코드하는 AUG를 들 수 있다. AUG 이외의 비정규의 개시 코돈으로서 CUG, GUG, UUG, ACG, AUC, AUU, AAG, AUA, AGG를 들 수도 있다. 종지 코돈으로서는 예컨대 UAA, UAG 및 UGA를 들 수 있다. 번역 영역을 구성하는 코돈의 종류는 특별히 한정되지 않고, 목적으로 하는 폴리펩티드에 따라서 적절하게 선택할 수 있다.
번역 영역을 구성하는 코돈의 수(n)는, 바람직하게는 2∼2000의 정수이며, 보다 바람직하게는 2∼1500의 정수이고, 더욱 바람직하게는 2∼1000의 정수이고, 가장 바람직하게는 2∼500의 정수이다. 또한, 상기 수치 범위의 하한을 5, 10, 50, 100, 200 등으로 변경하여도 좋다. 하한이 변경된 경우의 번역 영역을 구성하는 코돈의 수(n)는, 바람직하게는 5∼2000, 10∼2000, 50∼2000, 100∼2000 또는 200∼2000의 정수이며, 보다 바람직하게는 5∼1500, 10∼1500, 50∼1500, 100∼1500 또는 200∼1500의 정수이고, 더욱 바람직하게는 5∼1000, 10∼1000, 50∼1000, 100∼1000 또는 200∼1000의 정수이고, 가장 바람직하게는 5∼500, 10∼500, 50∼500, 100∼500 또는 200∼500의 정수이다.
각 코돈은 1번째, 2번째 및 3번째의 뉴클레오티드를 포함한다. 예컨대 개시 코돈(AUG)의 경우, 1번째의 뉴클레오티드는 A이고, 2번째의 뉴클레오티드는 U이고, 3번째의 뉴클레오티드는 G이다.
뉴클레오티드는 통상 당부, 염기부 및 인산부를 포함한다. 당부는 뉴클레오티드에 포함되는, 당에 대응하는 부분이고, 염기부는 뉴클레오티드에 포함되는, 염기에 대응하는 부분이고, 인산부는 뉴클레오티드에 포함되는, 인산에 대응하는 부분이다.
본 명세서에 있어서, 당부를 수식한 뉴클레오티드를 「당부 수식 뉴클레오티드」라고 부르고, 염기부를 수식한 뉴클레오티드를 「염기부 수식 뉴클레오티드」라고 부르고, 인산부를 수식한 뉴클레오티드를 「인산부 수식 뉴클레오티드」라고 부른다. 본 명세서에 있어서 「수식」이란, 당부, 염기부 또는 인산부의 구조를 변화시키는 것을 의미한다. 수식에 의한 구조의 변화는 특별히 한정되지 않는다. 수식으로서 예컨대 임의의 치환기에 의한 임의 부위의 치환을 들 수 있다.
본 명세서에 있어서, 당부의 2' 위치의 탄소에 결합한 OH를 H로 치환하는 것(즉, 리보오스부를 2'-데옥시리보오스부로 치환하는 것) 및 당부의 2' 위치의 탄소에 결합한 H를 OH로 치환하는 것(즉, 2'-데옥시리보오스부를 리보오스부로 치환하는 것)은 당부의 수식에 포함되지 않는다. 그 때문에, 리보뉴클레오티드를 기준으로 한 경우, 리보뉴클레오티드에 대응하는 2'-데옥시리보뉴클레오티드는 「당부 수식 뉴클레오티드」가 아니다. 또한, 2'-데옥시리보뉴클레오티드를 기준으로 한 경우, 2'-데옥시리보뉴클레오티드에 대응하는 리보뉴클레오티드는 「당부 수식 뉴클레오티드」가 아니다.
비수식 당부는, 리보오스 또는 2'-데옥시리보오스에 대응하는 당부인 것이 바람직하고, 리보오스에 대응하는 당부인 것이 보다 바람직하다. 즉, 본 실시형태의 폴리뉴클레오티드에 있어서, 당부 수식 뉴클레오티드 이외의 뉴클레오티드는, 리보오스 또는 2'-데옥시리보오스에 대응하는 당부를 포함하는 것이 바람직하고, 리보오스에 대응하는 당부를 포함하는 것이 보다 바람직하다.
[당부 수식 뉴클레오티드]
본 실시형태의 폴리뉴클레오티드에서는, 번역 영역을 구성하는 복수의 코돈에 포함되는 1번째의 뉴클레오티드의 적어도 2개가 당부 수식 뉴클레오티드이다. 당부 수식 뉴클레오티드를 포함하는 코돈의 위치는 특별히 한정되지 않는다. 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율은, 5% 이상, 10% 이상, 15% 이상, 20% 이상, 25% 이상, 30% 이상, 35% 이상, 40% 이상, 45% 이상, 50% 이상, 55% 이상, 60% 이상, 65% 이상, 70% 이상, 75% 이상, 80% 이상, 85% 이상, 90% 이상, 95% 이상 또는 100%인 것이 바람직하다. 상기 비율이 100%란, 1번째의 뉴클레오티드 전부가 당부 수식 뉴클레오티드인 것을 의미한다. 상기 비율이 클수록 효소에 대한 안정성이 우수한 경향이 있다. 도 2에, 1번째의 뉴클레오티드 전부가 당부 수식 뉴클레오티드인 번역 영역의 개략도를 도시한다. 특별히 한정하는 것은 아니지만, 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 경우, 1번째의 뉴클레오티드의 당부의 2' 위치의 치환기는 불소인 것이 바람직하다.
본 실시형태의 폴리뉴클레오티드에서는, 번역 영역을 구성하는 복수의 코돈에 포함되는 2번째의 뉴클레오티드의 적어도 1개가 당부 수식 뉴클레오티드라도 좋지만, 2번째의 뉴클레오티드의 당부가 수식되어 있지 않아도 좋다. 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율은, 50% 이하, 45% 이하, 40% 이하, 35% 이하, 30% 이하, 25% 이하, 20% 이하, 15% 이하, 10% 이하, 5% 이하 또는 0%라도 좋다. 상기 비율이 0%란, 2번째의 뉴클레오티드 전부가 당부 수식 뉴클레오티드가 아님을 의미한다. 특별히 한정하는 것은 아니지만, 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 경우, 2번째의 뉴클레오티드의 당부의 2' 위치의 치환기는 불소인 것이 바람직하다.
본 실시형태의 폴리뉴클레오티드에서는, 번역 영역을 구성하는 복수의 코돈에 포함되는 3번째의 뉴클레오티드의 적어도 1개가 당부 수식 뉴클레오티드라도 좋다. 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 비율은, 100%, 90% 이하, 80% 이하, 70% 이하, 60% 이하, 50% 이하, 45% 이하, 40% 이하, 35% 이하, 30% 이하, 25% 이하, 20% 이하, 15% 이하, 10% 이하, 5% 이하 또는 0%라도 좋다.
본 실시형태의 폴리뉴클레오티드에서는, 번역 활성을 향상시킨다는 관점에서, 종지 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드라도 좋다. 도 3에, 1번째의 뉴클레오티드 전부 및 종지 코돈의 뉴클레오티드 전부가 당부 수식 뉴클레오티드인 번역 영역의 개략도를 도시한다.
본 실시형태의 폴리뉴클레오티드에서는, 핵산 분해 효소에 대한 안정성을 향상시킨다는 관점에서, 개시 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드라도 좋다. 특별히 한정하는 것은 아니지만, 개시 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드의 당부의 2' 위치의 치환기가 모두 불소인 것이 바람직하다.
당부 수식 뉴클레오티드는, 뉴클레오티드의 당부가 수식된 것이라면 특별히 한정되지 않지만, 적어도 2' 위치가 수식된 당부를 포함하는 것이 바람직하다. 2' 위치가 수식됨으로써 효소에 대한 안정성을 향상시킬 수 있다. 적어도 2' 위치가 수식된 당부는 2' 위치와 4' 위치가 가교한 당부라도 좋다.
수식 당부로서는 예컨대 이하의 것을 들 수 있다.
Figure pct00005
[식 중, M은 R1, OR1, R2OR1, SH, SR1, NH2, NHR1, NR1 2, N3, CN, F, Cl, Br 또는 I이고,
R1은 각각 독립적으로 알킬 또는 아릴이고, 바람직하게는 탄소수 1∼6의 알킬이며, 보다 바람직하게는 탄소수 1∼3의 알킬이고,
R2는 알킬렌이며, 바람직하게는 탄소수 1∼6의 알킬렌이다]
본 명세서에 있어서, 탄소수 1∼6의 알킬로서는 예컨대 탄소수 1∼6의 직쇄 또는 분기쇄의 알킬을 들 수 있다. 탄소수 1∼6의 직쇄의 알킬로서는 예컨대 메틸, 에틸, 프로필, 부틸, 펜틸 및 헥실을 들 수 있다. 탄소수 1∼6의 분기쇄의 알킬로서는 예컨대 이소프로필, 이소부틸, sec-부틸, tert-부틸 및 메틸로 치환된 펜틸을 들 수 있다.
탄소수 1∼3의 알킬로서는 예컨대 메틸, 에틸, 프로필 및 이소프로필을 들 수 있다.
본 명세서에 있어서, 아릴로서는 예컨대 치환되어 있어도 좋은 페닐 및 치환되어 있어도 좋은 나프틸을 들 수 있다.
본 명세서에 있어서, 탄소수 1∼6의 알킬렌은 탄소수 1∼6의 알킬의 탄소 원자에 결합하는 수소 원자를 하나 제외한 기이다.
본 명세서에 있어서, 수식 당부란 당부 수식 뉴클레오티드에 포함되는 수식된 당 구조를 나타낸다. 수식 당부의 M으로서, 또한 2-(메톡시)에톡시, 3-아미노프로폭시, 2-[(N,N-디메틸아미노)옥시]에톡시, 3-(N,N-디메틸아미노)프로폭시, 2-[2-(N,N-디메틸아미노)에톡시]에톡시, 2-(메틸아미노)-2-옥소에톡시, 2-(N-메틸카르바모일)에톡시) 및 2-시아노에톡시를 예로 들 수도 있다.
수식 당부로서 또한 이하의 핵산의 당부를 예로 들 수 있다:
·Locked Nucleic Acid(LNA)[Tetrahedron Letters, 38, 8735(1997) 및 Tetrahedron, 54, 3607(1998)];
·Ethylene bridged nucleic acid(ENA)[Nucleic Acids Research, 32, e175(2004)];
·Constrained Ethyl(cEt)[The Journal of Organic Chemistry 75, 1569(2010)];
·Amido-Bridged Nucleic Acid(AmNA)[Chem Bio Chem 13, 2513(2012)];
·2'-O,4'-c-Spirocyclopropylene bridged nucleic acid(scpBNA)[Chem. Commun., 51, 9737(2015)];
·tricycloDNA(tcDNA)[Nat. Biotechnol., 35, 238(2017)];
·Unlocked Nucleic Acid(UNA)[Mol. Ther. Nucleic Acids 2, e103(2013)];
·3'-플루오로헥시톨 핵산(FHNA)[Nat. Biotechnol., 35, 238(2017)];
·펩티드 핵산(PNA)[Acc. Chem. Res., 32, 624(1999)];
·옥시펩티드 핵산(OPNA)[J. Am. Chem. Soc., 123, 4653(2001)];
·펩티드 리보핵산(PRNA)[J. Am. Chem. Soc., 122, 6900(2000)].
수식 당부는, 특별히 한정하는 것은 아니지만, 이하에서 선택되는 것이 바람직하다.
Figure pct00006
당부 수식 뉴클레오티드는, 아데닌(A), 구아닌(G), 시토신(C) 및 우라실(U)로 이루어지는 군에서 선택되는 염기에 대응하는 염기부를 포함하는 것이 바람직하고, 상기 염기의 종류는 적어도 2종류인 것이 바람직하다. 여기서, 「염기의 종류는 적어도 2종류」란, 예컨대 1개의 당부 수식 뉴클레오티드가 아데닌에 대응하는 염기부를 포함하고, 다른 당부 수식 뉴클레오티드가 구아닌에 대응하는 염기부를 포함하는 것을 의미한다.
당부 수식 뉴클레오티드는 염기부 수식 뉴클레오티드 및/또는 인산부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 당부 수식 뉴클레오티드는 수식 염기부 및/또는 수식 인산부를 더 포함하고 있어도 좋다.). 당부 수식 뉴클레오티드의 적어도 1개가 수식 염기부를 포함하고 있어도 좋다.
[염기부 수식 뉴클레오티드]
번역 영역은 염기부 수식 뉴클레오티드를 포함하고 있어도 좋다. 번역 영역에 있어서 염기부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 염기부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또는 인산부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 염기부 수식 뉴클레오티드는 수식 당부 및/또는 수식 인산부를 더 포함하고 있어도 좋다.).
염기부 수식 뉴클레오티드는 뉴클레오티드의 염기부가 수식된 것이라면 특별히 한정되지 않는다. 비수식 염기부로서는 예컨대 아데닌, 구아닌, 시토신 및 우라실에 대응하는 염기부를 들 수 있다. 수식 염기부로서는 예컨대 비수식 염기부의 산소가 유황으로 치환된 염기부, 비수식 염기부의 수소가 탄소수 1∼6의 알킬, 할로겐 등으로 치환된 염기부, 비수식 염기부의 메틸이 수소, 히드록시메틸, 탄소수 2∼6의 알킬 등으로 치환된 염기부, 비수식 염기부의 아미노가 탄소수 1∼6의 알킬, 탄소수 1∼6의 알카노일, 옥소, 히드록시 등으로 치환된 염기부를 들 수 있다.
염기부 수식 뉴클레오티드의 구체예로서, 5-메틸시토신(5-me-C), 5-히드록시메틸시토신, 크산틴, 히포크산틴, 2-아미노아데닌, 6-메틸아데닌, 6-메틸구아닌, 2-프로필아데닌, 2-프로필구아닌, 2-티오우라실, 2-티오티민, 2-티오시토신, 5-프로피닐우라실, 5-프로피닐시토신, 6-아조우라실, 6-아조시토신, 6-아조티민, 5-슈도우라실, 4-티오우라실, 8-할로아데닌, 8-할로구아닌, 8-아미노아데닌, 8-아미노구아닌, 8-메르캅토아데닌, 8-메르캅토구아닌, 8-알킬티오아데닌, 8-알킬티오구아닌, 8-히드록시아데닌, 8-히드록시구아닌, 5-브로모우라실, 5-브로모시토신, 5-트리플루오로메틸우라실, 5-트리플루오로메틸우라실, 7-메틸구아닌, 7-메틸아데닌, 8-아자구아닌, 8-아자아데닌, 7-데아자구아닌, 3-데아자구아닌, 7-데아자아데닌, 3-데아자아데닌, 피라졸로[3,4-d]피리미딘, 이미다조[1,5-a]1,3,5트리아지논, 9-데아자푸린, 이미다조[4,5-d]피라진, 티아졸로[4,5-d]피리미딘, 피라진-2-온, 1,2,4-트리아진, 피리다진 및 1,3,5-트리아진을 들 수 있다.
[인산부 수식 뉴클레오티드]
번역 영역은 인산부 수식 뉴클레오티드를 포함하고 있어도 좋다. 번역 영역에 있어서 인산부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 인산부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또 염기부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 인산부 수식 뉴클레오티드는 수식 당부 및/또는 수식 염기부를 더 포함하고 있어도 좋다.).
인산부 수식 뉴클레오티드는 뉴클레오티드의 인산부(인산디에스테르 결합)가 수식된 것이라면 특별히 한정되지 않는다. 수식 인산부로서는 예컨대 포스포로티오에이트 결합, 포스포로디티오에이트 결합, 알킬포스포네이트 결합 및 포스포로아미데이트 결합을 들 수 있다.
번역 영역은 수식 인산부가 광학 이성체(Rp, Sp)인 인산부 수식 뉴클레오티드를 포함하고 있어도 좋다. 포스포로티오에이트 결합의 광학 이성체를 선택적으로 합성하는 방법은 예컨대 J. Am. Chem. Soc., 124, 4962(2002), Nucleic Acids Research, 42, 13546(2014) 및 Science 361, 1234(2018)에 개시되어 있다.
(5' 측 비번역 영역)
본 실시형태의 폴리뉴클레오티드는 5' 측 비번역 영역(5' UTR)을 더 포함하고 있어도 좋다. 5' 측 비번역 영역은, 번역 영역의 상류(5' 말단 측)에 존재하며, 폴리펩티드 합성을 위한 번역이 이루어지지 않는 영역이다. 5' 측 비번역 영역을 구성하는 뉴클레오티드의 수는, 바람직하게는 1∼1000의 정수이며, 보다 바람직하게는 1∼500의 정수이고, 더욱 바람직하게는 1∼250의 정수이고, 특히 바람직하게는 1∼100의 정수이다.
5' 측 비번역 영역은 당부 수식 뉴클레오티드를 포함하고 있어도 좋다. 당부 수식 뉴클레오티드의 위치는 특별히 한정되지 않지만, 번역 활성을 향상시킨다는 관점에서, 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드라도 좋다.
또한, 5' 측 비번역 영역의 모든 뉴클레오티드가 당부 수식 뉴클레오티드라도 좋다.
당부 수식 뉴클레오티드의 수식 당부의 구체예로서는 상기 (번역 영역)의 [당부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
5' 측 비번역 영역은 염기부 수식 뉴클레오티드를 포함하고 있어도 좋다. 5' 측 비번역 영역에 있어서 염기부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 염기부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또는 인산부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 염기부 수식 뉴클레오티드는 수식 당부 및/또는 수식 인산부를 더 포함하고 있어도 좋다.).
염기부 수식 뉴클레오티드의 수식 염기부의 구체예로서는 상기 (번역 영역)의 [염기부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다. 특별히 한정하는 것은 아니지만, 번역 활성을 향상시킨다는 관점에서, 5' 측 비번역 영역은 이하의 수식 염기부를 포함하는 것이 바람직하다.
Figure pct00007
[식 중, R은 탄소수 1∼6의 알킬기이다]
수식 염기부의 알킬기 R은 메틸 또는 에틸인 것이 바람직하다.
탄소수 1∼6의 알킬의 구체예로서는 상기 (번역 영역)의 [당부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
5' 측 비번역 영역은 인산부 수식 뉴클레오티드를 포함하고 있어도 좋다. 5' 측 비번역 영역에 있어서 인산부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 인산부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또 염기부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 인산부 수식 뉴클레오티드는 수식 당부 및/또는 수식 염기부를 더 포함하고 있어도 좋다.).
인산부 수식 뉴클레오티드의 수식 인산부의 구체예로서는 상기 (번역 영역)의 [인산부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
(5' 캡 구조)
본 실시형태의 폴리뉴클레오티드는 5' 캡 구조를 더 포함하고 있어도 좋다. 5' 캡 구조는 5' 측 비번역 영역의 상류에 존재한다. 5' 캡 구조를 포함함으로써 번역 활성이 향상되는 경향이 있다.
(3' 측 비번역 영역)
본 실시형태의 폴리뉴클레오티드는 3' 측 비번역 영역(3' UTR)을 더 포함하고 있어도 좋다. 3' 측 비번역 영역은, 번역 영역의 하류에 존재하며, 폴리펩티드합성을 위한 번역이 이루어지지 않는 영역이다.
3' 측 비번역 영역을 구성하는 뉴클레오티드의 수는, 바람직하게는 1∼6000의 정수이며, 보다 바람직하게는 1∼3000의 정수이고, 더욱 바람직하게는 1∼1000의 정수이고, 특히 바람직하게는 1∼500의 정수이다.
3' 측 비번역 영역은 폴리A쇄를 포함하고 있어도 좋다. 3' 측 비번역 영역은, 폴리A쇄 이외의 폴리뉴클레오티드와 폴리A쇄 양쪽 모두를 포함하고 있어도 좋고, 어느 한쪽만을 포함하고 있어도 좋다. 폴리A쇄를 포함함으로써 번역 활성이 향상되는 경향이 있다.
폴리A쇄의 길이는, 바람직하게는 1∼500 염기 길이이며, 보다 바람직하게는 1∼200 염기 길이이고, 더욱 바람직하게는 1∼40 염기 길이이다.
3' 측 비번역 영역은 당부 수식 뉴클레오티드를 포함하고 있어도 좋다. 당부 수식 뉴클레오티드의 위치는 특별히 한정되지 않는다. 당부 수식 뉴클레오티드는, 폴리A쇄 이외의 폴리뉴클레오티드와 폴리A쇄 양쪽 모두에 포함되어 있어도 좋고, 어느 한쪽에만 포함되고 있어도 좋다. 번역 활성을 향상시킨다는 관점에서, 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드라도 좋다. 특별히 한정하는 것은 아니지만, 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드의 당부의 2' 위치의 치환기가 모두 2'-O-메톡시에틸(MOE)기인 것이 바람직하다.
당부 수식 뉴클레오티드의 수식 당부의 구체예로서는 상기 (번역 영역)의 [당부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
3' 측 비번역 영역은 염기부 수식 뉴클레오티드를 포함하고 있어도 좋다. 3' 측 비번역 영역에 있어서 염기부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 염기부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또는 인산부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 염기부 수식 뉴클레오티드는 수식 당부 및/또는 수식 인산부를 더 포함하고 있어도 좋다.).
염기부 수식 뉴클레오티드의 수식 염기부의 구체예로서는 상기 (번역 영역)의 [염기부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
3' 측 비번역 영역은 인산부 수식 뉴클레오티드를 포함하고 있어도 좋다. 3' 측 비번역 영역에 있어서 인산부 수식 뉴클레오티드가 존재하는 위치는 특별히 한정되지 않는다. 인산부 수식 뉴클레오티드는 당부 수식 뉴클레오티드 및/또 염기부 수식 뉴클레오티드라도 좋다(바꿔 말하면, 인산부 수식 뉴클레오티드는 수식 당부 및/또는 수식 염기부를 포함하고 있어도 좋다.).
인산부 수식 뉴클레오티드의 수식 인산부의 구체예로서는 상기 (번역 영역)의 [인산부 수식 뉴클레오티드] 항목에서 기재한 것을 들 수 있다.
인산부 수식 뉴클레오티드는, 핵산 분해 효소의 하나인 엔도뉴클레아제에 대한 안정성을 부여할 수 있기 때문에, 본 발명의 폴리뉴클레오티드의 5' 말단 및/또는 3' 말단에서부터 2 연속 이상 포함되는 것이 바람직하다.
(연결부)
본 실시형태의 폴리뉴클레오티드는 이하의 연결부를 포함하고 있어도 좋다.
Figure pct00008
[식 중,
R1 및 R2는 각각 독립적으로 H, OH, F 또는 OCH3을 나타내고,
B1 및 B2는 각각 독립적으로 염기부를 나타내고,
X1은 O, S 또는 NH를 나타내고,
X2는 O, S, NH 또는 이하의 구조를 나타내고,
Figure pct00009
X3은 OH, SH 또는 이들의 염을 나타내며(X3의 OH 및 SH는 각각 O- 및 S-로 표기되어도 좋다),
단, X1 및 X2는 동시에 O가 아니다]
상기 연결부에 있어서의 좌측 및 우측의 뉴클레오티드는 본 실시형태의 폴리뉴클레오티드를 구성하는 2개의 뉴클레오티드이다. 상기 연결부를 포함하고 있어도 번역 활성을 유지할 수 있다. 상기 연결부에 있어서의 우측(5' 말단 측)의 뉴클레오티드 A 및 좌측(3' 말단 측)의 뉴클레오티드 B, 그리고 상기 뉴클레오티드 B에 인접하는 3' 말단 측의 뉴클레오티드 C 및 상기 뉴클레오티드 C에 인접하는 3' 말단 측의 뉴클레오티드 D는 수식되어 있지 않아도 좋다.
상기 연결부의 X3의 OH 및 SH의 염으로서는 예컨대 제약학적으로 허용 가능한 염을 들 수 있다. 제약학적으로 허용 가능한 염으로서는 예컨대 알칼리 금속염, 알칼리 토류 금속염, 암모늄염, 유기 아민염 및 아미노산염을 들 수 있다. 알칼리 금속염으로서는 예컨대 나트륨염, 리튬염 및 칼륨염을 들 수 있다. 알칼리 토류 금속염으로서는 예컨대 칼슘염 및 마그네슘염을 들 수 있다.
상기 연결부의 구체예로서는 예컨대 이하의 것을 들 수 있다.
Figure pct00010
[식 중, R1, R2, B1, B2 및 X3은 상기한 것과 같다]
상기 연결부가 존재하는 위치는 특별히 한정되지 않는다. 연결부는, 번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역의 어디에 존재하고 있어도 좋지만, 연결부가 존재하는 경우에는, 연결부는 적어도 번역 영역에 존재하고 있는 것이 바람직하다.
상기 연결부의 수는 특별히 한정되지 않고, 폴리뉴클레오티드의 길이에 따라서 적절하게 선택할 수 있다. 연결부의 수는 예컨대 1∼200개, 1∼100개, 1∼50개, 1∼20개, 1∼10개, 1∼8개, 1∼6개, 1∼4개, 1∼3개 또는 1 혹은 2개를 들 수 있다.
본 실시형태의 폴리뉴클레오티드에서는, 번역 영역을 구성하는 복수의 코돈 중 적어도 1개의 코돈에 있어서의 1번째의 뉴클레오티드와 2번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있어도 좋다. 포스포로티오에이트 결합의 수는 특별히 한정되지 않고, 폴리뉴클레오티드의 길이에 따라서 적절하게 선택할 수 있다. 포스포로티오에이트 결합의 수는 예컨대 1∼200개, 1∼100개, 1∼50개, 1∼20개, 1∼10개, 1∼8개, 1∼6개, 1∼4개, 1∼3개 또는 1 혹은 2개를 들 수 있다.
번역 활성을 향상시킨다는 관점에서, 5' 측 비번역 영역의 5' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있어도 좋다. 또한, 예컨대 1∼3번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있다는 것은, 1번째의 뉴클레오티드와 2번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되며 또한 2번째의 뉴클레오티드와 3번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 것을 의미한다.
번역 활성을 향상시킨다는 관점에서, 3' 측 비번역 영역의 3' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있어도 좋다.
본 발명의 다른 실시형태는, 번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역 및 5' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
본 발명의 다른 실시형태는, 번역 영역, 5' 측 비번역 영역 및 3' 측 비번역 영역을 포함하고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 5' 측 비번역 영역의 5' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드이고,
상기 3' 측 비번역 영역의 3' 말단에서부터 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 폴리뉴클레오티드에 관한 것이다.
(기타 서열)
본 실시형태의 폴리뉴클레오티드는 Kozak 서열 및/또는 Ribosome Binding sequence(RBS)를 더 포함하고 있어도 좋다.
<폴리뉴클레오티드의 제조 방법>
본 실시형태의 폴리뉴클레오티드는 예컨대 화학 합성에 의해서 제조할 수 있다. 구체적으로는, 공지된 화학 합성법을 이용하여, 폴리뉴클레오티드쇄를 신장시키면서 소정의 위치에서 소정의 당부 수식 뉴클레오티드를 도입함으로써, 본 실시형태의 폴리뉴클레오티드를 제조할 수 있다. 공지된 화학 합성법으로서는, 예컨대 포스포로아미다이트법, 포스포로티오에이트법, 포스포트리에스테르법 및 CEM법(Nucleic Acids Research, 35, 3287(2007)을 참조)을 들 수 있다. 또한, ABI3900하이스루풋 핵산 합성기(어플라이드바이오시스템즈사 제조)를 이용할 수도 있다.
공지된 화학 합성법으로서 보다 구체적으로는 이하의 문헌 등에 기재된 방법을 들 수 있다:
·테트라헤드론(Tetrahedron), 제48권, 제12호, 2223-2311 페이지(1992년);
·커런트 프로토콜즈 인 뉴클레익 애시즈 케미스트리(Current Protocols in Nucleic Acids Chemistry), John Wiley & Sons(2000년);
·프로토콜즈 포 올리고뉴클레오티즈 앤드 아날로그즈(Protocols for Oligonucleotides and Analogs), Human Press(1993년);
·케미스트리 앤드 바이올로지 오브 아티피셜 뉴클레익 애시즈(Chemistry and Biology of Artificial Nucleic Acids), Wiley-VCH(2012년);
·게놈 케미스트리 인공 핵산을 활용하는 과학적 어프로치, 고단샤(2003년);
·핵산 화학의 뉴트렌드, 가가쿠도진(2011년).
시판되고 있지 않은 포스포로아미다이트를 화학 합성하고, 그것을 원재료에 이용하여 본 실시형태의 폴리뉴클레오티드를 제조할 수 있다.
염기부 수식 뉴클레오티드의 원재료가 되는 포스포로아미다이트(f)의 합성 방법에 관해서 이하에 나타낸다.
Figure pct00011
[합성 스킴 중, Ra는 수소 원자, F, OMe 또는 OCH2CH2OMe를 나타내고, Rb는 예컨대 디-tert-부틸실릴 등의 불화물 이온으로 제거할 수 있는 보호기이고, Rc는 탄소수 1∼6의 알킬을 나타내고, Rd는 핵산 고상 합성에 있어서 이용되는 보호기이며, 예컨대 p,p'-디메톡시트리틸기를 나타낸다.]
(공정 A)
화합물(b)은, 용매 중, 염기 존재 하에, 화합물(a)과 예컨대 상당하는 실릴화제를, 0℃와 80℃ 사이의 온도에서, 10분간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 DMF, DMA, NMP 등을 들 수 있고, 이들은 단독으로 또는 혼합하여 이용된다.
염기로서는 예컨대 이미다졸, 트리에틸아민, 디이소프로필에틸아민 등을 들 수 있다.
실릴화제로서는 예컨대 비스(트리플루오로메탄술폰산)디-tert-부틸실릴 등을 들 수 있다.
(공정 B)
화합물(c)은, 용매 중, 염기 존재 하에, 화합물(b)과 상당하는 알킬화제를, 0℃와 150℃ 사이의 온도에서, 10분간부터 3일간 반응시킴으로써 제조할 수 있다. 적당한 첨가제에 의해 반응을 촉진시킬 수도 있다.
용매로서는 예컨대 DMF, 피리딘, 디클로로메탄, THF, 아세트산에틸, 1,4-디옥산, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용된다.
염기로서는 예컨대 수산화나트륨 수용액, 탄산칼륨, 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민 등을 들 수 있다.
알킬화제로서는 예컨대 요오드화메틸, 요오드화에틸, 브롬화메틸 등을 들 수 있다.
첨가화제로서는 예컨대 테트라부틸암모늄브로미드를 들 수 있다.
(공정 C)
화합물(d)은, 용매 중, 화합물(c)과 불소 시약을 -80℃와 200℃ 사이의 온도에서, 10초간부터 72시간 반응시킴으로써 제조할 수 있다. 이때, 염기를 가할 수도 있다.
불소 시약으로서는 예컨대 불화수소, 불화수소산트리에틸아민염, 불화테트라부틸암모늄(TBAF) 등을 들 수 있다.
염기로서는 예컨대 트리에틸아민, N,N-디이소프로필에틸아민 등을 들 수 있다.
용매로서는 예컨대 디클로로메탄, 클로로포름, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, N,N-디메틸아세트아미드(DMA), NMP, 디메틸술폭시드(DMSO) 등을 들 수 있다.
(공정 D)
화합물(e)은, 용매 중, 염기 존재 하에, 화합물(d)과 상당하는 알킬화제를, 0℃와 150℃ 사이의 온도에서, 10분간부터 3일간 반응시킴으로써 제조할 수 있다. 적당한 활성화제에 의해 반응을 촉진시킬 수도 있다.
용매로서는 예컨대 DMF, 피리딘, 디클로로메탄, THF, 아세트산에틸, 1,4-디옥산, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용된다.
염기로서는 예컨대 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민, 2,6-루티딘 등을 들 수 있다.
알킬화제로서는 예컨대 트리틸클로리드, p,p'-디메톡시트리틸클로리드 등을 들 수 있다.
활성화제로서는 예컨대 4-디메틸아미노피리딘 등을 들 수 있다.
(공정 E)
화합물(f)은, 용매 중, 화합물(e)과 화합물(g)을, 염기 존재 하에, 0℃와 100℃ 사이의 온도에서, 10초간부터 24시간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용된다.
염기로서는 예컨대 트리에틸아민, N,N-디이소프로필에틸아민, 피리딘 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용된다.
5' 캡 구조는 공지된 방법(예컨대 효소법 및 화학 합성법)을 이용하여 도입할 수 있다. 공지된 방법으로서는 예컨대 Top. Curr. Chem.(Z)(2017) 375:16 및 Beilstein J. Org. Chem. 2017, 13, 2819-2832에 기재된 방법을 들 수 있다.
본 실시형태의 폴리뉴클레오티드의 염기 길이가 긴 경우, 복수의 폴리뉴클레오티드 단위를 연결하여도 좋다. 연결 방법은 특별히 한정되지 않고, 예컨대 효소법 및 화학 합성법을 들 수 있다.
효소법에 의한 연결로서는 예컨대 리가아제를 이용한 연결을 들 수 있다. 리가아제로서는 예컨대 T4 DNA Ligase, T4 RNA Ligase 1, T4 RNA Ligase 2, T4 RNA Ligase 2, truncated T4 RNA Ligase 2, truncated KQ, E. Coli DNA Ligase, Taq. DNA Ligase 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다. 효소법에서는, 일반적으로 폴리뉴클레오티드의 5' 말단 측을 구성하는 폴리뉴클레오티드 단위(이하 「5' 말단 측 폴리뉴클레오티드 단위」라고 부른다.)의 3' 말단의 뉴클레오티드 A와, 폴리뉴클레오티드의 3' 말단 측을 구성하는 폴리뉴클레오티드 단위(이하 「3' 말단 측 폴리뉴클레오티드 단위」라고 부른다.)의 5' 말단의 뉴클레오티드 B와(연결한 폴리폴리뉴클레오티드에 있어서 뉴클레오티드 A 및 B는 서로 인접한다.), 상기 뉴클레오티드 B에 인접하는 뉴클레오티드 C와, 상기 뉴클레오티드 C에 인접하는 뉴클레오티드 D가, 수식되어 있지 않은 것이 바람직하다. 한편, Molecular Cell, Vol. 16, 211-221, October 22, 2004에 기재된 T4 RNA ligase 2 등을 사용하는 경우에는 상기 뉴클레오티드 A∼D는 수식되어 있어도 좋다.
효소법에 의한 연결에서는, 분자 크라우딩 효과에 의해 연결 반응을 촉진하기 때문에, 다분산 폴리에틸렌글리콜(PEG)을 이용하여도 좋다. 다분산 PEG로서는, 예컨대 PEG4000, PEG6000, PEG8000, PEG10000 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화학 합성법에 의한 연결(「케미칼 라이게이션」이라고도 한다)로서는, 예컨대 하기에 기재하는 것과 같이, 5' 말단 측 폴리뉴클레오티드 단위의 3' 말단(하기의 우측)과, 3' 말단 측 폴리뉴클레오티드 단위의 5' 말단(하기의 좌측)을, 축합제의 존재 하에서 축합하는 방법을 들 수 있다.
Figure pct00012
[식 중, R1, R2, B1, B2, X1, X2 및 X3은 상기한 것과 같다]
축합제로서는 예컨대 1,3-디시클로헥산카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드·염산염(EDC), 카르보닐디이미다졸, 벤조트리아졸-1-일옥시트리스(디메틸아미노)포스포늄헥사플루오로포스파이트, (벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스파이트, O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스파이트(HATU), O-(벤조트리아졸-1-일)-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스파이트(HBTU) 및 요오드화 2-클로로-1-메틸피리디늄을 들 수 있다.
상기 축합 반응은, 5' 말단 측 폴리뉴클레오티드 단위의 3' 말단 측의 뉴클레오티드쇄 및 3' 말단 측 폴리뉴클레오티드 단위의 5' 말단 측의 뉴클레오티드쇄와 상보적인 뉴클레오티드쇄를 포함하는 템플레이트 DNA의 존재 하에서 실시하는 것이 바람직하다. 템플레이트 DNA는, 5' 말단 측 폴리뉴클레오티드 단위의 3' 말단으로부터, 바람직하게는 2∼50 염기 길이, 보다 바람직하게는 5∼40 염기 길이의 뉴클레오티드쇄 및 3' 말단 측 폴리뉴클레오티드 단위의 5' 말단으로부터, 바람직하게는 2∼50 염기 길이, 보다 바람직하게는 5∼40 염기 길이의 뉴클레오티드쇄와 상보적인 뉴클레오티드쇄인 것이 바람직하다. 여기서 「상보적」이란, 염기 서열의 동일성이 예컨대 50% 이상, 60% 이상, 70% 이상, 80% 이상, 90% 이상 또는 100%인 것을 의미한다.
상기 축합 반응에 있어서 첨가제를 첨가하여도 좋다. 첨가제로서는 예컨대 1-히드록시벤조트리아졸(HOBt) 및 4-디메틸아미노피리딘(DMAP)을 들 수 있다.
상기 축합 반응은 완충액의 존재 하에서 실시하여도 좋다. 완충액으로서는 예컨대 아세트산 완충액, 트리스 완충액, 시트르산 완충액, 인산 완충액 및 물을 들 수 있다.
상기 축합 반응의 온도는 특별히 한정되지 않지만, 예컨대 실온∼200℃로 하여도 좋다. 상기 축합 반응의 시간은 특별히 한정되지 않지만, 예컨대 5분간∼100시간으로 하여도 좋다.
5' 말단 측 폴리뉴클레오티드 단위의 3' 말단(하기의 우측)과 3' 말단 측 폴리뉴클레오티드 단위의 5' 말단(하기의 좌측)의 축합 반응의 구체예로서는 이하의 것을 들 수 있다.
Figure pct00013
[식 중, R1, R2, B1, B2 및 X3은 상기한 것과 같고, X4는 탈리기이다.]
탈리기의 구체예로서는 클로로기, 브로모기, 요오드기, 메탄술포닐기, p-톨루엔술포닐기, 트리플루오로메탄술포닐기를 들 수 있다. 탈리기는 특별히 한정되는 것은 아니지만, 클로로기, 브로모기인 것이 바람직하다.
폴리뉴클레오티드 단위의 연결은 목적으로 하는 폴리뉴클레오티드의 길이에 따라서 여러 번 반복하여도 좋다. 연결 횟수는 특별히 한정되지 않으며, 예컨대 1∼200회, 1∼100회, 1∼50회, 1∼20회, 1∼10회, 1∼8회, 1∼6회, 1∼4회, 1∼3회 또는 1 혹은 2회로 하여도 좋다.
연결에 이용하는 5' 말단 측 폴리뉴클레오티드 단위인 화합물(M) 및 화합물(N)의 제조법을 이하에 나타낸다.
Figure pct00014
[식 중, Bp는 보호기로 보호되어 있어도 좋은 염기를 나타내고, B는 염기를 나타내고, Polymer는 고상 지지체를 나타낸다. R4는 선택적으로 탈보호 가능한 보호기이며, 예컨대 tert-부틸디메틸실릴기, 트리에틸실릴기를 나타내고, R3은 핵산 고상 합성에 있어서 이용되는 보호기이며, 예컨대 p,p'-디메톡시트리틸기를 나타내고, Xa는 핵산 서열을 나타내고, Ya 및 Yb는 각각 독립적으로 탈리기이며, 예컨대 할로겐을 나타내고, 바람직하게는 염소 원자 또는 브롬 원자를 나타낸다. 본 명세서에 있어서, 핵산 서열이란, 각각 결합하는 화합물과 함께가 되어 핵산을 형성하는, 핵산에 있어서의 부분 구조이다. 또한, 분자 중에 B가 복수 존재하는 경우, 각각의 B는 동일하여도 좋고, 다르더라도 좋다.]
(공정 1)
화합물(B)은, 화합물(A)을 용매 중, 60℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 톨루엔, 크실렌, 1,2-디클로로에탄, 1,4-디옥산, N,N-디메틸포름아미드(DMF), N-메틸피롤리돈(NMP), 1,2-디클로로벤젠, 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화합물(A)은 예컨대 J. Am. Chem. Soc. (1999), 121, 5661-5665.에 기재된 방법 등에 의해 제조할 수 있다.
화합물(A)에 있어서의 Bp는 특별히 한정되는 것은 아니지만, 하기 구조 중 어느 하나인 것이 바람직하다.
Figure pct00015
R6은 염기의 보호기의 일부를 구성하는 기이며, 예컨대 메틸기, 이소프로필기, 치환기를 갖더라도 좋은 페닐기 등을 나타낸다. 치환기를 갖더라도 좋은 페닐기에 있어서의 치환기로서는 예컨대 메틸기, 이소프로필기 또는 tert-부틸기를 나타낸다.
(공정 2)
화합물(C)은, 화합물(B)을 용매 중, 1∼100 당량의 산화제의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간, 바람직하게는 1∼100 당량의 첨가제와 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 클로로포름이나 디클로로메탄 등의 비프로톤성 용매 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
산화제로서는, 예컨대 존스 시약, 크롬산, 이크롬산피리디늄, 사산화루테늄, 아염소산나트륨, 디스-마틴(Dess-Martin) 시약 등의 유기계 산화제 또는 클로로크롬산피리디늄 등의 무기계 산화제 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
첨가제로서 예컨대 피리딘, 트리에틸아민, N,N-디이소프로필에틸아민 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 3)
화합물(D)은, 화합물(C)을 피리딘 등의 용매 중, 히드록실아민염산염의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
(공정 4)
화합물(E)은, 화합물(D)을 용매 중, 1∼100000 당량의 탈보호제의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 톨루엔, 크실렌, 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
탈보호제로서는 예컨대 트리플루오로아세트산, 트리클로로아세트산, 아세트산, 염산 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 5)
화합물(F)은, 화합물(E)을 용매 중, 환원제의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매는 예컨대 트리플루오로아세트산, 트리클로로아세트산, 아세트산, 염산, 톨루엔, 크실렌, 톨루엔, 크실렌, 테트라히드로푸란, 메탄올, 에탄올, 1,4-디옥산, 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
환원제는 예컨대 수소화붕소나트륨, 수소화시아노붕소나트륨, 수소화붕소리튬, 트리아세톡시수소화붕소나트륨 등을 들 수 있다.
(공정 6)
화합물(G)은, 화합물(F)을 용매 중, 촉매의 존재 하, 수소 분위기 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매는 예컨대 트리플루오로아세트산, 아세트산, 희염산, 메탄올, 에탄올, 이소프로판올, 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
촉매는 예컨대 팔라듐탄소, 루테늄탄소 등을 들 수 있다.
화합물(G)은 예컨대 국제공개 제2017/123669호에 기재한 방법 등으로도 제조할 수 있다.
(공정 7)
화합물(H)은, 화합물(G)을 용매 중, 1∼100 당량의 화합물(G') 및 염기의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간, 바람직하게는 1∼1000 당량의 염기와 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 메탄올, 에탄올, 이소프로판올, 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, 테트라히드로푸란(THF), 1,4-디옥산, N,N-디메틸포름아미드(DMF), N-메틸피롤리돈(NMP), 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
염기로서는 예컨대 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민, 2,6-루티딘 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화합물(G')은 시판 제품을 이용할 수 있다.
(공정 8)
화합물(I)은, 화합물(H)과 p,p'-디메톡시트리틸클로리드를, 피리딘 등의 용매 중, 필요에 따라서 공용매의 존재 하에, 0℃와 100℃ 사이의 온도에서, 5분간∼100시간 반응시킴으로써 제조할 수 있다.
공용매로서는 예컨대 메탄올, 에탄올, 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 톨루엔, 아세트산에틸, 아세토니트릴, 디에틸에테르, 테트라히드로푸란, 1,2-디메톡시에탄, 디옥산, N,N-디메틸포름아미드(DMF), N,N-디메틸아세트아미드, N-메틸피롤리돈, 트리에틸아민, N,N-디이소프로필에틸아민, 물 등을 들 수 있고, 이들은 단독으로 또는 혼합하여 이용할 수 있다.
(공정 9)
화합물(J)은, 화합물(I)을 용매 중, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10분간부터 10일간, 1∼10 당량의 첨가제와 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, DMA, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
첨가제로서는 예컨대 테트라부틸암모늄플루오리드, 트리에틸아민삼불화수소산염 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 10)
화합물(K)은, 화합물(J)과 숙신산무수물을, 용매 중, 1∼30 당량의 염기 존재 하에, 실온과 200℃ 사이의 온도에서, 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 메탄올, 에탄올, 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 톨루엔, 아세트산에틸, 아세토니트릴, 디에틸에테르, 테트라히드로푸란, 1,2-디메톡시에탄, 디옥산, N,N-디메틸포름아미드(DMF), N,N-디메틸아세트아미드, N-메틸피롤리돈, 피리딘, 물 등을 들 수 있고, 이들은 단독으로 또는 혼합하여 이용할 수 있다.
염기로서는 예컨대 탄산세슘, 탄산칼륨, 수산화칼륨, 수산화나트륨, 나트륨메톡시드, 칼륨 tert-부톡시드, 트리에틸아민, 디이소프로필에틸아민, N-메틸모르폴린, 피리딘, 1,8-디아자비시클로[5.4.0]-7-운데센(DBU), N,N-디메틸-4-아미노피리딘(DMAP) 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 11)
화합물(L)은, 화합물(K)과 말단이 아미노화된 고상 지지체를, 무용매로 또는 용매 중, 1∼30 당량의 염기, 축합제 및 필요에 따라서 0.01∼30 당량의 첨가제의 존재 하에, 실온과 200℃ 사이의 온도에서, 5분간∼100시간 반응한 후, 무수아세트산/피리딘 용액 중, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 공정 4에서 예시한 것을 들 수 있다.
염기로서는 예컨대 탄산세슘, 탄산칼륨, 수산화칼륨, 수산화나트륨, 나트륨메톡시드, 칼륨 tert-부톡시드, 트리에틸아민, 디이소프로필에틸아민, N-메틸모르폴린, 피리딘, 1,8-디아자비시클로[5.4.0]-7-운데센(DBU), N,N-디메틸-4-아미노피리딘(DMAP) 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
축합제로서는 예컨대 1,3-디시클로헥산카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드·염산염(EDC), 카르보닐디이미다졸, 벤조트리아졸-1-일옥시트리스(디메틸아미노)포스포늄헥사플루오로포스파이트, (벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스파이트, O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스파이트(HATU), O-(벤조트리아졸-1-일)-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스파이트(HBTU), 요오드화 2-클로로-1-메틸피리디늄 등을 들 수 있다.
첨가제로서는 예컨대 1-히드록시벤조트리아졸(HOBt), 4-디메틸아미노피리딘(DMAP) 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
고상 지지체로서는, 고상 합성을 행함에 있어서 공지된 아미노화된 고상 지지체가 이용되는 한 특별히 한정되는 것은 아니지만, 예컨대 장쇄 알킬아미노기로 수식된 CPG(controlled poreglass)나 PS(polystyrene resign) 등의 고상 지지체를 들 수 있다.
예컨대 장쇄 알킬아민 세공성 유리(LCAA-CPG)는 시판 제품을 이용할 수 있다.
(공정 12)
화합물(M)은, 화합물(L)을 이용하여, 공지된 올리고뉴클레오티드 화학 합성법으로, 대응하는 뉴클레오티드쇄를 신장한 후에, 고상으로부터의 탈리, 보호기의 탈보호 및 정제를 행함으로써 제조할 수 있다.
고상으로부터의 탈리, 탈보호는, 올리고뉴클레오티드 화학 합성 후, 용매 또는 무용매 중, -80℃부터 200℃ 사이의 온도에서, 10초간부터 72시간 염기로 처리함으로써 제조할 수 있다.
염기로서는 예컨대 암모니아, 메틸아민, 디메틸아민, 에틸아민, 디에틸아민, 이소프로필아민, 디이소프로필아민, 피페리딘, 트리에틸아민, 에틸렌디아민, 1,8-디아자비시클로[5.4.0]-7-운데센(DBU), 탄산칼륨 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
용매로서는 예컨대 물, 메탄올, 에탄올, THF 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
올리고뉴클레오티드는, C18 역상 컬럼 혹은 음이온 교환 컬럼, 바람직하게는 상술한 2개의 수법을 조합에 의해 정제할 수 있다.
정제 후의 핵산 복합체 순도는 바람직하게는 90% 이상, 보다 바람직하게는 95% 이상이다.
(공정 13)
화합물(N)은, 화합물(M)을 이용하여, 완충액 중, 1∼1000 당량의 화합물(O)의 존재 하에, 실온과 100℃ 사이의 온도에서, 5분간∼100시간 반응시킴으로써 제조할 수 있다.
완충액으로서는 예컨대 아세트산 완충액, 트리스 완충액, 시트르산 완충액, 인산 완충액, 물 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화합물(O)은 시판 제품을 이용할 수 있다.
연결에 이용하는 3' 말단 측 폴리뉴클레오티드 단위인 화합물(W)의 제조 방법에 관해서 이하에 나타낸다.
Figure pct00016
[식 중, Bp는 보호기로 보호되어 있어도 좋은 염기를 나타내고, B는 염기를 나타내고, R7은 보호기이며, 예컨대 tert-부틸디메틸실릴기, 트리에틸실릴기를 나타내고, Yc는 예컨대 염소 원자, 브롬 원자, 토실레이트기를 나타내고, Xb는 핵산 서열을 나타낸다. 또한, 분자 중에 B가 복수 존재하는 경우, 각각의 B는 동일하여도 좋고, 다르더라도 좋다.]
(공정 14)
화합물(Q)은, 화합물(P)을 용매 중, 첨가제 및 염기의 존재 하에, 0℃와 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, DMA, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
첨가제로서는 예컨대 토실산무수물, 토실클로리드, 티오닐클로리드, 옥살릴클로리드 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
염기로서는 예컨대 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민, 탄산칼륨 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화합물(P)은 시판 제품을 이용할 수 있다.
(공정 15)
화합물(R)은, 화합물(Q)을 용매 중, 아지드화제와 필요에 따라서 염기의 존재 하에, 실온과 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, DMA, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
아지드화제로서는 예컨대 아지화나트륨 등을 들 수 있다.
염기로서는 예컨대 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민, 탄산칼륨 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 16)
화합물(S)은, 화합물(R)을 용매 중, 실릴화제와 염기의 존재 하에, 실온과 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, DMA, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
실릴화제로서는 예컨대 tert-부틸디메틸실릴클로리드, tert-부틸디메틸실릴트리플레이트, 트리에틸실릴클로리드 등을 들 수 있다.
염기로서는 예컨대 피리딘, 트리에틸아민, N-에틸-N,N-디이소프로필아민, 탄산칼륨, 수산화칼륨, 수산화나트륨, 나트륨메톡시드, 칼륨 tert-부톡시드, 트리에틸아민, 디이소프로필에틸아민, N-메틸모르폴린, 피리딘, 1,8-디아자비시클로[5.4.0]-7-운데센(DBU), N,N-디메틸-4-아미노피리딘(DMAP) 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
(공정 17)
화합물(T)은, 화합물(S)을 용매 중, 환원제를 가하여, 실온과 이용하는 용매의 비점 사이의 온도에서, 10초간부터 3일간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 메탄올, 에탄올, 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 톨루엔, 아세트산에틸, 아세토니트릴, 디에틸에테르, 테트라히드로푸란, 1,2-디메톡시에탄, 디옥산, N,N-디메틸포름아미드(DMF), N,N-디메틸아세트아미드, N-메틸피롤리돈, 트리에틸아민, N,N-디이소프로필에틸아민, 아세트산, 물 등을 들 수 있고, 이들은 단독으로 또는 혼합하여 이용할 수 있다.
환원제로서는 예컨대 수소화붕소나트륨, 수소화시아노붕소나트륨, 수소화붕소리튬, 트리아세톡시수소화붕소나트륨, 수소 분위기 하에 있어서의 팔라듐탄소 등을 들 수 있다.
(공정 18)
화합물(U)은 화합물(T)을 이용하여 공정 7과 같은 식으로 제조할 수 있다.
(공정 19)
화합물(V)은, 용매 중, 화합물(U)과 화합물(AA)을, 염기 존재 하에, 0℃와 100℃ 사이의 온도에서, 10초간부터 24시간 반응시킴으로써 제조할 수 있다.
용매로서는 예컨대 디클로로메탄, 아세토니트릴, 톨루엔, 아세트산에틸, THF, 1,4-디옥산, DMF, NMP 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
염기로서는 예컨대 트리에틸아민, N,N-디이소프로필에틸아민, 피리딘 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다.
화합물(AA)은 시판 제품을 이용할 수 있다.
(공정 20)
화합물(W)은 화합물(V)을 이용하여 공정 12와 같은 식으로 제조할 수 있다.
본 실시형태의 폴리뉴클레오티드를 복수의 폴리뉴클레오티드 단위를 연결하여 제조하는 경우, IVT로 제조한 폴리뉴클레오티드 단위를 일부 포함하고 있어도 좋다. IVT로 제조한 폴리뉴클레오티드를 연결하는 방법은 특별히 한정되지 않고, 예컨대 상술한 효소법 및 화학 합성법을 들 수 있다. IVT를 이용하여 폴리뉴클레오티드 단위를 제조하는 방법으로서는, 프로모터 서열을 갖는 주형 DNA로부터 RNA 폴리메라아제를 이용하여 RNA를 전사하는 방법을 들 수 있다. 공지된 IVT로서, 보다 구체적으로는 이하의 문헌 등에 기재된 방법을 들 수 있다.
·알엔에이 메소즈 인 몰레큘러 바이올로지 메소즈 앤드 프로토콜즈(RNA, Methods in Moleculer Biology(Methods and Protocols)), 제703권, 제3장(2011년);
·카디악 진 테라피 메소즈 인 몰레큘러 바이올로지 메소즈 앤드 프로토콜즈(Cardiac Gene Therapy: Methods in Moleculer Biology(Methods and Protocols)), 제1521권, 제8장(2016년);
·저널 오브 몰레큘러 바이올로지(Journal of Molecular Biology), 제249권, 398 페이지∼408 페이지(1995)
IVT에 이용하는 주형 DNA로서는, 예컨대 화학 합성에 의해서 제조된 것, 폴리메라아제 연쇄 반응에 의해서 제조된 것, 플라스미드 DNA, 플라스미드 DNA를 제한 효소에 의해서 선형화하여 제조된 것 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다. RNA 폴리메라아제로서는 T3RNA 폴리메라아제, T7RNA 폴리메라아제, SP6RNA 폴리메라아제 등을 들 수 있고, 이들을 단독으로 또는 혼합하여 이용할 수 있다. 전사 시에 이용하는 리보뉴클레오시드3인산은 수식되어 있어도 좋고, 복수 종류의 리보뉴클레오시드3인산을 혼합하여 이용할 수도 있다. Cardiac Gene Therapy: Methods in Moleculer Biology(Methods and Protocols), 제1521권, 제8장(2016년)에 기재된 것과 같이, m7G(5')ppp(5')G(트리링크사 제조, 카탈로그 번호 S1404)나 Anti Reverse Cap Analog, 3'-O-Me-m7G(5')ppp(5')G(트리링크사 제조, 카탈로그 번호 N-7003) 등의 화합물을 이용하여 5' Cap 구조를 부여할 수 있다. Journal of Molecular Biology, 제249권, 398 페이지∼408 페이지(1995)에 기재된 것과 같이, 주형 DNA에 Hepatitis delta virus(HDV) 리보자임 등의 서열을 삽입해 둠으로써, 전사 후에 RNA의 5' 말단이나 3' 말단을 절단할 수 있다.
<의약 조성물>
본 발명의 일 실시형태는 상기 폴리뉴클레오티드를 포함하는 의약 조성물에 관한 것이다. 본 실시형태의 의약 조성물을, 질환을 가진 환자에게 투여함으로써, 폴리뉴클레오티드가 번역되고, 상기 폴리뉴클레오티드가 코드하는 폴리펩티드가 합성되어, 상기 질환이 치료된다.
특별히 한정하는 것은 아니지만, 특정 단백질의 기능 또는 활성을 잃었거나 이상(異常)인 것을 특징으로 하는 질환에 대하여, 상기 폴리뉴클레오티드로부터 번역되는 폴리펩티드에 의해서 그 기능이나 활성을 보충함으로써 치료하는 방법이 제공된다. 혹은, 외래의 항원 펩티드 및 그 유연체(類緣體)를 상기 폴리뉴클레오티드로부터 번역되는 폴리펩티드에 의해서 생체 내에 발현시킴으로써, 면역 응답을 인공적으로 제어하는 치료 방법도 제공된다. 또한, 전사 인자 등의 생체 중의 특정 단백질 또는 생체 중에 원래 존재하지 않는 폴리펩티드를, 상기 폴리뉴클레오티드로부터 번역되는 폴리펩티드에 의해서 생체에 발현시킴으로써, 세포의 기능, 분화, 증식 등을 인위적으로 제어, 개변하는 것도 가능하며, 이에 따라, 조직이나 세포가 손상되었거나, 그 기능이나 활성이 저하했거나 이상으로 된 것을 특징으로 하는 질환에 대하여, 조직이나 세포의 기능을 회복시키는 치료 방법도 제공된다.
질환으로서는, 특별히 한정하는 것은 아니지만, 예컨대 암 및 증식성 질환, 감염증 및 기생충증, 혈액 및 조혈기의 질환, 자기면역 질환, 내분비, 영양 및 대사 질환(선천성 대사이상증을 포함한다), 정신, 신경계 질환, 피부 및 피하조직의 질환, 눈 질환, 귀 질환, 호흡기계 질환, 소화기계 질환, 신요로생식기계 질환, 심혈관 질환, 뇌혈관 질환, 근골격계 및 결합 조직의 질환, 유산, 주산기 질환, 선천기형, 후천적인 손상 및 중독 등을 들 수 있다.
의약 조성물은 소정의 제제 형태로 투여하여도 좋다. 제제로서는 예컨대 경구 투여 또는 비경구 투여를 위한 액체 제형을 들 수 있고, 액체 제형으로서는 예컨대 약학적으로 허용 가능한 유제, 마이크로에멀젼, 용액, 현탁액, 시럽제 및 엘릭시르제를 들 수 있다. 액체 제형은, 활성 성분에 더하여, 해당 기술분야에서 일반적으로 사용되는 불활성의 희석제(예컨대 물 또는 다른 용매), 가용화제 및 유화제(예컨대 에틸알코올, 이소프로필알코올, 탄산에틸, 아세트산에틸, 벤질알코올, 안식향산벤질, 프로필렌글리콜, 1,3-부틸렌글리콜, 디메틸포름아미드, 오일(특히 면실(綿實), 낙화생류, 옥수수, 배아, 올리브, 아주까리 및 참깨의 오일), 글리세롤, 테트라히드로푸르푸릴알코올, 폴리에틸렌글리콜 및 소르비탄의 지방산에스테르, 그리고 이들의 혼합물)을 포함하고 있어도 좋다. 경구 투여용 제제는, 아쥬반트(예컨대 습윤제, 유화제 및 현탁화제), 감미료, 향미료 및 착향제 중 적어도 어느 하나를 포함하고 있어도 좋다. 비경구 투여용 제제는, 가용화제(예컨대 Cremophor(등록상표), 알코올, 오일, 변성유, 글리콜, 폴리솔베이트, 시클로덱스트린, 폴리머 및 이들의 조합)를 포함하고 있어도 좋다.
의약 조성물의 투여 방법으로서는, 예컨대 림프절 국소 투여, 종양내 국소 투여, 근육내 투여, 피내 투여, 피하 투여, 기관내 투여, 수강내 투여, 뇌실내 투여, 안내 투여, 고실내 투여, 관동맥에의 카테터 투여, 간문맥에의 카테터 투여, 심근에의 카테터 투여, 경요도적 카테터 투여 및 정맥내 투여를 들 수 있다.
의약 조성물은 상기 폴리뉴클레오티드에 더하여 임의 성분을 포함하고 있어도 좋다. 임의 성분으로서는, 예컨대 용매, 수성 용매, 비수성 용매, 분산매, 희석제, 분산물, 현탁조제, 계면활성제, 등장제, 증점제, 유화제, 방부제, 지질, 리피도이드 리포솜, 지질 나노 입자, 코어·셸형 나노 입자, 폴리머, 리포플렉스(lipoplexe), 펩티드, 단백질, 세포, 히알로니다아제 및 이들의 혼합물에서 선택된 하나 이상의 약학적으로 허용 가능한 첨가제를 들 수 있다.
실시예
이하, 실시예 및 참고예를 이용하여 본 발명을 보다 상세히 설명하지만, 본 발명의 기술적 범위는 이것에 한정되는 것은 아니다.
화합물의 합성에서 이용한 시약은 시그마알드리치사, 도쿄가세이고교가부시키가이샤, 와코쥰야쿠고교가부시키가이샤, 간토가가쿠가부시키가이샤에서 구입한 것을 정제하지 않고서 사용했다. 무수 용매는 활성화한 몰레큘러 시브 4A 상에서 12시간 건조시킴으로써 조제했거나, 시판되는 무수 등급의 용매를 사용했다. 반응의 추적은 박층 실리카겔 크로마토그래피(실리카겔 70F254 TLC 플레이트-와코, 와코쥰야쿠고교가부시키가이샤)에 의해 추적했다. 화합물의 정제에는 플래시 크로마토그래피용 실리카겔 60N(구상(球狀), 중성, 입자경 40∼50 ㎛)(간토가가쿠가부시키가이샤)를 사용했다. NMR은 중수소화 용매(CDCl3, CD3OD, DMSO-d6)(간토가가쿠가부시키가이샤)를 측정 용매로 하여, JEOL ECS 400MHz(니혼덴시가부시키가이샤)를 이용하여 측정했다. 취득한 NMR의 데이터 해석은 소프트웨어로서 JEOL Delta(니혼덴시가부시키가이샤)를 이용하여 행하고, 화학 시프트치는 중수소화 용매 중의 잔류 시그널(CDCl3: 7.26, CD3OD: 3.31, DMSO-d6: 2.50)(Organometallics 2010, 29, 2176-2179)을 이용하여 보정을 행했다. 1H NMR의 데이터는 화학 시프트치(δ), 적분치(H), 시그널의 분열 양식, 커플링 상수(Hz)로서 기재했다(s: Singlet, d: Doublet, t: Triplet, sept.: Septet, m: Multiplet, br.: Broad). 고분해능 질량 분석은 micrOTOF-QII ESI(Bruker Daltonics사)를 이용하여 측정하고, ESI TUNING MIX(Agilent Technologies사)를 내부 표준으로 하여 정밀 질량의 보정을 행했다.
폴리뉴클레오티드의 원료가 되는 화합물 12의 합성은 하기 스킴으로 합성했다.
Figure pct00017
공정 1: 화합물 4의 합성
N-(9-((2R,3S,4S,5R)-3-(tert-부틸디메틸실릴옥시)-5-((tert-부틸디메틸실릴옥시)메틸)-4-히드록시-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
문헌 기재의 방법(J. Am. Chem. Soc., 1999, 121, 5661-5665) 등에 의해 얻어지는 화합물 3을 이용하여, 1,2-디클로로벤젠(2.0 mL)에 용해시키고, 유욕(油浴) 상(160℃)에서 4시간 교반했다. 반응액을 실온까지 되돌린 후, 농축하지 않고서 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=40:1)로 정제하여, 화합물 4를 백색 고체로서 얻었다(0.31 g, 수율 53%).
1H NMR(400 MHz, CDCl3)δ 12.01(1H, s), 8.50(1H, s), 8.07(1H, s), 5.86(1H, d, J=6.0 Hz), 4.47(1H, s), 4.24-4.23(1H, m), 4.22-4.21(1H, m), 3.93(1H, dd, J=11.6, 2.0 Hz), 3.82(1H, dd, J=11.6, 2.0 Hz), 2.66(1H, sept., J=6.8 Hz), 1.27(3H, d, J=6.8 Hz), 1.25(3H, d, J=6.8 Hz), 0.93(9H, s), 0.82(9H, s), 0.13(3H, s), 0.12(3H, s), -0.07(3H, s), -0.20(3H, s)
13C NMR(100 MHz, CDCl3) δ 179.0, 155.7, 148.5, 148.7, 147.8, 136.8, 121.0, 87.4, 85.4, 77.6, 71.8, 63.6, 36.2, 25.9, 25.4, 19.1, 18.7, 18.3, 17.8, -5.3, -5.4, -5.5, -5.6
ESI-HRMS: calcd for C26H48N5O6Si2 582.31[M+H]+, found: 582.31[M+H]+
공정 2: 화합물 5의 합성
N-(9-((2R,3S,5S)-3-(tert-부틸디메틸실릴옥시)-5-((tert-부틸디메틸실릴옥시)메틸)-4-(히드록시이미노)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
크롬산(129 mg, 1.29 mmol)의 무수디클로로메탄(2.0 mL) 용액에 몰레큘러 시브 3A(분말형)(258 mg)을 가하여 빙욕 상에서 냉각했다. 이 용액에 교반 하에 무수피리딘(207 μL, 1.29 mmol)을 적하하여, 빙욕 상에서 교반했다. 30분 후, 무수아세트산(122 μL, 1.29 mmol)을 적하하여 빙욕 상에서 교반했다. 30분 후, 화합물 4(250 mg, 0.43 mmol)의 디클로로메탄(1.3 mL) 용액을 적하하여 실온에서 2시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 아세트산에틸로 희석하여 실리카 패드(2 cm 두께)로 여과하고, 여과액을 감압 농축하여 무색 고체를 얻었다. 이 조생성물 4'는 이대로 다음 반응에 이용했다.
조생성물 4'(0.43 mmol로서)의 피리딘(4 mL) 용액에 히드록실아민염산염(299 mg, 4.30 mmol)을 가하여 실온에서 교반했다. 24시간 후, 반응액을 감압 농축하고, 잔사에 물을 가하여 아세트산에틸로 추출했다. 유기층을 포화 식염수로 세정하여, 무수황산나트륨 상에서 건조시켰다. 유기층을 감압 농축하여, 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=40:1)로 정제하여, 화합물 5를 백색 고체로서 얻었다(255 mg, 수율 68% for 2 steps).
1H NMR(400 MHz, CDCl3) δ 12.14(1H, s), 9.27(1H, s), 8.78(1H, s), 8.11(1H, s), 5.78(1H, d, J=7.6 Hz), 5.09(1H, s), 4.92(1H, d, J=7.2 Hz), 4.14(1H, d, J=11.4 Hz), 3.92(1H, d, J=11.4 Hz), 2.79-2.74(1H, m), 1.27-1.21(6H, m), 0.91(9H, s), 0.71(9H, s), 0.10(3H, s), 0.07(3H, s), -0.10(3H, s), -0.23(3H, s)
13C NMR(100 MHz, CDCl3) δ 178.9, 157.8, 155.6, 148.7, 147.8, 136.8, 120.8, 87.5, 86.5, 62.2, 36.3, 25.9, 25.5, 25.2, 19.1, 18.8, 18.3, 18.0, -5.0, -5.5, -5.6, -5.7
ESI-HRMS: calcd for C26H47N6O6Si2 595.31[M+H]+, found: 595.31[M+H]+
공정 3: 화합물 6의 합성
N-(9-((2R,3S,5S)-3-(tert-부틸디메틸실릴옥시)-4-(히드록시이미노)-5-(히드록시메틸)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
화합물 5(129 mg, 0.22 mmol)에 빙냉한 90% 트리플루오로아세트산 수용액(1.0 mL)을 가하여 빙욕 상에서 30분간 교반했다. 반응액을 감압 농축하여, 얻어진 잔사를 톨루엔과 물(1:1, v/v)로 감압 하에서 3회 공비(共沸)시켰다. 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=50:1부터 40:1)로 정제하여, 화합물 6을 백색 고체로서 얻었다(96 mg, 수율 92%).
1H NMR(400 MHz, CD3OD) δ 8.36(1H, s), 5.87(1H, d, J=7.6 Hz), 5.18(1H, dd, J=7.6, 2.0 Hz), 5.02(1H, d, J=2.0 Hz), 4.11(1H, dd, J=12.0, 2.0 Hz), 3.92(1H, d, J=12.0, 2.0 Hz), 2.71(1H, sept., J=7.2 Hz), 1.21(6H, d, J=7.2 Hz), 0.72(9H, s), 0.00(3H, s), -0.16(3H, s)
13C NMR(100 MHz, CD3OD) δ 181.8, 157.4, 156.8, 151.0, 150.0, 139.8, 121.3, 88.4, 79.7, 76.5, 61.6, 36.9, 25.9, 19.4, 19.2, -4.5, -5.5
ESI-HRMS: calcd for C20H32N6NaO6Si 503.21[M+Na]+, found: 503.20[M+Na]+
공정 4: 화합물 7의 합성
N-(9-((2R,3S,4S,5S)-4-아미노-3-(tert-부틸디메틸실릴옥시)-5-(히드록시메틸)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
화합물 6(93 mg, 0.19 mmol)의 아세트산(1.9 mL) 용액에 수소화붕소나트륨(15 mg, 0.38 mmol)을 가하여 실온에서 1시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 감압 농축하고, 잔사를 아세트산에틸에 용해시켜, 포화 식염수로 세정하고, 무수황산나트륨 상에서 건조시켰다. 유기층을 감압 농축하고, 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=20:1)로 정제하여, 화합물 7을 백색 고체로서 얻었다(51 mg, 수율 55%).
1H NMR(400 MHz, CD3OD) δ 8.34(1H, s), 6.06(1H, d, J=6.0 Hz), 4.75(1H, t, J=6.4 Hz), 4.27(1H, d, J=2.8 Hz), 3.86(1H, dd, J=12.4, 2.0 Hz), 3.73(1H, d, J=12.4, 2.0 Hz), 3.62-3.60(1H, m), 2.71(1H, sept., J=6.8 Hz), 1.21(6H, d, J=6.8 Hz), 0.82(9H, s), -0.02(3H, s), -0.23(3H, s)
13C NMR(100 MHz, CD3OD) δ 181.8, 157.4, 150.8, 149.8, 139.6, 139.4, 121.1, 89.7, 84.5, 77.7, 65.4, 65.2, 36.9, 26.0, -5.2, -5.3
ESI-HRMS: calcd for C20H35N6O6Si 483.24[M+H]+, found: 483.23[M+H]+
공정 5: 화합물 8의 합성
N-(9-((2R,3S,4S,5S)-4-아미노-3-(tert-부틸디메틸실릴옥시)-5-(히드록시메틸)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
화합물 7(50 mg, 0.10 mmol)의 90% 아세트산 수용액(1.5 mL) 용액에 10% 팔라듐탄소(20 mg)를 가하여, 수소 분위기 하에, 실온에서 18시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 메탄올로 희석하여 팔라듐탄소를 세라이트 여과로 제거했다. 여과액을 감압 농축하고, 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=15:1로부터 10:1)로 정제하여, 화합물 8을 백색 고체로서 얻었다(아세트산염으로서 41 mg, 수율 75%).
1H NMR(400 MHz, CD3OD) δ 8.32(1H, s), 5.99(1H, s), 4.60(1H, s), 3.95-3.68(4H, m), 2.73(1H, br. s), 1.22(6H, br. s), 0.05(3H, s), -0.06(3H, s)
ESI-HRMS: calcd for C20H34N6NaO5Si 489.2258[M+Na]+, found: 489.2231[62 M+Na]+
공정 6: 화합물 9의 합성
N-(9-((2R,3S,4R,5S)-3-(tert-부틸디메틸실릴옥시)-5-(히드록시메틸)-4-(2,2,2-트리플루오로아세트아미도)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로 -1H-푸린-2-일)이소부티르아미드
문헌 기지(WO2017/123669)의 화합물 8(40 mg, 0.076 mmol)과 트리에틸아민(45 L, 0.38 mmol)의 메탄올 용액(0.76 mL) 용액에 트리플루오로아세트산에틸(0.76 mL)을 가하여, 실온에서 24시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 감압 농축하고, 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=20:1부터 12:1)로 정제하여, 화합물 9를 백색 고체로서 얻었다(12 mg, 수율 28%).
1H NMR(400 MHz, CDCl3) δ 12.26(1H, s), 10.11(1H, s), 7.76(1H, s), 7.26(1H, d, J=3.6 Hz), 5.71(1H, d, J=3.6 Hz), 4.98(1H, dd, J=6.8 Hz), 4.78(1H, dd, J=6.8, 3.6 Hz), 4.21(1H, d, J=6.8 Hz), 4.03(1H, dd, J=11.2 Hz), 3.82(1H, dd, J=11.2 Hz), 2.79(1H, sept., J=6.8 Hz), 1.26(3H, d, J=6.8 Hz), 1.24(3H, d, J=6.8 Hz), 0.85(9H, s), -0.01(3H, s), -0.11(3H, s)
13C NMR(100 MHz, CDCl3) δ 179.8, 158.0, 157.7, 157.3, 156.9, 155.2, 148.3, 147.3, 138.6, 122.0, 120.0, 117.1, 114.2, 111.3, 91.6, 83.7, 74.5, 61.3, 51.0, 36.1, 25.2, 18.9, 17.7, -5.0, -5.4
ESI-HRMS: calcd for C22H33F3N6NaO6Si 585.21[M+Na]+, found: 585.21[M+Na]+
공정 7: 화합물 10의 합성
N-(9-((2R,3S,4R,5S)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-3-(tert-부틸디메틸실릴옥시)-4-(2,2,2-트리플루오로아세트아미도)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
화합물 9(10 mg, 0.017 mmol)의 무수피리딘(1 mL) 용액에 디메톡시트리틸클로리드(18 mg, 0.053 mmol)를 가하여, 실온에서 1.5시간 교반했다. 그 후, 디메톡시트리틸클로리드(18 mg, 0.053 mmol)를 추가하여, 실온에서 30분간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액에 메탄올(1 mL)을 가한 후, 감압 농축했다. 잔사를 아세트산에틸에 용해시키고, 물, 이어서 포화 식염수로 세정했다. 유기층을 무수황산나트륨 상에서 건조시키고, 감압 농축하여 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 헥산/아세트산에틸=5:1부터 2:1)로 정제하여, 화합물 10을 백색 고체로서 얻었다(15.2 mg, 수율 99%).
1H NMR(400 MHz, CDCl3) δ 11.99(1H, s), 10.11(1H, s), 8.07(1H, s), 7.81(1H, s), 7.45(2H, dd, J=8.2, 2.0 Hz), 7.32(4H, dd, J=9.2, 3.6 Hz), 7.24-7.29(3H, m), 7.01(1H, d, J=7.2 Hz), 6.76(4H, J=9.2, 3.6 Hz), 5.71(1H, d, J=4.2 Hz), 5.16(1H, dd, J=6.4, 4.2 Hz), 4.20-4.17(1H, m), 3.76(3H, s), 3.75(3H, s), 3.56(1H, dd, J=11.2, 2.8 Hz), 3.22(1H, dd, J=11.2, 2.8 Hz), 1.82(1H, d, J=6.8 Hz), 0.97(3H, d, J=6.8 Hz), 0.68(9H, s), 0.79(3H, d, J=6.8 Hz), 0.04(3H, s), -0.06(3H, s)
13C NMR(100 MHz, CDCl3) δ 171.2, 158.7, 158.0, 157.6, 157.2, 156.8, 155.4, 147.6, 147.2, 144.8, 139.2, 135.9, 135.4, 130.0, 127.9, 127.1, 122.6, 120.0, 117.0, 114.1, 111.2, 90.1, 86.3, 81.7, 73.4, 62.4, 60.4, 55.2, 51.4, 36.1, 25.4, 18.4, 17.8, -5.0, -5.3
ESI-HRMS: calcd for C43H52F3N6O8Si 865.36[M+H]+, found: 865.35[M+H]+
공정 8: 화합물 11의 합성
N-(9-((2R,3S,4S,5S)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-3-히드록시-4-(2,2,2-트리플루오로아세트아미도)-테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
화합물 10(14 mg, 0.016 mmol)의 테트라히드로푸란(1 mL) 용액에 테트라부틸암모늄플루오리드(1M 테트라히드로푸란 용액, 19 μL, 0.019 mmol)을 가하여, 실온에서 1시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 감압 농축했다. 얻어진 잔사를 플래시 컬럼 크로마토그래피(중성 실리카겔, 디클로로메탄/메탄올=30:1로부터 15:1)로 정제하여, 화합물 11을 백색 고체로서 얻었다(10.8 mg, 수율 83%).
1H NMR(400 MHz, CDCl3) δ 12.12(1H, br. s), 8.76(1H, br. s), 7.74(1H, s), 7.81(1H, s), 7.68(1H, d, J=5.4 Hz), 7.48(2H, d, J=7.6 Hz), 7.37(2H, d, J=9.2 Hz), 7.34(2H, d, J=9.2 Hz), 7.25-7.21(2H, m), 7.17(1H, t, J=7.2 Hz), 6.81(2H, d, J=9.2 Hz), 6.78(2H, d, J=9.2 Hz), 5.80(1H, d, J=4.0 Hz), 5.35(1H, br. s), 5.08(1H, dd, J=12.4, 6.4 Hz), 4.30-4.29(1H, m), 3.76(3H, s), 3.74(3H, s), 3.57-3.53(1H, m), 3.29-3.26(1H, m), 1.84-1.57(1H, m), 0.94(3H, d, J=6.8 Hz), 0.68(3H, d, J=6.8 Hz)
13C NMR(100 MHz, CDCl3) δ 179.4, 158.6, 158.4, 158.0, 157.6, 157.3, 147.8, 147.2, 144.8, 139.4, 136.3, 135.7, 130.1, 129.9, 128.1, 128.0, 127.0, 121.0, 120.0, 117.1, 114.2, 111.3, 91.2, 86.1, 82.5, 71.5, 62.7, 55.1, 51.2, 35.9, 18.5, 18.2
ESI-HRMS: calcd for C37H38F3N6O8 751.27[M+H]+, found: 751.27[M+H]+
공정 9: 화합물 12의 합성
화합물 11(0.90 g, 1.20 mmol), 트리에틸아민(0.42 mL, 3.0 mmol)의 아세토니트릴(12 mL) 용액에 숙신산무수물(0.24 g, 2.40 mmol), 디메틸아미노피리딘(29 mg, 0.24 mmol)을 가하여, 실온에서 1시간 교반했다. 박층 크로마토그래피로 원료의 소실을 확인한 후, 반응액을 감압 농축했다. 잔사를 아세트산에틸에 용해시키고, 포화 탄산수소나트륨 수용액으로 2회, 이어서 포화 식염수로 세정했다. 유기층을 무수황산나트륨 상에서 건조시켜, 감압 농축했다. 잔사에 대하여 디클로로메탄/메탄올 용액(1:1, v/v)으로 감압 농축에 의한 공비 조작을 행함으로써, 백색 거품형 고체(트리에틸아민염으로서 1.11 g, 97%)를 얻었다. 이 화합물 12는 이대로 다음 반응에 이용했다.
화합물 12는 하기 출발 원료 13으로부터 중간체 6을 얻어 합성하는 것도 가능하다.
Figure pct00018
공정 10: 화합물 14의 합성
N-(9-((2R,3R,5S)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-3-((tert-부틸디메틸실릴)옥시)-4-(히드록시이미노)테트라히드로푸란-2-일)-6-옥소-6,9-디히드로-1H-푸린-2-일)이소부티르아미드
아르곤 분위기 하, 화합물 13(ChemGenes사 제조, 5.0 g, 6.5 mmol)을 탈수디클로로메탄(50 mL)에 용해시켜, 빙욕으로 냉각하면서 교반했다. 반응액을 냉각하면서 탄산수소나트륨(8.2 g, 97.3 mmol), nor-AZADO(36 mg, 0.260 mmol)을 가하고, 요오도벤젠디아세타이트(3.14 g, 9.73 mmol)를 내부 온도 상승에 주의하면서 분할하여 가하고, 실온으로 승온하면서 21시간10분간 교반했다. 원료의 소실을 확인한 후, 이소프로필알코올(7.5 mL)을 반응액에 가하여 4시간 교반했다(과잉 산화제의 켄치). 반응액을 얼음물에 가하고, 추가로 클로로포름을 가하여 분액하고, 물층을 재차 클로로포름으로 추출했다. 유기층을 하나로 합친 후, 물로 1회, 포화 식염수로 1회 세정한 다음, 무수황산나트륨으로 탈수했다. 건조제를 여과 분별한 후, 여과액을 농축함으로써 조생성물(9.01 g, 일부 DMTr기가 탈보호된 화합물을 포함한다)을 귤색 고체로서 얻었다.
아르곤 분위기 하, 조생성물(9.01 g)을 탈수피리딘(40 mL)에 용해하여, 빙욕으로 냉각하면서 교반했다. 반응액을 냉각하면서 히드록실아민염산염(4.06 g, 58.7 mmol)을 가하고, 실온으로 승온하면서 17시간25분간 교반했다. 원료의 소실을 확인한 후, 반응액을 가지형 플라스크로 클로로포름(1% 트리에틸아민 함유)으로 씻으면서 옮겨 농축했다. 잔사를 포화 중조수에 가하여 15분간 교반한 후, 클로로포름으로 2회 추출했다. 유기층을 하나로 합친 후, 포화 식염수로 1회 세정한 다음, 무수황산나트륨으로 탈수했다. 건조제를 여과 분별한 후, 여과액을 농축함으로써 화합물 14(4.13 g, 디아스테레오머 혼합물, 2단계 수율 81%)를 귤색 거품형 물질로서 얻었다.
1H NMR(400 MHz, CDCl3) δ:12.04(1H, d, J=23.3 Hz), 9.23(1H, s), 8.49(1H, s), 7.89(1H, s), 7.79(1H, s), 7.66-7.58(2H, m), 7.49-7.39(4H, m), 7.31-7.14(5H, m), 6.81-6.76(2H, m), 6.73-6.68(2H, m), 5.92(1H, dd, J=8.0, 1.6 Hz), 5.83(1H, d, J=3.7 Hz), 5.64(1H, d, J=8.2 Hz), 5.54(1H, dd, J=3.9, 1.1 Hz), 5.01(1H, t, J=7.3 Hz), 3.80-3.73(6H, m), 3.54-3.46(2H, m), 1.28(1H, m), 1.08(1H, d, J=6.9 Hz), 0.99(1H, d, J=6.9 Hz), 0.86-0.76(9H, m), 0.47(2H, m), 0.11(1H, s), 0.02--0.02(3H, m), -0.07(2H, s)[디아스테레오머 혼합물]
ESI-HRMS: calcd for C41H50N6O8Si 781.97[M-H]-, found: 781.84[M-H]-
공정 11: 화합물 14로부터 화합물 6의 합성
공정 10에서 얻어진 화합물 14(3.80 g)를 이용하여, 공정 3과 같은 식으로 화합물 6(2.12 g, 4.41 mmol, 수율 91%)을 얻었다.
또한, 화합물 6의 상세 데이터에 관해서는 공정 3에 기재한 것과 같다.
화합물 15의 합성
Figure pct00019
화합물 12(380 mg, 0.50 mmol)의 N,N-디메틸아미포름아미드(2.5 mL) 용액에 Native amino lcaa CPG(1000A, ChemGenes사)(84 μmol/g, 1.20 g, 0.10 mmol), 이어서 HOBt(136 mg, 1.01 mmol), EDC-HCl(193 mg, 1.01 mmol)의 DMF(2.5 mL) 용액을 가하여 실온에서 진탕했다. 20시간 후, 반응액을 버리고, 고상 담체를 N,N-디메틸아미포름아미드(5 mL, 4회), 이어서 디클로로메탄(5 mL, 4회)으로 세정했다. 고상 담체 상의 미반응의 아미노기는 10% 무수아세트산/피리딘 용액(5 mL)에 의해서 캡핑했다(실온, 16시간 진탕). 반응액을 버리고, 고상 담체를 피리딘(5 mL, 1회), 이어서 디클로로메탄(5 mL, 4회)으로 세정한 후, 진공 하에서 건조시킴으로써, 화합물 12를 고상 담체에 담지한 화합물 15를 얻었다(1.20 g).
화합물 12의 고상 상으로의 담지량은 이하에 나타내는 방법에 의해서 산출했다. 얻어진 고상 담체를 규정량 취하여, 데블로킹(Deblocking) 시약(3 w/v% 트리클로로아세트산/디클로로메탄 용액)의 첨가에 의해 생긴 4,4'-디메톡시트리틸 양이온의 발색을 자외가시 흡광 광도 측정(석영 셀, 셀 길이: 10 mm)에 의해서 측정했다. 504 nm에 있어서의 흡광도와 4,4'-디메톡시트리틸 양이온의 몰 흡광 계수(파장 504 nm: 76,000)로부터 고상 상으로의 화합물 12의 담지량을 Lambert-Beer식에 의해 산출했다. 즉, 얻어진 고상 담체(2.0 mg)를 2 mL 정량 플라스크에 재서 취하고, 데블로킹 시약을 가하여 전량을 2 mL로 하여 전도(轉倒) 혼화한 것을 측정 샘플로 했다. 3 w/v% 트리클로로아세트산/디클로로메탄 용액을 이용하여 블랭크 측정을 행한 후, 측정 샘플을 이용하여 측정을 실시했다. 504 nm에 있어서의 흡광도: 0.377에서부터, 담지량: 24.8 μmol/g)
화합물 24의 합성은 하기 스킴으로 행했다.
Figure pct00020
공정 12: 화합물 17의 합성
N-(9-((3aR,4R,6R,6aR)-6-(히드록시메틸)-2,2-디메틸테트라히드로푸로[3,4-d][1,3]디옥솔-4-일)-9H-푸린-6-일)벤즈아미드
아르곤 분위기 하, 10 L의 4구 플라스크에 시판되는 N6-벤질아데노신(화합물 16)(100 g, 269 mmol, 1.0 eq.), 아세톤(2.70 L), 디메톡시프로판(166 mL, 1.35 mol, 5.0 eq.)을 순차 가했다. 반응 용액에, 농황산(1.44 mL, 26.9 mmol, 0.10 eq.)을 가하여, 실온에서 15시간 교반했다. 원료의 잔존을 확인했기 때문에, 농황산(1.44 mL, 26.9 mmol, 0.10 eq.)을 추가하여, 24시간 교반했다. 원료의 잔존을 확인했기 때문에, 농황산(1.44 mL, 26.9 mmol, 0.10 eq.)을 첨가하여 1시간30분 교반한 후, 농황산(2.87 mL, 53.8 mmol, 0.20 eq.)을 첨가하여, 4시간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액을 빙욕으로 냉각하고, 내부 온도가 3∼5℃가 되도록 포화 탄산수소나트륨 수용액(400 mL)을 5분간 걸쳐 적하하여, 용액을 중성으로 했다. 감압 하에, 반응액을 농축하고, 잔사에 증류수(2.0 L)를 가했다. 용액을 클로로포름(1.0 L)으로 3회 추출하여, 유기층을 무수황산나트륨으로 탈수했다. 여과 후, 용매를 감압 유거하여, 화합물 17(222 g)을 얻었다. 얻어진 화합물 17은 추가적인 정제 조작을 실시하지 않고서 다음 공정에 이용했다.
공정 13: 화합물 18의 합성
((3aR,4R,6R,6aR)-6-(6-벤즈아미도-9H-푸린-9-일)-2,2-디메틸테트라히드로푸로[3,4-d][1,3]디옥솔-4-일)메틸메탄솔포네이트
아르곤 분위기 하, 2 L의 4구 플라스크에, 공정 12에서 얻어진 화합물 17(222 g), 피리딘(520 mL)을 가하여, 반응액을 빙욕으로 냉각하고, 내부 온도가 4℃∼9℃가 되도록 메탄술포닐클로리드(25.0 mL, 321 mmol, 1.2 eq.)를 15분간 걸쳐 적하하여, 2시간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액에 증류수(500 mL)를 가하고, 용액을 아세트산에틸(1.0 L)로 3회 추출한 후, 유기층을 1N 염산(1.0 L×1,500 mL×2), 포화 탄산수소나트륨 수용액(500 mL×2), 포화 식염수(500 mL×2)로 순차 세정하여, 무수황산나트륨으로 탈수했다. 여과 후, 용매를 감압 유거하고, 얻어진 잔사를 톨루엔으로 공비함으로써 화합물 18(150 g, 17.6 wt% 톨루엔 함유)을 얻었다. 얻어진 화합물 18은 추가적인 정제 조작을 실시하지 않고서 다음 공정에 이용했다.
공정 14: 화합물 19의 합성
N-(9-((3aR,4R,6R,6aR)-6-(아지도메틸)-2,2-디메틸테트라히드로푸로[3,4-d][1,3]디옥솔-4-일)-9H-푸린-6-일)벤즈아미드
아르곤 분위기 하, 3 L의 4구 플라스크에, 공정 13에서 얻어진 화합물 18(150 g)과 탈수DMF(1.26 L)를 가했다. 반응액에 아지화나트륨(82.8 g, 1.26 mol, 5.0 eq.)을 첨가하고, 30분간 걸쳐 60℃까지 승온하여, 60℃에서 3시간30분간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액을 실온까지 서냉하여, 증류수(1.0 L)와 아세트산에틸(600 mL)을 가했다. 얻어진 용액에 증류수(3.0 L)를 가하여, 물층을 아세트산에틸(500 mL)로 6회 추출했다. 유기층을 증류수(800 mL)로 2회, 포화 식염수(800 mL)로 2회 세정하여, 무수황산나트륨으로 탈수했다. 여과 후, 용매를 감압 유거하여, 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(SiO2 700g, 아세트산에틸)로 정제함으로써, 화합물 19(55.7 g, 128 mmol, 수율 48%(3 steps from 화합물 16))를 얻었다.
공정 15: 화합물 20의 합성
N-(9-((3aR,4R,6R,6aR)-2,2-디메틸-6-((2,2,2-트리플루오로아세트아미도)메틸)테트라히드로푸로[3,4-d][1,3]디옥솔-4-일)-9H-푸린-6-일)벤즈아미드
아르곤 분위기 하, 3 L의 4구 플라스크에, 공정 14에서 얻어진 화합물 19(55.7 g, 128 mmol, 1.0 eq.), 메탄올(1.28 L)을 가했다. 반응액에, 10% Pd/C(76.8 g, 21.2 mmol, 0.17 eq.)를 첨가하고, 반응액 안을 수소로 치환하여, 실온에서 16시간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액 안을 아르곤 가스로 치환하여, 반응액을 세라이트 여과했다. 여과액을 감압 농축한 후, 얻어진 잔사를 메탄올(985 mL)에 용해하여, 3 L의 4구 플라스크로 옮겼다. 용액을 빙욕으로 냉각하고, 내부 온도가 2∼4℃가 되도록 1-(트리플루오로아세틸)이미다졸(17.0 mL, 149 mmol, 1.2 eq.)을 15분간 걸쳐 적하하여, 4℃에서 2시간 교반했다. LC/MS로 반응의 진행을 확인한 후, 반응액을 감압 농축했다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(SiO2 800g, 헵탄/아세트산에틸=1:4)로 정제함으로써, 화합물 20(21.4 g, 42.2 mmol, 수율 33%)을 얻었다.
공정 16: 화합물 21의 합성
N-(9-((2R,3R,4S,5R)-3,4-디히드록시-5-((2,2,2-트리플루오로아세트아미도)메틸)테트라히드로푸란-2-일)-9H-푸린-6-일)벤즈아미드
1 L의 가지형 플라스크에, 공정 15에서 얻어진 화합물 20(10.0 g, 19.8 mmol, 10 eq.), 증류수(50.0 mL)를 가하여, 용액을 빙욕으로 냉각했다. 빙냉 하에, 트리플루오로아세트산(50.0 mL, 640 mmol, 32.4 eq.)을 5분간 걸쳐 적하하고, 반응액을 실온까지 승온하여, 4시간30분간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액을 감압 농축하여, 잔사를 톨루엔 공비했다. 얻어진 잔사에 이소프로필에테르를 가하여, 고체를 석출시키고, 여과하여 취했다. 얻어진 고체를 감압 하에 실온에서 건조하여, 화합물 21(8.86 g, 19.0 mmol, 수율 96%)을 얻었다.
공정 17: 화합물 22의 합성
N-(9-((2R,3R,4R,5R)-3-((tert-부틸디메틸실릴)옥시)-4-히드록시-5-((2,2,2-트리플루오로아세트아미도)메틸)테트라히드로푸란-2-일)-9H-푸린-6-일)벤즈아미드
아르곤 분위기 하, 500 mL의 가지형 플라스크에, 공정 16에서 얻어진 화합물 21(15.6 g, 33.6 mmol, 1.0 eq.), 탈수DMF(111 mL)를 가하여, 용액을 빙욕으로 냉각했다. 빙냉 하에, 내부 온도가 6℃ 미만이 되도록 이미다졸(9.16 g, 134 mmol, 4.0 eq.), t-부틸디메틸실릴클로리드(15.2 g, 101 mmol, 3.0 eq.)을 첨가하여, 같은 온도에서 30분간 교반했다.
LC/MS로 반응의 진행을 확인한 후, 반응액에 얼음물을 가했다. 물층을 아세트산에틸로 3회 추출하고, 포화 식염수로 세정하여, 무수황산나트륨으로 탈수했다. 여과 후, 용매를 감압 유거하여, 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(SiO2 800g, 클로로포름/2-부타논=100:0부터 85:15)로 정제함으로써, 화합물 22와 화합물 23의 혼합물(10.9 g)을 얻었다. 얻어진 화합물 22와 화합물 23의 혼합물은 추가적인 정제 조작을 실시하지 않고서 다음 공정에 이용했다.
공정 18: 화합물 24의 합성
(2R,3R,4R,5R)-5-(6-벤즈아미도-9H-푸린-9-일)-4-((tert-부틸디메틸실릴)옥시)-2-((2,2,2-트리플루오로아세트아미도)메틸)테트라히드로푸란-3-일(2-시아노에틸)디이소프로필포스포르아미다이트
아르곤 분위기 하, 200 mL의 가지형 플라스크에, 공정 17에서 얻어진 화합물 22와 화합물 23의 혼합물(1.19 g, 2.05 mmol, 화합물 22:화합물 23=9:1), 탈수디클로로메탄(6.83 mL)을 가하여, 용액을 빙욕으로 냉각했다. 빙냉 하에, 디이소프로필에틸아민(0.537 mL, 3.07 mmol, 1.5 eq.), 3-((클로로(디이소프로필아미노)포스파닐)옥시)프로판니트릴(0.857 mL, 3.07 mmol, 1.5 eq.)의 디클로로메탄 혼합 용액을 적하한 후, 반응액을 실온까지 승온하여, 실온에서 2시간 교반했다.
TLC로 원료의 소실을 확인한 후, 반응액에 증류수를 가하여, 클로로포름(50 mL)으로 2회 추출하고, 유기층을 무수황산나트륨으로 탈수했다. 여과 후, 용매를 감압 유거하여, 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50:50부터 30:70, 0.5% 트리에틸아민 함유)로 여러 번 정제함으로써, 목적으로 하는 화합물 24(608 mg, 0.779 mmol, 수율 38%)를 담황색 아모르퍼스형 물질로서 얻었다.
1H NMR(400 MHz, CDCl3) δ: 9.82(1H, d, J=8.8 Hz), 9.07(1H, s), 8.83-8.80(1H, m), 8.06-8.01(3H, m), 7.66-7.52(3H, m), 5.86(1H, d, J=7.8 Hz), 4.88(1H, dd, J=7.8, 5.2 Hz), 4.50(1H, br s), 4.39-4.29(1H, m), 4.21-3.88(3H, m), 3.74-3.63(1H, m), 3.48-3.35(1H, m), 2.73-2.66(2H, m), 1.28-1.23(12H, m), 1.08-1.04(1H, m), 0.72-0.68(9H, m), -0.17(3H, s), -0.45(3H, s).
31P NMR(CDCl3) δ: 149.95
폴리뉴클레오티드의 원료가 되는 화합물 6a의 합성은 하기 스킴으로 합성했다.
Figure pct00021
공정 1: 화합물 2a의 합성
N-(9-((3aR,5R,6R,6aS)-2,2-디-tert-부틸-6-메톡시테트라히드로푸로[2,3-d][1,3,2]디옥사실롤-5-일)-9H-푸린-6-일)벤즈아미드
시판되는 화합물 1a(30.0 g, 78.0 mmol)의 DMF(300 mL) 용액에, 빙냉 하에, 디-t-부틸실릴비스(트리플루오로메탄술포네이트)(68.6 g, 156 mmol)를 천천히 가했다. 빙냉 하에, 1시간 교반 후, 반응액을 포화 탄산수소나트륨 수용액에 가하고, 헵탄/아세트산에틸의 혼합 용매를 가하여, 2회 추출했다. 유기층을 물로 2회, 포화 식염수로 1회 세정한 후, 무수황산나트륨으로 건조했다. 여과 후, 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=7/3→3/7)로 정제하여 화합물 2a(38.7 g, 73.7 mmol)를 무색 고체로서 얻었다(수율 95%).
ESI-MS: 계산치: 524.23[M-H]-, 실측치: 524.5[M-H]-
1H-NMR(CDCl3, 400 MHz) δ: 9.32(s, 1H), 8.76(s, 1H), 8.05(s, 1H), 8.03(t, J=6.6 Hz, 2H), 7.60(t, J=7.3 Hz, 1H), 7.51(t, J=7.8 Hz, 2H), 6.01(s, 1H), 4.66(dd, J=9.6, 5.0 Hz, 1H), 4.48(dd, J=8.9, 4.8 Hz, 1H), 4.31(d, J=4.6 Hz, 1H), 4.20(ddd, J=10.1, 5.0, 5.0 Hz, 1H), 4.03(t, J=9.8 Hz, 1H), 3.70(s, 3H), 1.10(s, 9H), 1.06(s, 9H).
공정 2: 화합물 3a의 합성
N-(9-((3aR,5R,6R,6aS)-2,2-디-tert-부틸-6-메톡시테트라히드로푸로[2,3-d][1,3,2]디옥사실롤-5-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 2a(10.0 g, 19.0 mmol)를 디클로로메탄(50 mL)에 용해하고, 테트라부틸암모늄브로미드(9.20 g, 28.5 mmol), 1M 수산화나트륨 수용액(50 ml)을 가했다. 요오드화메틸(4.76 ml, 76.0 mmol)을 천천히 적하했다. 그 후, 실온에서 1시간10분간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 물/클로로포름=1/1에 가하여 켄치했다. 유기층을 물로 2회 세정한 후, 무수황산나트륨으로 탈수하고, 건조제를 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=90/10→50/50)로 정제함으로써, 화합물 3a(6.25 g, 11.6 mmol)를 무색 아모르퍼스로서 얻었다.(수율 61%)
ESI-MS: 계산치: 540.26[M+H]+, 실측치: 540.4[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.56(s, 1H), 7.94(s, 1H), 7.49-7.46(m, 2H), 7.34-7.29(m, 1H), 7.21(t, J=7.6 Hz, 2H), 5.94(s, 1H), 4.61(dd, J=9.6, 5.0 Hz, 1H), 4.46(dd, J=9.2, 5.0 Hz, 1H), 4.22(d, J=4.6 Hz, 1H), 4.17(ddd, J=10.0, 5.2, 5.0 Hz, 1H), 4.00(dd, J=10.5, 9.2 Hz, 1H), 3.79(s, 3H), 3.67(s, 3H), 1.08(s, 9H), 1.05(s, 9H).
공정 3: 화합물 4a의 합성
N-(9-((2R,3R,4S,5S)-4,5-디히드록시-3-메톡시테트라히드로푸란-2-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 3a(6.25 g, 11.6 mmol)를 테트라히드로푸란(63 mL)에 용해하여 빙욕으로 냉각했다. 트리에틸아민(8.07 ml, 57.9 mmol), 트리에틸아민삼불화수소산염(1.89 ml, 11.6 mmol)을 가하여, 빙욕으로 냉각하면서 1시간5분간 교반했다. 원료 소실을 확인한 후, 트리에틸아민(10 ml, 76.0 mmol)을 가하여 켄치하고, 클로로포름으로 희석한 후에, 반응액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=100/0→90/10)로 정제함으로써, 화합물 4a(4.25 g, 10.6 mmol)를 무색 아모르퍼스로서 얻었다.(수율 quant.)
ESI-MS: 계산치: 400.16[M+H]+, 실측치: 400.3[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.56(s, 1H), 7.97(s, 1H), 7.50-7.48(m, 2H), 7.35-7.31(m, 1H), 7.22(t, J=7.8 Hz, 2H), 5.87(d, J=7.3 Hz, 1H), 5.86(dd, J=11.4, 2.3 Hz, 1H), 4.63(dd, J=7.3, 4.6 Hz, 1H), 4.57-4.56(m, 1H), 4.36-4.34(m, 1H), 3.99-3.94(m, 1H), 3.81(s, 3H), 3.77(td, J=12.3, 1.7 Hz, 1H), 3.31(s, 3H), 2.77(d, J=1.4 Hz, 1H).
공정 4: 화합물 5a의 합성
N-(9-((2R,3R,4S,5S)-5-(비스(4-메톡시페닐)(페닐)메톡시)-4-히드록시-3-메톡시테트라히드로푸란-2-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 4a(4.25 g, 10.6 mmol)를 피리딘(43 mL)에 용해하여 빙욕으로 교반했다. 반응액에 4,4'-디메톡시트리틸클로리드(5.41 g, 20.0 mmol)를 가하여, 실온에서 2시간25분간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 중조수에 가하여 켄치하고, 아세트산에틸로 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시켜, 여과 분별한 다음, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 화합물 5a(5.35 g, 7.62 mmol)를 무색 아모르퍼스로서 얻었다.(수율 71%)
ESI-MS: 계산치: 702.29[M+H]+, 실측치: 702.6[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.50(s, 1H), 8.14(s, 1H), 7.45-7.40(m, 4H), 7.33-7.22(m, 8H), 7.16(t, J=7.6 Hz, 2H), 6.81(dd, J=8.9, 1.1 Hz, 4H), 6.15(d, J=3.7 Hz, 1H), 4.48(dd, J=11.9, 5.0 Hz, 1H), 4.35(dd, J=5.3, 3.9 Hz, 1H), 4.21-4.19(m, 1H), 3.80(s, 3H), 3.79(s, 6H), 3.53(s, 3H), 3.50(dd, J=10.8, 3.0 Hz, 1H), 3.40(dd, J=10.8, 4.4 Hz, 1H), 2.66(d, J=6.4 Hz, 1H).
공정 5: 아미다이트 6a의 합성
(2S,3S,4R,5R)-2-(비스(4-메톡시페닐)(페닐)메톡시)-4-메톡시-5-(6-(N-메틸벤즈아미도)-9H-푸린-9-일)테트라히드로푸란-3-일(2-시아노에틸)디이소프로필포스포르아미다이트
화합물 5a(5.30 g, 7.55 mmol)를 디클로로메탄(48 mL)에 용해하고, 디이소프로필에틸아민(2.64 mL, 15.1 mmol)을 가하여, 빙욕으로 냉각했다. 디클로로메탄(5 mL)에 용해한 2-시아노에틸디이소프로필클로로포스포로아미디트(2.68 g, 11.3 mmol)를 5분간 걸쳐 적하했다. 그 후, 실온까지 승온하면서 1시간10분간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 포화 중조수에 가하여 켄치했다. 아세트산에틸을 가하여 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시키고, 건조제를 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 아미다이트 6a(6.22 g, 6.90 mmol)를 무색 아모르퍼스로서 얻었다.(수율 91%)
ESI-MS: 계산치: 902.40[M+H]+, 실측치: 902.5[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.47(s, 0.35H), 8.47(s, 0.65H), 8.14(s, 0.35H), 8.09(s, 0.65H), 7.44-7.39(m, 4H), 7.33-7.21(m, 8H), 7.16-7.12(m, 2H), 6.93-6.78(m, 4H), 6.12(d, J=5.5, 0.65H), 6.10(d, J=5.0, 0.35H), 4.66-4.53(m, 2H), 4.41-4.38(m, 0.35H), 4.34-4.32(m, 0.65H), 3.97-3.78(m, 10H), 3.70-3.44(m, 7H), 3.36-3.30(m, 1H), 2.64(t, J=6.2 Hz, 1.3H), 2.38(t, J=6.4 Hz, 0.70H), 1.22-1.17(m, 8H), 1.06(d, J=6.9 Hz, 4H).
31P-NMR(CDCl3, 162 MHz) δ: 150.70, 150.94.
폴리뉴클레오티드의 원료가 되는 화합물 6b의 합성은 하기 스킴으로 합성했다.
Figure pct00022
공정 1: 화합물 2b의 합성
N-(9-((4aR,6R,7R,7aS)-2,2-디-tert-부틸-7-플루오로테트라히드로-4H-푸로[3,2-d][1,3,2]디옥사실린-6-일)-9H-푸린-6-일)벤즈아미드
시판되는 화합물 1b(30.0 g, 80.4 mmol)의 DMF(300 mL) 용액에, 빙냉 하에, 디-t-부틸실릴비스(트리플루오로메탄술포네이트)(70.8 g, 161 mmol)를 천천히 가했다. 빙냉 하에, 1시간 교반한 후, 반응액을 포화 탄산수소나트륨 수용액에 가하고, 헵탄/아세트산에틸의 혼합 용매를 가하여, 2회 추출했다. 유기층을 물로 2회, 포화 식염수로 1회 세정한 후, 무수황산나트륨으로 건조했다. 여과 후, 농축 잔사를 헵탄/아세트산에틸=9/1로 슬러리 정제하여, 화합물 2b(38.7 g, 75.4 mmol)를 무색 고체로서 얻었다(수율 94%).
ESI-MS: 계산치: 514.23[M+H]+, 실측치: 514.5[M+H]+
1H-NMR(DMSO-d6, 400 MHz) δ: 11.27(s, 1H), 8.74(s, 1H), 8.65(s, 1H), 8.04(d, J=8.7 Hz, 2H), 7.65(t, J=7.5 Hz, 1H), 7.55(t, J=7.5 Hz, 2H), 6.45(d, J=23 Hz, 1H), 5.71(dd, J=54.5, 4.1 Hz, 1H), 5.03(m, 1H), 4.44(q, J=3.7 Hz, 1H), 4.09(m, 2H), 1.11(s, 9H), 1.02(s, 9H).
공정 2: 화합물 3b의 합성
N-(9-((4aR,6R,7R,7aS)-2,2-디-tert-부틸-7-플루오로테트라히드로-4H-푸로[3,2-d][1,3,2]디옥사실린-6-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 2b(10.0 g, 19.5 mmol)를 디클로로메탄(50 mL)에 용해하고, 테트라부틸암모늄브로미드(9,41 g, 29.2 mmol), 1M 수산화나트륨 수용액(50 ml)을 가했다. 요오드화메틸(1.83 ml, 29.2 mmol)을 천천히 적하했다. 그 후, 실온에서 1시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 물/클로로포름=1/1에 가하여 켄치했다. 유기층을 물로 2회 세정한 후, 무수황산나트륨으로 탈수하고, 건조제를 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=90/10→50/50)로 정제함으로써, 화합물 3b(6.86 g, 12.8 mmol)를 무색 아모르퍼스로서 얻었다.(수율 65%)
ESI-MS: 계산치: 528.24[M+H]+, 실측치: 538.6[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.54(s, 1H), 7.94(s, 1H), 7.47(d, J=8.1 Hz, 2H), 7.32(t, J=7.3 Hz, 2H), 7.21(t, J=7.6 Hz, 2H), 6.10(d, J=22.0 Hz, 1H), 5.46(dd, J=54.5, 4.1 Hz, 1H), 4.86(ddd, J=27.2, 9.8, 4.1 Hz, 1H), 4.47(dd, J=9.2, 5.0 Hz, 1H), 4.14(m, 1H), 4.03(t, J=9.8 Hz, 1H), 3.78(s, 3H), 1.11(s, 9H), 1.05(s, 9H).
공정 3: 화합물 4b의 합성
N-(9-((2R,3R,4R,5R)-3-플루오로-4-히드록시-5-(히드록시메틸)테트라히드로푸란-2-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 3b(6.67 g, 12.6 mmol)를 테트라히드로푸란(66 mL)에 용해하여, 빙욕으로 냉각했다. 트리에틸아민(8.81 ml, 63.2 mmol), 트리에틸아민삼불화수소산염(2.05 ml, 12.6 mmol)을 가하여, 빙욕으로 냉각하면서 1시간5분간 교반했다. 원료 소실을 확인한 후, 트리에틸아민(10.6 ml, 76.0 mmol)을 가하여 켄치하고, 클로로포름으로 희석한 후에, 반응액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=100/0→90/10)로 정제함으로써, 화합물 4b(4.98 g, 12.9 mmol)를 무색 아모르퍼스로서 얻었다.(수율 quant.)
ESI-MS: 계산치: 388.14[M+H]+, 실측치: 388.4[M+H]+
1H-NMR(DMSO-d6, 400 MHz) δ: 8.70(s, 1H), 8.58(s, 1H), 7.30(m, 5H), 6.31(dd, J=16.9, 2.3 Hz, 1H), 5.75(d, J=6.4 Hz, 1H), 5.41(m, 781H), 5.15(t, J=5.3 Hz, 1H), 4.46(m, 1H), 3.98(m, 1H), 3.75(dq, J=12.4, 2.6 Hz, 1H), 3.67(s, 3H), 3.61-3.56(m, 1H).
공정 4: 화합물 5b의 합성
N-(9-((2R,3R,4R,5R)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-3-플루오로-4-히드록시테트라히드로푸란-2-일)-9H-푸린-6-일)-N-메틸벤즈아미드
화합물 4b(4.93 g, 12.7 mmol)를 피리딘(49 mL)에 용해하여 빙욕으로 교반했다. 반응액에 4,4'-디메톡시트리틸클로리드(6.47 g, 29.2 mmol)를 가하여, 실온에서 1시간20분간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 중조수에 가하여 켄치하고, 아세트산에틸로 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시키고, 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 화합물 5b(8.34 g, 12.1 mmol)를 무색 아모르퍼스로서 얻었다.(수율 95%)
ESI-MS: 계산치: 690.27[M+H]+, 실측치: 690.7[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.51(s, 1H), 8.10(s, 1H), 7.43(dd, J=8.2, 1.4 Hz, 2H), 7.37(dd, 8.2, 1.4 Hz, 2H), 7.28-7.20(m, 8H), 7.12(t, J=7.5 Hz, 2H), 6.79(d, J=8.7 Hz), 6.23(dd, J=17.1, 2.5 Hz, 1H), 5.58(dq, J=52.9, 2.3 Hz, 1H), 4.78(m, 1H), 4.19(m, 1H), 3.78(s, 6H), 3.47(ddd, J=57.9, 10.6, 3.5 Hz, 2H), 2.44(dd, J=7.5, 2.5 Hz, 1H).
공정 5: 아미다이트 6b의 합성
(2R,3R,4R,5R)-2-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-4-플루오로-5-(6-(N-메틸벤즈아미도)-9H-푸린-9-일)테트라히드로푸란-3-일(2-시아노에틸)디이소프로필포스포르아미다이트
화합물 5b(10.0 g, 14.6 mmol)를 디클로로메탄(80 mL)에 용해하고, 디이소프로필에틸아민(5.08 mL, 29.1 mmol)을 가하여, 빙욕으로 냉각했다. 디클로로메탄(15 mL)에 용해한 2-시아노에틸디이소프로필클로로포스포로아미디트(4.18 g, 21.8 mmol)를 5분간 걸쳐 적하했다. 그 후, 실온까지 승온하면서 1시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 포화 중조수에 가하여 켄치했다. 아세트산에틸을 가하여 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시키고, 건조제를 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 아미다이트 6b(12.1 g, 13.6 mmol)를 무색 아모르퍼스로서 얻었다.(수율 93%)
ESI-MS: 계산치: 890.38[M+H]+, 실측치: 890.8[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.53(s, 0.49H), 8.50(s, 0.51H), 8.14(s, 1H), 7.43-7.39(m, 2H), 7.37-7.33(m, 2H), 7.27-7.20(m, 8H), 7.09-7.04(m, 2H), 6.77(t, J=9.1 Hz, 4H), 6.28-6.19(m, 1H), 5.74(dq, J=18.5, 2.2 Hz, 0.50H), 5.61(dq, J=19.2, 2.3 Hz, 0.50H), 5.10-5.00(m, 0.47H), 4.94-4.85(m, 0.53H), 4.31(m, 1H), 3.97-3.82(m, 1H), 3.79(s, 3H), 3.79(s, 3H), 3.63-3.53(m, 4H), 3.31-3.27(m, 1H), 2.59(t, J=6.2 Hz, 1H), 2.41(t, J=6.4 Hz, 1H), 1.20-1.15(m, 9H), 1.04(d, J=6.4 Hz, 3H).
31P-NMR(CDCl3, 162 MHz) δ: 151.97, 151.92, 151.19, 151.11.
폴리뉴클레오티드의 원료가 되는 화합물 6c의 합성은 하기 스킴으로 합성했다.
Figure pct00023
공정 1: 화합물 3c의 합성
N-(9-((4aR,6R,7R,7aS)-2,2-디-tert-부틸-7-메톡시테트라히드로-4H-푸로[3,2-d][1,3,2]디옥사실린-6-일)-9H-푸린-6-일)-N-에틸벤즈아미드
화합물 2a(11.7 g, 22.3 mmol)를 디클로로메탄(58.5 mL)에 용해하고, 테트라부틸암모늄브로미드(10.8 g, 33.4 mmol), 1M 수산화나트륨 수용액(58.5 ml)을 가했다. 요오드화에틸(10.8 ml, 134 mmol)을 천천히 적하했다. 그 후, 실온에서 2시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 물/클로로포름=1/1에 가하여 켄치했다. 유기층을 물로 2회 세정한 후, 무수황산나트륨으로 건조시켰다. 여과 후, 여과액을 농축했다. 농축 잔사를 톨루엔에 의해 슬러리 정제하여, 재차 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=90/10→70/30)로 정제함으로써, 화합물 3c(6.14 g, 11.1 mmol)를 무색 아모르퍼스로서 얻었다.(수율 49%)
ESI-MS: 계산치: 554.28[M+H]+, 실측치: 554.6[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.56(s, 1H), 7.91(s, 1H), 7.47-7.45(m, 2H), 7.31-7.27(m, 1H), 7.19(t, J=7.5 Hz, 2H), 5.94(s, 1H), 4.61(dd, J=9.6, 4.6 Hz, 1H), 4.46(dd, J=9.1,5.0 Hz, 1H), 4.40(q, J=7.0 Hz, 2H), 4.22(d, J=4.6 Hz, 1H), 4.16(ddd, J=10.1, 4.9, 4.8 Hz, 1H), 4.00(dd, J=10.5, 9.6 Hz, 1H), 3.67(s, 3H), 1.34(t, J=7.1 Hz, 3H), 1.09(s, 9H), 1.05(s, 9H).
공정 2: 화합물 4c의 합성
N-에틸-N-(9-((2R,3R,4R,5R)-4-히드록시-5-(히드록시메틸)-3-메톡시테트라히드로푸란-2-일)-9H-푸린-6-일)벤즈아미드
화합물 3c(6.14 g, 11.1 mmol)를 테트라히드로푸란(61.4 mL)에 용해하여, 빙욕으로 냉각했다. 트리에틸아민(7.73 ml, 55.4 mmol), 트리에틸아민삼불화수소산염(1.81 ml, 11.1 mmol)을 가하여, 빙욕으로 냉각하면서 2시간 교반했다. 원료 소실을 확인한 후, 트리에틸아민(10 ml, 76.0 mmol)을 가하여 켄치하고, 클로로포름으로 희석한 후에, 반응액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=100/0→90/10)로 정제함으로써, 화합물 4c(4.60 g, 11.1 mmol)를 무색 아모르퍼스로서 얻었다.(수율 quant.)
ESI-MS: 계산치: 414.18[M+H]+, 실측치: 414.3[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.56(s, 1H), 7.92(s, 1H), 7.50-7.46(m, 2H), 7.32-7.28(m, 1H), 7.20(t, J=7.5 Hz, 2H), 5.89(dd, J=11.6, 2.1 Hz, 1H), 5.85(d, J=7.3 Hz, 1H), 4.62(dd, J=7.3, 4.6 Hz, 1H), 4.57-4.56(m, 1H), 4.45-4.39(m, 2H), 4.36-4.34(m, 1H), 3.96(dt, J=12.9, 1.9, 1H), 3.80-3.73(m, 1H), 3.29(s, 3H), 2.70(d, J=1.4 Hz, 1H), 1.37(t, J=7.1 Hz, 3H).
공정 3: 화합물 5c의 합성
N-(9-((2R,3R,4R,5R)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-4-히드록시-3-메톡시테트라히드로푸란-2-일)-9H-푸린-6-일)-N-에틸벤즈아미드
화합물 4c(4.58 g, 11.1 mmol)를 피리딘(46 mL)에 용해하여 빙욕으로 교반했다. 반응액에 4,4'-디메톡시트리틸클로리드(5.63 g, 16.6 mmol)를 가하여, 실온에서 2시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 중조수에 가하여 켄치하고, 아세트산에틸로 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조했다. 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 화합물 5c(7.55 g, 10.6 mmol)를 무색 아모르퍼스로서 얻었다.(수율 95%)
ESI-MS: 계산치: 716.31[M+H]+, 실측치: 716.2[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.51(s, 1H), 8.11(s, 1H), 7.43-7.40(m, 4H), 7.32-7.22(m, 8H), 7.13(t, J=7.5 Hz, 2H), 6.81(dd, J=9.1, 1.4 Hz, 4H), 6.14(d, J=3.7 Hz, 1H), 4.47(dd, J=5.7, 5.6 Hz, 1H), 4.41(q, J=7.0 Hz, 2H), 4.34(dd, J=8.4, 4.1 Hz, 1H), 4.21-4.17(m, 1H), 3.79(s, 6H), 3.53(s, 3H), 3.50(dd, J=10.5, 3.2 Hz, 1H), 3.39(dd, J=10.7, 4.3 Hz, 1H), 2.64(d, J=6.4 Hz, 1H), 1.34(t, J=7.1 Hz, 3H).
공정 4: 아미다이트 6c의 합성
(2R,3R,4R,5R)-2-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-5-(6-(N-에틸벤즈아미도)-9H-푸린-9-일)-4-메톡시테트라히드로푸란-3-일(2-시아노에틸)디이소프로필포스포르아미다이트
화합물 5c(8.83 g, 12.3 mmol)를 디클로로메탄(74 mL)에 용해하고, 디이소프로필에틸아민(4.31 mL, 24.7 mmol)을 가하여, 빙욕으로 냉각했다. 탈수디클로로메탄(14 mL)에 용해한 2-시아노에틸디이소프로필클로로스포로아미디트(4.40 g, 18.6 mmol)를 9분간 걸쳐 적하했다. 그 후, 실온까지 승온하면서 1시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 포화 중조수에 가하여 켄치했다. 아세트산에틸을 가하여 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시켰다. 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=70/30→50/50)로 정제함으로써, 아미다이트 6c(10.4 g, 11.3 mmol)를 무색 아모르퍼스로서 얻었다.(수율 92%)
ESI-MS: 계산치: 916.42[M+H]+, 실측치: 917.3[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.49(s, 0.37H), 8.48(s, 0.63H), 8.11(s, 0.34H), 8.05(s, 0.66H), 7.43-7.38(m, 4H), 7.32-7.21(m, 8H), 7.11(t, J=7.8 Hz, 2H), 6.80(m, 4H), 6.10(m, 1H), 4.64-4.52(m, 2H), 4.43-4.32(m, 3H), 3.94-3.83(m, 1H), 3.79-3.78(m, 6H), 3.67-3.46(m, 4H), 3.35-3.29(m, 1H), 2.64(t, J=6.4 Hz, 1.3H), 2.37(t, J=6.4 Hz, 0.70 H), 1.33(t, J=7.1 Hz, 3H), 1.18(m, 8H), 1.06(d, J=6.9 Hz, 4H).
31P-NMR(CDCl3, 162 MHz) δ: 151.67, 150.92.
폴리뉴클레오티드의 원료가 되는 화합물 6d의 합성은 하기 스킴으로 합성했다.
Figure pct00024
공정 1: 화합물 3d의 합성
N-(9-((4aR,6R,7R,7aS)-2,2-디-tert-부틸-7-플루오로테트라히드로-4H-푸로[3,2-d][1,3,2]디옥사실린-6-일)-9H-푸린-6-일)-N-에틸벤즈아미드
화합물 2b(1.00 g, 1.95 mmol)를 디클로로메탄(5.0 mL)에 용해하고, 테트라부틸암모늄브로미드(0.942 g, 2.92 mmol), 1M 수산화나트륨 수용액(5.0 ml)을 가했다. 요오드화메틸(0.942 ml, 11.7 mmol)을 천천히 적하했다. 그 후, 실온에서 2시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 물/클로로포름=1/1에 가하여 켄치했다. 유기층을 물로 2회 세정한 후, 무수황산나트륨으로 탈수하고, 건조제를 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=80/20→70/30)로 정제함으로써, 화합물 3d(629 mg, 1.16 mmol)를 무색 아모르퍼스로서 얻었다.(수율 60%)
ESI-MS: 계산치: 542.26[M+H]+, 실측치: 542.6[M+H]+
1H-NMR(CDCl3, 400 MHz) δ: 8.55(s, 1H), 7.91(s, 1H), 7.46(d, J=7.3 Hz, 2H), 7.30(t, J=7.1 Hz, 1H), 7.19(t, J=7.8 hz, 2H), 6.09(d, J=22.4 Hz, 1H), 5.45(dd, J=54.1, 3.9 Hz, 1H), 4.86(ddd, J=27.2, 9.8, 4.1 Hz, 1H), 4.48(dd, J=9.1, 5.0, 1H), 4.40(q, J=7.2 Hz, 2H), 4.04(t, J=9.8 Hz, 1H), 1.34(t, J=7.1 Hz, 3H), 1.11(s, 9H), 1.05(s, 9H).
공정 2: 화합물 4d의 합성
N-에틸-N-(9-((2R,3R,4R,5R)-3-플루오로-4-히드록시-5-(히드록시메틸)테트라히드로푸란-2-일)-9H-푸린-6-일)벤즈아미드
화합물 4c를 얻는 공정과 같은 식으로 화합물 4d를 얻었다.
ESI-MS: 계산치: 401.40[M+H]+, 실측치: 402.1[M+H]+
공정 3: 화합물 5d의 합성
N-(9-((2R,3R,4R,5R)-5-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-3-플루오로-4-히드록시테트라히드로푸란-2-일)-9H-푸린-6-일)-N-에틸벤즈아미드
화합물 5c를 얻는 공정과 같은 식으로 하여 화합물 5d를 얻었다.
ESI-MS: 계산치: 738.25[M+Cl]-, 실측치: 738.7[M+Cl]-
1H-NMR(CDCl3, 400 MHz) δ: 8.52(s, 1H), 8.07(s, 1H), 7.43-7.41(m, 2H), 7.38-7.35(m, 2H), 7.30-7.20(m, 8H), 7.10(t, J=7.8 Hz, 2H), 6.79(d, J=8.2 Hz, 4H), 6.22(dd, J=17.4, 2.3 Hz, 1H), 5.58(ddd, J=53.0, 2.4, 1.2 Hz, 1H), 4.93-4.74(m, 1H), 4.40(q, J=7.2 Hz, 2H), 4.19-4.16(m, 1H), 3.78(s, 6H), 3.54(dd, J=11.0, 3.2 Hz, 1H), 3.40(dd, J=10.5, 3.1 Hz, 1H), 2.23(dd, J=6.9, 2.3 Hz, 1H), 1.33(t, J=7.1 Hz, 3H).
공정 4: 아미다이트 6d의 합성
(2R,3R,4R,5R)-2-((비스(4-메톡시페닐)(페닐)메톡시)메틸)-5-(6-(N-에틸벤즈아미도)-9H-푸린-9-일)-4-플루오로테트라히드로푸란-3-일(2-시아노에틸)디이소프로필포스포르아미다이트
화합물 5d(1.93 g, 2.74 mmol)를 디클로로메탄(16 mL)에 용해하고, 디이소프로필에틸아민(0.958 mL, 5.48 mmol)을 가하여, 빙욕으로 냉각했다. 탈수디클로로메탄(3.8 mL)에 용해한 2-시아노에틸디이소프로필클로로포스포로아미디트(970 mg, 4.11 mmol)를 적하했다. 그 후, 실온까지 승온하면서 1시간 교반했다. 원료 소실을 확인한 후, 반응액을 빙냉한 포화 중조수에 가하여 켄치했다. 아세트산에틸을 가하여 추출했다. 유기층을 포화 식염수로 세정한 후, 무수황산나트륨으로 건조시켰다. 여과 분별한 후, 여과액을 농축했다. 농축 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸(1% 트리에틸아민 함유)=90/10→60/40)로 정제함으로써, 아미다이트 6d(2.29 g, 2.53 mmol)를 무색 아모르퍼스로서 얻었다.(수율 92%)
ESI-MS: 계산치: 938.36[M+Cl]-, 실측치: 938.7[M+Cl]-
1H-NMR(CDCl3, 400 MHz) δ: 8.53(s, 0.5H), 8.51(s, 0.5H), 8.11(s, 1H), 7.41-7.33(m, 4H), 7.27-7.16(m, 8H), 7.03(t, J=7.8 Hz, 2H), 6.79-6.75(m, 4H), 6.27-6.18(m, 1H), 5.78-5.58(m, 1H), 5.10-4.85(m, 1H), 4.42-4.38(m, 2H), 4.31-4.30(m, 1H), 3.96-3.72(m, 7H), 3.68-3.51(m, 4H), 3.29-3.27(m, 1H), 2.59(t, J=6.2 Hz, 1H), 2.40(t, J=6.4 Hz, 1H), 1.33-1.31(m, 3H), 1.19-1.15(m, 9H), 1.04(d, J=6.9 Hz, 3H).
31P-NMR(CDCl3, 162 MHz) δ: 151.94, 151.89, 151.20, 151.11.
RNA 올리고뉴클레오티드는 2'-TOM(트리이소프로필실릴옥시메틸) 보호 β-시아노에틸포스포로아미다이트(DMT-2'-O-TOM-rA(Ac), DMT-2'-O-TOM-rG(Ac), DMT-2'-O-TOM-rC(Ac), DMT-2'-O-TOM-rU)(각각 Glen Research사 혹은 ChemGenes사)를 이용하고, DNA 올리고뉴클레오티드는 β-시아노에틸포스포로아미다이트(DMT-dA(Bz), DMT-dG(iBu), DMT-dC(Ac), DMT-T)를 이용했다. 각각의 포스포로아미다이트 모노머는 0.05 mol/L 아세토니트릴 용액이 되도록 조제하고, 고상 담체를 0.2 μmol 혹은 0.8 μmol 이용하여 DNA/RNA 고상 합성 장치(NTSM-2-MX, 닛폰테크노서비스사)에 의해 합성했다.
DNA 올리고뉴클레오티드는 고상 담체로서 CPG 1000A(dA-CPG, dG-CPG, Ac-dC-CPG, dT-CPG)(Glen Research사)를 이용하고, 축합 시간은 2분간으로 했다.
5' 말단에 인산기를 갖는 RNA(5'-모노인산 RNA)는 고상 담체로서 Universal UnyLinker Support 2000A(ChemGenes사)를 이용하고, 1번째 염기의 축합 시간은 15분간, 그 이후는 각 3분간으로 했다. 5' 말단의 수산기의 인산화는 화학 인산화 시약(0.05 mol/L 아세토니트릴 용액)(Glen Research사 혹은 ChemGenes사)을 이용하여 행했다.
3'-아미노구아노신 모노머가 3' 말단에 도입된 RNA 올리고뉴클레오티드의 고상 합성은 화합물 15를 이용하여 행했다. 1번째 염기의 축합 시간은 15분간, 그 이후에는 각 3분간으로 했다.
고상 합성 장치에서 사용한 시약에 관해서는 이하의 것을 사용했다. 5' 말단의 수산기의 디메톡시트리틸기의 제거는 시판되는 데블로킹 시약(Deblocking Solution-1,3 w/v% 트리클로로아세트산/디클로로메탄 용액)(와코쥰야쿠가부시키가이샤)을 이용하여, 10초간 반응시킴으로써 행했다. 포스포로아미다이트의 액티베이터로서 시판되는 액티베이터 용액(액티베이터 용액 3)(와코쥰야쿠가부시키가이샤)을 이용했다. 미반응의 5' 말단의 수산기의 캡핑은 시판되는 캡핑 용액(캡 A 용액-2 및 캡 B 용액-2)(와코쥰야쿠가부시키가이샤)을 이용하여, 10초간 반응시킴으로써 행했다. 인산에스테르를 제조할 때의 산화제로서는, 피리딘, THF, 물 및 요오드를 함유하는 용액(Oxidizer, 0.01M 요오드, 29.2% 물, 6.3% 피리딘, 64.5% 아세토니트릴), Honeywell사)을 이용하여, 10초간 반응시켰다. 고상 합성 후, RNA 올리고뉴클레오티드의 5' 말단의 수산기의 디메톡시트리틸기는 고상 담체 상에서 탈보호했다. 합성한 DNA 및 RNA 올리고뉴클레오티드는 전부 정해진 규칙에 따라 탈수지·탈보호를 행했다(농암모니아수, 55℃, 12시간). DNA 올리고뉴클레오티드는 카트리지 컬럼(Micro Pure II Column, LGC Biosearch Technology사)을 이용하여 제품 프로토콜에 따라서 정제했다. RNA 올리고뉴클레오티드는 탈수지에 의해서 얻어진 용액을 원심 에바포레이터에 의한 농축에 의해 완전히 건고(乾固)한 후, 테트라부틸암모늄플루오리드(1M 테트라히드로푸란 용액)(1 mL)를 이용하여 2' 수산기의 TOM 보호기를 제거했다(50℃, 10분간, 이어서 실온에서 12시간. 혹은 50℃, 10분간, 이어서 35℃에서 6시간). 용액에 트리스염산 완충액(이하, Tris-HCl)(1 M, pH 7.4)(1 mL)을 가하여 혼화한 후, 원심 에바포레이터에 의한 농축에 의해 테트라히드로푸란을 제거했다. 얻어진 용액을 초순수에 의해서 평형화한 겔 여과 컬럼(NAP-25, GE Healthcare사)을 이용하여, 제품 프로토콜에 의해서 처리했다. 얻어진 RNA 올리고뉴클레오티드를 포함하는 획분을 원심 에바포레이터에 의해서 농축한 후, 변성 폴리아크릴아미드 겔(이하, dPAGE)를 이용하여 정제했다.
(dPAGE를 이용한 RNA 단편의 정제)
아크릴아미드 겔 용액(변성제로서 7M 요소를 포함한다)에 과황산암모늄(이하, APS)의 수용액과 N,N,N',N'-테트라메틸에틸렌디아민(이하, TEMED)을 중합제로서 첨가하여, 고형화(실온, 6∼12시간)시킴으로써 겔을 제작했다. RNA 샘플은 겔 로딩 버퍼(80% 포름아미드, TBE)와 혼합하고, 90℃에서 3분간 가열한 후, 겔에 로드했다. 전기 영동 후, RNA의 밴드는 UV광 조사(254 nm)에 의해서 검출하고, 면도날을 이용하여 겔로부터 잘라냈다. 잘라낸 겔 조각은 미세하게 파쇄한 후, 초순수로 겔로부터 추출했다(실온에서 6∼12시간 진탕). RNA의 추출액은 Amicon Ultra 10K(Millipore사)를 이용하여 탈염·농축하고, 에탄올 침전(0.3M 아세트산나트륨(pH 5.2)/70% 에탄올)을 행함으로써 RNA의 펠릿을 얻었다. RNA 펠릿은 80% 에탄올로 린스한 후, 실온에서 1시간 풍건(風乾)시켰다. 얻어진 RNA 펠릿은 초순수에 용해시켜, 적절한 농도로 희석한 후, 자외가시 흡광 광도 측정(NanoDrop, Thermo scientific사)에 의해서 260 nm의 흡광도를 측정하여, 각 RNA 서열의 몰 흡광 계수로부터 농도를 결정했다(각 염기의 몰 흡광 계수로서 이하의 수치를 사용했다. A=15300, G=11800, C=7400, T=9300, U=9900).
정제한 올리고뉴클레오티드의 구조 결정은 MALDI-TOF MS(Ultraflex III, Bruker Daltonics사)(매트릭스: 3-히드록시피콜린산)를 이용한 질량 분석법 혹은 변성 폴리아크릴아미드 겔 전기 영동을 이용한 분석에 의해 결정했다.
(dPAGE를 이용한 케미칼 라이게이션 반응의 분석)
케미칼 라이게이션 반응의 분석에서는 반응액을 초순수로 적절하게 희석한 것을 샘플로서 사용했다. 희석한 샘플은 겔 로딩 버퍼(80% 포름아미드/TBE)와 혼합하여, 90℃에서 3분간 가열한 후, 겔에 로드했다. 전기 영동 후, 초순수로 10,000배 희석한 SYBR(등록상표) Green II Nucleic Acid Stain(Lonza사)을 이용하여 겔 염색(실온, 15분간)함으로써 RNA의 밴드를 검출했다(사용 기기: ChemiDoc, BIORAD 사).
케미칼 라이게이션 반응의 수율은, RNA 연결 산물의 밴드 강도를 dPAGE로 단리 정제한 연결 산물을 기준 물질로서 비교함으로써 산출했다.
(dPAGE를 이용한 케미칼 라이게이션 산물의 정제)
케미칼 라이게이션 반응에 의해서 얻어진 RNA 연결 산물은, 반응액으로부터 에탄올 침전(0.3M 아세트산나트륨(pH 5.2)/70% 에탄올)에 의해서 RNA 펠릿으로서 회수한 후, dPAGE에 의해서 정제를 실시했다.
이하에 실시예 1∼4에서 이용한 화합물(폴리뉴클레오티드)의 서열 정보를 나타낸다. 표 1 및 2에서의 각 뉴클레오티드 N은 RNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, dN은 DNA를 나타낸다. p는 3' 또는 5' 말단이 인산화되어 있음을 나타낸다. 밑줄이 그어진 「AUG」는 개시 코돈을, 밑줄이 그어진 「UGA」는 종지 코돈을 나타낸다. 서열에서의 사선(/)은 그 부분에서 폴리뉴클레오티드끼리 연결되었음을 나타낸다.
Figure pct00025
Figure pct00026
실시예 1
화학 합성에 의해 서열 2로서 얻어진 RNA 단편 E1-1(10 nmol) 및 서열 3으로서 얻어진 5' 인산 RNA 단편 E1-2(10 nmol), 템플레이트 DNA1(10 nmol)의 초순수 용액(200 μL, 핵산 종농도; 50 μM)을 3 배치(batch) 조제했다. 각각의 조제 용액에 T4 RNA Ligase 2 Reaction Buffer(10X)(New England BioLabs사 제조)를 100 μL, 그리고 초순수 440 μL를 가하여 90℃에서 5분간 가열한 후, 30분간 이상 걸쳐 실온으로 되돌렸다. 이 각각의 용액에 60% PEG6000 수용액을 종농도 15%가 되도록 가했다. 이 용액에 T4 RNA Ligase 2(New England BioLabs사 제조)(10 units/μL)(10 μL)를 가하여 혼합한 후, 온도 제어된 히트 블록 상에 정치했다(37℃, 16시간). 반응액에 같은 체적의 클로로포름을 가하여 볼텍스에 의해 혼합, 원심 분리한 후, 상층을 취하여 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 각각의 배치에서 얻어진 RNA를 통합하고, 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 E1(9.7 nmol, 수율 32%)을 얻었다.
실시예 2
화학 합성에 의해 서열 6으로서 얻어진 RNA 단편 E2-1 및 서열 7로서 얻어진 5' 인산 RNA 단편 E2-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 E2(10.9 nmol, 수율 36%)를 얻었다.
실시예 3
화학 합성에 의해 서열 9로서 얻어진 RNA 단편 E3-1 및 서열 10으로서 얻어진 5' 인산 RNA 단편 E3-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 E3(13.4 nmol, 수율 45%)을 얻었다.
실시예 4
화학 합성에 의해 서열 12로서 얻어진 RNA 단편 E4-1 및 서열 13으로서 얻어진 5' 인산 RNA 단편 E4-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 E4(6.8 nmol, 수율 34%)를 얻었다.
이하에 참고예 1∼18에서 이용한 화합물(폴리뉴클레오티드)의 서열 정보를 나타낸다. 표 3∼8에서의 각 뉴클레오티드 N은 RNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, N(L)은 LNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를, dN은 DNA를 나타낸다. A(m6)는 염기부가 N6-메틸아데닌임을 나타낸다. p는 3' 또는 5' 말단이 인산화되어 있음을 나타내고, p(S)는 3' 또는 5' 말단이 포스포로티오에이트화되어 있음을 나타낸다. NH2는 3' 또는 5' 말단의 수산기가 아미노기로 치환되어 있음을 나타낸다. -N/P- 및 -P/N-은 뉴클레오티드의 인산 결합이 인산아미드 결합으로 치환되어 있음을 나타내고, -NHAc/S-는 뉴클레오티드의 인산 결합이 -NHC(O)-CH2-S-P(O)(OH)-O-로 치환되어 있음을 나타낸다. 밑줄이 그어진 「AUG」는 개시 코돈을, 밑줄이 그어진 「UGA」는 종지 코돈을 나타낸다. 서열 중의 사선(/)은 그 부분에서 폴리뉴클레오티드가 연결되었음을 나타낸다.
Figure pct00027
Figure pct00028
Figure pct00029
Figure pct00030
Figure pct00031
Figure pct00032
참고예 1
화학 합성에 의해 서열 15로서 얻어진 3'-아미노 RNA 단편 R1-1(200 μM) 및 서열 16으로서 얻어진 5' 인산 RNA 단편 R1-2(200 μM), 템플레이트 DNA2(200 μM)의 초순수 용액을 90℃에서 3분간 가열한 후, 30분간 이상 걸쳐 실온으로 되돌렸다. 이 용액에, 별도 조제한 축합제의 완충 용액(1M EDC-HCl/1M HOBt의 500 mM HEPES-NaOH(pH 8.5), 200 mM NaCl, 200 mM MgCl2)을 같은 체적 가하여, 혼화함으로써 연결 반응을 시작했다. 반응액(핵산 농도: 100 μM, 0.5M EDC-HCl/0.5M HOBt, 250 mM HEPES-NaOH(pH 8.5), 100 mM NaCl, 100 mM MgCl2)은 온도 제어된 히트 블록(25℃) 상에 밤새 정치하게 했다. 반응 후, 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다.
이 RNA를 7.5% 변성 폴리아크릴아미드 겔로 해석하여 반응 수율(수율 52%)을 산출했다.
참고예 2
화학 합성에 의해 얻어진 R2-1, R2-2, 템플레이트 DNA1을 이용하여 참고예 1과 같은 식으로 RNA 연결 산물 R2의 생성 수율(73%)을 산출했다.
참고예 3
화학 합성에 의해 얻어진 R3-1(100 μM), R3-2(100 μM), 템플레이트 DNA3(100 μM)을 이용하여 참고예 1과 같은 식으로 RNA 연결 산물 R3(7.7 nmol, 수율 26%)을 얻었다.
참고예 4
화학 합성에 의해 얻어진 R4-1(100 μM), R4-2(100 μM), R4-3(100 μM), 템플레이트 DNA1(100 μM), 템플레이트 DNA4(100 μM)를 이용하여 참고예 1과 같은 식으로 RNA 연결 산물 R4(2.4 nmol, 수율 5.6%)를 얻었다.
참고예 5
화학 합성에 의해 얻어진 R5-1(100 μM)에 인산 버퍼(50 mM), MiliQ수를 가하고, 요오드아세트산 NHS 에스테르(5 mM)의 DMF 용액을 가하여, 30도에서 2시간 인큐베이트했다. 이어서 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 요오드아세틸화한 R5-1의 펠릿을 얻었다. 화학 합성에 의해 얻어진 R5-2(50 μM), 템플레이트 DNA1(50 μM), 염화나트륨 수용액(100 mM), 인산 버퍼(20 mM, pH 7.5)를 혼화하여, 90℃에서 3분간 가열한 후, 30분간 이상 걸쳐 실온으로 되돌렸다. 이 용액에 대하여, 상기 요오드아세틸화한 R5-1(50 μM)을 첨가하여, 30도에서 6시간 인큐베이트했다. 반응 후, 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 이 RNA를 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 R5(2.32 nmol, 수율 7.3%)을 얻었다.
참고예 6
화학 합성에 의해 얻어진 R6-1, R6-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R6(11.1 nmol, 수율 37%)을 얻었다.
참고예 7
화학 합성에 의해 얻어진 R7-1, R7-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R7(3.1 nmol, 수율 10%)을 얻었다.
참고예 8
화학 합성에 의해 얻어진 R8-1, R8-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R8(2.6 nmol, 수율 9%)을 얻었다.
참고예 9
화학 합성에 의해 얻어진 R9-1, R9-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R9(5.9 nmol, 수율 20%)를 얻었다.
참고예 10
화학 합성에 의해 얻어진 R10-1, R10-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R10(2.1 nmol, 수율 9%)을 얻었다.
참고예 11
화학 합성에 의해 서열 49로서 얻어진 RNA 단편 R11-1(200 μM) 및 서열 50으로서 얻어진 5'-아미노 RNA 단편 R11-2(200 μM), 템플레이트 DNA1(200 μM)의 초순수 용액을 90℃에서 3분간 가열한 후, 30분간 이상 걸쳐 실온으로 되돌렸다. 이 용액에, 별도 조제한 축합제의 완충 용액(1M EDC-HCl/1M HOBt의 500 mM HEPES-NaOH(pH 8.5), 200 mM NaCl, 200 mM MgCl2)을 같은 체적 가하여 혼화함으로써 연결 반응을 시작했다. 반응액(핵산 농도: 100 μM, 0.5M EDC-HCl/0.5M HOBt, 250 mM HEPES-NaOH(pH 8.5), 100 mM NaCl, 100 mM MgCl2)은 온도 제어된 히트 블록(25℃) 상에 정치하게 했다(7시간). 반응 후, 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 이 RNA를 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 R11(1.2 nmol, 수율 15%)을 얻었다.
참고예 12
화학 합성에 의해 얻어진 R12-1(10 μM), R12-2(10 μM), 템플레이트 DNA1(10 μM)의 1x T4 DNA ligase 버퍼 용액(66 mM Tris-HCl(pH 7.6), 6.6 mM MgCl2, 10 mM DTT, 0.1 mM ATP)(다카라바이오)(계 2.1 mL)을 90℃에서 5분간 가열한 후, 실온까지 서냉했다. 이 용액에 60% PEG6000을 종농도 15%가 되도록 가했다. 이 용액에 T4 DNA ligase(다카라바이오)(350 units/μL)(135 μL)를 가하여 혼합한 후, 온도 제어된 히트 블록 상에 정치했다(25℃, 16시간). 반응액에 같은 체적의 클로로포름을 가하여 볼텍스에 의해 혼합, 원심 분리한 후, 상층을 취하여 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 이 RNA를 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 R12(1.4 nmol, 수율 27%)를 얻었다.
참고예 13
화학 합성에 의해 얻어진 R13-1, R13-2, 템플레이트 DNA1을 이용하여 참고예 12와 같은 식으로 RNA 연결 산물 R13(1.3 nmol, 수율 26%)을 얻었다.
참고예 14
화학 합성에 의해 얻어진 R14-1, R14-2, 템플레이트 DNA1을 이용하여 실시예 1과 같은 식으로 RNA 연결 산물 R14(9.4 nmol, 수율 31%)를 얻었다.
참고예 15
화학 합성에 의해 얻어진 R15-1, R15-2, 템플레이트 DNA1을 이용하여 실시예 1과 같은 식으로 RNA 연결 산물 R15(8.6 nmol, 수율 29%)를 얻었다.
참고예 16
화학 합성에 의해 얻어진 R16-1(10 μM), R16-2(10 μM), 템플릿 DNA1(10 μM)를 이용하여, 참고예 12와 같은 식으로 RNA 연결 산물 R16(1.1 nmol, 수율 37%)을 얻었다.
참고예 17
화학 합성에 의해 얻어진 R17-1(50 μM), R17-2(50 μM), 템플레이트 DNA5(100 μM)의 1x T4 DNA ligase 버퍼 용액(66 mM Tris-HCl(pH 7.6), 6.6 mM MgCl2, 10 mM DTT, 0.1 mM ATP)(다카라바이오)(계 2.1 mL)을 90℃에서 5분간 가열한 후, 실온까지 서냉했다. 이 용액에 50% PEG6000을 종농도 10%가 되도록 가했다. 이 용액에 T4 DNA ligase(다카라바이오)(350 units/μL)(135 μL)를 가하여 혼합한 후, 온도 제어된 히트 블록 상에 정치했다(25℃, 16시간). 반응액에 같은 체적의 클로로포름을 가하여 볼텍스에 의해 혼합, 원심 분리한 후, 상층을 취하여 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 이 RNA를 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 L84(P-O)(30 nmol, 수율 22%)을 얻었다.
L84(P-O)(50 μM, 20 μL), R17-3(160 μM, 12.5 μL), 템플레이트 DNA6(160 μM, 12.5 μL)의 1x T4 DNA ligase 버퍼 용액(66 mM Tris-HCl(pH 7.6), 6.6 mM MgCl2, 10 mM DTT, 0.1 mM ATP)(다카라바이오)(계 80 μL)을 90℃에서 5분간 가열한 후, 실온까지 서냉했다. 이 용액에 50% PEG6000을 종농도 10%가 되도록 가했다. 이 용액에 T4 DNA ligase(다카라바이오)(350 units/μL)(5 μL)를 가하여 혼합한 후, 온도 제어된 히트 블록 상에 정치했다(25℃, 16시간). 반응액에 같은 체적의 클로로포름을 가하여 볼텍스에 의해 혼합, 원심 분리한 후, 상층을 취하여 알코올 침전(0.3M 아세트산나트륨 수용액(pH 5.2)/70% 에탄올)에 의해서 RNA의 펠릿을 얻었다. 이 RNA를 7.5% 변성 폴리아크릴아미드 겔에 의해서 정제함으로써, RNA 연결 산물 R17(360 pmol, 수율 36%)을 얻었다.
참고예 18
화학 합성에 의해 얻어진 R18-1, R18-2, 템플레이트 DNA1을 이용하여, 실시예 1과 같은 식으로 RNA 연결 산물 R18(11.9 nmol, 수율 40%)을 얻었다.
시험예 1
(mRNA 샘플의 번역 반응)
번역 반응은 시판되는 번역 키트를 이용하여 제품 프로토콜에 따라서 행했다. 원핵세포계에 있어서의 번역 반응에 관해서는, 화합물 R1 및 화합물 R17을 기질 RNA로 하고, 시약으로서 PURExpress(등록상표)(New England BioLabs사)를 이용하여 행했다.
진핵세포계에 있어서의 번역 반응에 관해서는, 화합물 R2 및 화합물 R18을 기질 RNA로 하고, 시약으로서 Rabbit Reticulocyte Lysate System, Nuclease Treated(이하, RRL)(Promega사)를 이용하여 행했다.
(번역 반응에 있어서의 샘플의 조제)
각각의 키트의 장려 프로토콜에 따라서 조제했다. 기질이 되는 RNA 이외의 재료를 포함하는 반응액을 번역 반응액으로 했다. 원심 에바포레이터로 건고한 RNA 샘플을 포함하는 튜브에 대하여, 번역 반응액을 첨가·혼합한 후, 적절한 온도의 히트 블록 상에 둠으로써 번역 반응을 시작했다. 번역 산물은 항FLAG 항체를 이용한 웨스턴 블로팅에 의해서 검출했다. 일차 항체로서 항FLAG 항체(anti FLAG antibody)(F1804, Sigma사), 이차 항체로서 항마우스 IgG 항체(anti-mouse IgG-HRP)(A9044, Sigma사)를 사용했다.
(원핵세포계에 있어서의 번역 반응)
PURExpress(등록상표) 키트 부속의 Solution A(2 μL), Solution B(1.5 μL), RNase 저해제(Murine RNase Inhibitor, New England BioLabs)(0.1 μL), 초순수(1.4 μL)를 혼합한 것을 번역 반응액으로 했다. 이 용액을 RNA 샘플을 포함하는 튜브에 대하여 첨가·혼합함으로써 번역 반응을 행했다(37℃, 2시간).
(진핵세포계에 있어서의 번역 반응)
Rabbit Reticulocyte Lysate System 키트 부속의 Rabbit Reticulocyte Lysate(14.0 μL), Amino Acid Mixture-Met(0.20 μL), Amino Acid Mixture-Leu(0.20 μL), Murine RNase Inhibitor(New England BioLabs)(0.4 μL), 초순수(5.2 μL)를 혼합한 것을 번역 반응액으로 했다. 이 용액을 RNA 샘플을 포함하는 튜브에 대하여 첨가·혼합함으로써 번역 반응을 행했다(30℃, 2시간).
(번역 산물의 SDS-PAGE 분석)
SDS-PAGE에서는 불연속 완충액계를 이용했다. 사용한 겔의 조성을 이하에 나타낸다. 상층에는 농축 겔 영역(약 1.5 cm)으로서 5% 폴리아크릴아미드(아크릴아미드:비스아크릴아미드=29:1)(0.125M Tris-HCl(pH 6.8), 0.1% SDS), 하층에는 분리 겔 영역으로서 15% 폴리아크릴아미드(아크릴아미드:비스아크릴아미드=29:1)(0.375M Tris-HCl(pH 8.8), 0.1% SDS)를 사용하고, APS의 수용액과 TEMED를 중합제로서 첨가하여, 고형화(실온, 30분간)시킴으로써 겔을 제작했다. 번역 반응의 반응액을 2x SDS-PAGE용 로딩 버퍼(125 mM Tris-HCl(pH 6.8), 30(v/v)% 글리세롤, 4% 도데실황산나트륨(이하, SDS), 0.03% 브로모페놀 블루(이하, BPB))과 혼합한 후, 90℃에서 3분간 가열한 것을 SDS-PAGE 분석용 샘플로 했다. SDS-PAGE 분석용 샘플은 즉시 SDS-PAGE 겔로 영동(영동용 완충액으로서 25 mM Tris, 192 mM Glycine, 0.1% SDS를 사용)을 행했다.
(웨스턴 블로팅에 의한 번역 산물의 검출)
전기 영동 후, 겔 상의 번역 산물은 세미드라이법으로 웨스턴 블로팅용의 멤브레인(Immobilon(등록상표)-P)(IPVH00010, Millipore사)(멤브레인은 전처리로서 메탄올로 친수화한 후, 블로팅 버퍼(25 mM Tris, 192 mM Glycine, 20% MeOH)에 침지한 것을 사용)에 전사했다. 전사에 있어서는 정전류 조건(통전 시간: 1시간)을 사용하고, 멤브레인의 사이즈로부터 이용하는 전류치를 결정했다. 즉, 멤브레인 면적(cm2)x2가 되도록 전류치(mA)를 설정했다.
이후의 조작에서 사용하고 있는 5% ECL Prime의 TBS-T 용액은 Amersham ECL Prime(GE Healthcare)과 TBS-T(0.05M Tris-HCl(pH 7.4), 150 mM NaCl, 0.05% tween20)을 혼합함으로써 조제했다. 번역 산물을 전사한 멤브레인은 블로킹 처리(5% ECL Prime의 TBS-T 용액, 실온, 1시간 진탕)한 후, 일차 항체 처리(4,000배 희석, 0.5% ECL Prime의 TBS-T 용액, 4℃, 12시간 진탕), 세정(TBS-T, 5분간x 5회 진탕), 이차 항체 처리(50,000배 희석, 0.5% ECL Prime의 TBS-T 용액, 실온, 1시간 진탕), 세정(TBS-T, 5분간x5)을 행했다. 항체 처리 후, 멤브레인 상의 번역 산물은 화학 발광 시약(SuperSignal West Femto Maximum Sensitivity Substrate(Thermo Scientific사)을 이용하여, 제품 장려 프로토콜에 따라서 검출했다. 화학 발광 시약에 의한 처리 후, ChemiDoc(BIORAD사)를 이용하여 번역 산물의 시그널을 검출했다(검출 모드: 화학 발광, 노광 시간: 90-300초). 결과를 도 4 및 도 5에 나타낸다.
상기한 화합물 R1 및 화합물 R17을 기질로 한 PURExpress(등록상표)에 의한 번역 반응 산물의 웨스턴 블롯 해석 결과, 그리고 화합물 R2 및 화합물 R18을 기질로 한 RRL에 의한 번역 반응 산물의 웨스턴 블롯 해석에 의해, 비천연형의 연결부를 포함하는 화합물 R1 및 화합물 R2로부터의 번역 산물량과, 천연형의 화합물 R17 및 화합물 R18로부터의 번역 산물량이, 원핵생물계 및 진핵생물계에 있어서 손색없다는 것을 이해할 수 있다.
시험예 2
(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)
실시예 1∼3 및 참고예 6∼10, 14, 15, 18에서 얻어진 각 화합물에 관해서, Rabbit-Reticulocyte-Lysate-System-Nuclease-Treated 키트(프로메가사 제조, 카탈로그 번호 L4960)를 이용하여 진핵세포계에 있어서의 번역 활성을 평가했다. 우선, 각 화합물의 종농도가 0.3 μM가 되도록 THE RNA storage solution(서모피셔사이엔티픽사, 카탈로그 번호 AM7001)으로 희석한 각 mRNA 샘플을, 96 well PCR 플레이트(아즈원사 제조)에 2 μL씩 분주(分注)했다. 이어서, 1 반응 당 7.0 μL의 Reticulocyte Lysate, Nuclease Treated, 1 반응 당 0.1 μL의 Amino Acid Mixture Minus Leucine, 1 반응 당 0.1 μL의 Amino Acid Mixture Minus Methionine, 1 반응 당 0.4 μL의 RNase Inhibitor, Murine(뉴잉글랜드바이오라보사 제조, 카탈로그 번호 M0314) 및 1 반응 당 0.4 μL의 정제수를 혼합하여 마스터 믹스를 조제하고, mRNA 샘플을 첨가한 PCR 플레이트에 8 μL씩 분주하여, 첨가, 혼합한 후, 37℃에서 1시간 정치함으로써 번역 반응을 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은 이하에 기재한 샌드위치 ELISA법에 의해 검출했다. 우선, 6*His, His-Tag 항체(프로테인테크사, 카탈로그 번호 66005-1-Ig)를 0.1M 카보네이트 버퍼(pH 9.4)로 3 μg/mL로 희석하고, 96 Well ELISA용 플레이트(눙크사 제조)에 1 웰 당 50 μL씩 분주하여, 4℃에서 밤새 정치함으로써, 항체의 고정화를 행한 플레이트를 제작했다. 이어서, 플레이트를 정제수로 1배 농도로 희석한 Tris Buffered Saline with Tween 20(산타크루즈사, 카탈로그 번호 sc-24953)(이하, 세정 용액이라고 기재한다)로 세정한 후, 소혈청 알부민(와코쥰야쿠사, 카탈로그 번호 017-22231)을 종농도 3%가 되도록 희석한 세정 용액(이하, 블로킹 용액이라고 기재한다)을 1 웰 당 200 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 100배 희석한 번역 반응 용액을, 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 이때, 번역 산물 폴리펩티드 표품(스크럼사 제조)을 마찬가지로 블로킹 용액으로 각 농도로 희석하여 플레이트에 분주했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 10,000배로 희석한 Monoclonal ANTI-FLAG M2-Peroxidase(HRP) Ab produced in mouse(SIGMA사 제조, 카탈로그 항체 A8592-1 MG)를 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 1-Step Ultra TMB-ELISA(서모피셔사이엔티픽사 제조, 카탈로그 번호 34028)를 1 웰 당 50 μL씩 분주하여, 실온에서 수분 정치했다. 그 후, 0.5M 황산(와코쥰야쿠고교사 제조)을 1 웰 당 50 μL씩 분주하여 반응을 정지시킨 후, 흡광광도계(바이오라드사 제조)를 이용하여, 측정 파장 450 nm, 참조 파장 570 nm의 흡광도를 측정했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(μM) 및 당부 수식을 갖지 않는 R18을 1로 했을 때의 상대 번역 산물량을 표 9∼11에 기재했다.
Figure pct00033
Figure pct00034
Figure pct00035
표 9∼11로부터 분명한 것과 같이, 각 화합물은, 토끼 적혈구 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
실시예 1∼4 및 참고예 6, 10, 14, 15, 18에서 얻어진 각 화합물에 관해서, 1-Step Human Coupled IVT kit(서모피셔사이엔티픽사 제조, 카탈로그 번호 88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 우선, 각 화합물의 종농도가 0.3 μM가 되도록 THE RNA storage solution(서모피셔사이엔티픽사, 카탈로그 번호 AM7001)으로 희석한 각 화합물을, 96 well PCR 플레이트(아즈원사 제조)에 1 μL씩 분주했다. 이어서, 1 반응 당 5.0 μL의 Hela Lysate, 1 반응 당 1.0 μL의 Accessory Proteins, 1 반응 당 2.0 μL의 Reaction Mix, 1 반응 당 0.2 μL의 RNase Inhibitor, Murine(뉴잉글랜드바이오라보사 제조, 카탈로그 번호 M0314) 및 1 반응 당 0.8 μL의 정제수를 혼합하여 마스터 믹스를 조제하고, mRNA 샘플을 첨가한 PCR 플레이트에 9 μL씩 분주하여, 첨가, 혼합한 후, 37℃에서 45분간 정치함으로써 번역 반응을 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 2(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법에 의해, 번역 반응 용액을 블로킹 용액으로 20배 희석하여 플레이트에 첨가하는 것 이외에는 완전히 동일한 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(μM) 및 당부 수식을 갖지 않는 화합물 R18을 1로 했을 때의 상대 번역 산물량을 표 12∼14에 기재했다.
Figure pct00036
Figure pct00037
Figure pct00038
표 12∼14로부터 분명한 것과 같이, 각 화합물은, Hela 세포 라이세이트에 첨가 후, 인간세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
실시예 2, 3 및 참고예 6, 15에서 얻어진 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro에서의 번역 활성을 평가했다. 우선, 10% 소태아 혈청을 포함하는 RPMI 배지(나카라이테스크사 제조)로 현탁한 Hela 세포를 1 웰 당 세포수 10,000 cells/100 μL가 되도록 96 웰 접착 세포용 배양 플레이트에 파종하여, 37℃, 5% CO2 조건 하에서 밤새 배양했다. 밤새 배양 후의 세포로부터 배양 상청을 제거하여, 1 웰 당 40 μL의 10% 소태아 혈청을 포함하는 RPMI 배지를 첨가한 후, 각 화합물의 종농도가 0.3 μM가 되도록 각 화합물과 Lipofectamin Messenger MAX Transfection Reagent(서모피셔사이엔티픽사 제조, 카탈로그 번호: LMRNA008)를 옵티멤(서모피셔사이엔티픽사 제조, 카탈로그 번호: 31985-070)으로 희석하여 혼합하고, 혼합액을 1 웰 당 10 μL가 되도록 각각의 배양 플레이트에 첨가하여, 37℃, 5% CO2 조건 하에서 6시간 배양했다. 6시간 배양 후의 세포로부터 배양 상청을 제거하고, 빙냉한 D-PBS(-)(나카라이테스크사 제조)로 한 번 세정한 후, 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 NP-40(인비트로젠사, FNN0021)을 1 웰 당 20 μL 가하고, 5분간 격하게 침투하여 세포를 용해했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 2(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법에 의해, 세포 용해액을 블로킹 용액으로 10배 희석하여 플레이트에 첨가하는 것 이외에는 완전히 동일한 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 당부 수식을 갖지 않는 화합물 R6을 1로 했을 때의 상대 번역 산물량을 표 15에 기재했다.
Figure pct00039
표 15로부터 분명한 것과 같이, 각 화합물은, Hela 세포에 첨가 후, 유전자 서열로 코드된 폴리펩티드를 산생했다.
시험예 3(각 화합물의 포스포디에스테라아제 I에 의한 안정성 시험)
실시예 1 및 참고예 10, 18에서 제작한 각 화합물(RNA 용액)을 이용하여, 이하의 방법으로 포스포디에스테라아제 I(SVPD)에 대한 안정성을 평가했다. MQ수 10 μL, 5 μM RNA 용액 4 μL, 5x 반응 버퍼(Tris-HCl pH 8.00. 1 M, NaCl 0.5M, MgCl2 0.075M) 4 μL, 5.5 U/μL의 SVPD(warthington, 카탈로그 번호 3926) 4 μL를 첨가하여 37℃에서 인큐베이트했다. 반응 시작 후, 15, 30, 60분의 타이밍에 6 μL 씩 샘플링했다.
(PAGE에 의한 RNA 분해 평가)
5% dPAGE(5% 아크릴아미드, 7M 우레아, small gel, 8 cmx8cm)에 샘플링한 검체 전량을 어플라이하여, 300 V constant, 18 min 영동했다. SYBR Green II로 염색하여 촬영 및 정량을 행했다. 각 시료 중의 각 화합물의 잔존량을 효소 미반응(0분)에 대한 상대 잔존량으로서 산출한 것을 표 16에 기재했다.
Figure pct00040
표 16으로부터 분명한 것과 같이, 당부 수식을 갖는 화합물은 당부 수식을 갖지 않는 화합물 R18과 비교하여, 포스포디에스테라아제 I에 대한 내성이 향상되었다.
시험예 4
(mRNA 샘플의 포스포디에스테라아제 I에 의한 안정성 시험)
실시예 1∼4 및 참고예 6, 14, 15, 18에서 얻어진 각 화합물에 관해서, 포스포디에스테라아제 I(warthington, 카탈로그 번호 3926)을 이용하여 효소 안정성을 평가했다. 우선, 포스포디에스테라아제 I을 SVPD 스톡 용액(110 mM Tris-HCl(닛폰진, 카탈로그 번호 314-90401), 110 mM NaCl(Ambion, 카탈로그 번호 AM9759), 15 mM MgCl2(나카라이테스크, 카탈로그 번호 20942-34))로 종농도가 55 U/mL가 되도록 조제하고, 이것을 또한 5×SVPD 반응 버퍼(100 mM Tris-HCl(Ambion, 카탈로그 번호 AM9855G), 500 mM NaCl, 75 mM MgCl2)로 10배 희석하여 5.5 U/mL SVPD 효소 용액을 조제했다. 각 화합물은 종농도가 5 μM가 되도록 THE RNA storage solution(서모피셔사이엔티픽사, 카탈로그 번호 AM7001)으로 희석했다.
96 well PCR 플레이트에 증류수 30 μL, 5 μM mRNA 12 μL, 5×SVPD 반응 버퍼 12 μL를 순차 가하여 효소 반응 프리믹스 용액을 제작했다. 효소 미반응(0 min)용으로서 별도의 96 well PCR 플레이트에 효소 반응 프리믹스 용액을 9 μL 분주하고, SVPD 용액 1 μL와 25 mM EDTA(Ambion, 카탈로그 번호 AM9260G) 2.5 μL의 혼합 용액 3.5 μL를 첨가하여 -30℃에서 보존했다. 효소 반응용으로서, 또 별도의 96 well PCR 플레이트에 효소 반응 프리믹스 용액을 40.5 μL 분주하고, 5.5 U/mL SVPD 효소 용액을 4.5 μL 첨가하여 잘 혼합했다. 이것을 10 μL씩 새로운 96 well PCR 플레이트 4장에 분주하여 각 플레이트 소정 시간(15 min, 30 min, 60 min) 37℃에서 반응시킨 후, 25 mM EDTA를 2.5 μL 첨가하여 측정까지 -30℃에서 보존했다.
효소 반응 후의 반응 용액 중의 잔존 mRNA량은 이하에 기재한 RT-qPCR법에 의해 검출했다. 우선, 검량선에는 화합물 E4를 사용하고, THE RNA storage solution에 의해서 4 μM부터 4배 희석으로 11점 농도를 취하여, 희석 계열을 제작했다. 검량선 및 효소 반응 후의 샘플 2.5 μL는 Ribonuclease Inhibitor(다카라바이오, 카탈로그 번호 2311B)를 종농도 0.2 U/mL로 가한 증류수를 이용하여 1071배 희석했다. 이 희석한 시료 5 μL 및 2 μM RT primer(시그마알드리치사) 2 μL를 이용하여 iScript Select cDNA Synthesis kit(BIO-RAD, 카탈로그 번호 1708897)에 의해 역전사 산물 cDNA를 제작했다. 반응 온도는 25℃ 5 min→42℃ 30 min→85℃ 5 min로 실시했다. cDNA 2 μL, TaqMan Gene Expression Master Mix 10 μL, Fw primer(시그마알드리치사) 0.28 μL, Rv primer(시그마알드리치사) 0.33 μL, TaqMan MGB Probe(서모피셔사이엔티픽사, 카탈로그 번호 4316033) 0.38 μL 및 증류수 7. 01 μL를 혼합하여, qPCR 측정을 행했다. 기기는 Quantstudio 12K Flex(Applied Biosystems)를 사용했다. 또한, 사용한 Primer 및 Taqman MGB Probe의 DNA 서열은 이하와 같다. 측정 결과, 표품의 CT 값을 바탕으로 검량선을 이용하여, 각 시료 중의 각 화합물의 농도를 정량하고, 효소 미반응(0분)에 대한 상대 잔존량으로서 산출한 것을, 표 17에 기재했다.
RT primer: 5'-TCAGTGGTGGTGGTGGTGGTGTTTG-3' (서열 번호 75)
Fw primer: 5'-ATCTTGTCGTCGTCGTCCTT-3' (서열 번호 76)
Rv primer: 5'-GAATACAAGCTACTTGTTCTTTT-3' (서열 번호 77)
Taqman MGB Probe: 5'-CAGCCACCATG-3' (서열 번호 78)
Figure pct00041
표 17로부터 분명한 것과 같이, 당부 수식을 갖는 E1, E4, R14 및 R15는 당부 수식을 갖지 않는 화합물 R18과 비교하여 포스포디에스테라아제 I에 대한 내성이 향상되었다.
마찬가지로, 당부 수식을 갖는 E2 및 E3은 당부 수식을 갖지 않는 화합물 R6과 비교하여 포스포디에스테라아제 I에 대한 내성이 향상되었다.
시험예 5
(진핵세포계에 있어서의 번역 반응)
참고예 3∼5, 11∼13, 16, 18에서 얻어진 각 화합물(RNA)에 관해서 이하의 방법으로 진핵세포계에 있어서의 번역 반응을 평가했다. Rabbit-Reticulocyte-Lysate-System_-Nuclease-Treated(Promega L4960)에 포함되는 용액, RNase inhibitor Murine(New England Biolab, M0314S) 및 RNA를 이하의 조성으로 혼합했다. RRL 7.0 μL, 1 mM AA-Leu 0.1 μL, 1 mM AA-Met 0.1 μL, Rnase Inhibitor 0.4 μL, RNA 5 μM 2.0 μL, MQ 0.4 μL. 이 용액을 37℃에서 1시간 인큐베이트했다. 인큐베이트 후의 용액 5 μL를 분취하여 블로킹 버퍼(3% BSA/TBST) 495 μL로 100배 희석했다. 희석 번역액 100 μL를 ELISA에 사용했다.
(샌드위치 ELISA에 의한 번역 산물의 검출)
96 well 플레이트에 100 μL/well의 Anti-Histag 용액(프로테인테크사, 카탈로그 번호 66005-1-Ig)(3 μg/mL in 0.1M 카보네이트 버퍼 pH 9.4)를 첨가했다. 파라필름으로 덮어, 4℃에서 12시간 인큐베이트했다. 플레이트 내의 용액을 폐기하고, 200 μL/well의 TBST로 3회 세정했다. 200 μL/well의 블로킹 버퍼(3% BSA/TBST)를 첨가하여 실온에서 1시간 인큐베이트했다. 플레이트 내의 용액을 폐기하고, 200 μL/well의 TBST로 3회 세정했다. 100 μL/well로 번역 반응 용액을 첨가하여 실온에서 1시간 인큐베이트했다. 플레이트 내의 번역 반응 용액을 폐기하고, 200 μL/well의 TBST로 3회 세정했다. 100 μL/well의 Anti-Flag 용액(Cell Signaling Tecnorogy사, 카탈로그 번호 2368)(1:1000 in bloking buffer)을 첨가했다. 건조 농축하지 않도록 파라필름으로 덮어, 밤새 4℃에서 인큐베이트했다. 플레이트 내의 용액을 폐기하고, 200 μL/well의 TBST로 3회 세정했다. 100 μL/well의 Anti-rabbit IgG HRP 용액(시그마알드리치사)(1:10000 in bloking buffer)를 첨가하여, 실온에서 1시간 인큐베이트했다. 플레이트 내의 용액을 폐기하고, 200 μL/well의 TBST로 4회 세정했다. 100 μL/well의 TMB substrate 용액을 첨가하여, 실온에서 5분 인큐베이트했다. TBM subustrate 용액을 첨가해 놓은 well에 100 μL/well의 2M H2SO4 용액을 첨가했다. 플레이트 리더(Mithras LB940(Berthold))를 사용하여, 450 nm의 흡광도를 측정하여, 번역 효율을 평가했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량하여, 각 번역 반응 용액 중의 번역 산물 농도(μM) 및 당부 수식을 갖지 않는 R18을 1로 했을 때의 상대 번역 산물량을 표 18∼20에 기재했다.
Figure pct00042
Figure pct00043
Figure pct00044
표 18∼20로부터 분명한 것과 같이, 각 화합물은, 토끼 적혈구 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
이하에, 실시예 화합물(폴리뉴클레오티드)의 서열 정보를 나타낸다.
이하, 표에서의 각 뉴클레오티드 N(대문자)은 RNA를, 각 뉴클레오티드 n(소문자)은 DNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, N(L)은 LNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를 나타낸다. Am6은 염기부가 N6-메틸아데닌인 것, Ae6은 염기부가 N6-에틸아데닌인 것을 나타낸다. p는 3' 또는 5' 말단이 인산화되어 있음을 나타낸다. ^는 당부 사이를 잇는 인산기가 포스포로티오에이트임을 나타낸다. N(B)는 하기에 나타내는 당부를 포함하는 2',4'-BNANC(Me)를 나타낸다.
Figure pct00045
BDBD는 이하의 구조를 갖는 인공 댕글링 엔드(Dangling end)를 나타낸다.
Figure pct00046
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시험예 6
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 나타낸 각 화합물에 관해서, 1-Step Human Coupled IVT Kit(서모피셔사이엔티픽사 제조, 카탈로그 번호88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)와 같은 조건으로 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은 이하에 기재한 샌드위치 ELISA법에 의해 검출했다. 우선, 6*His, His-Tag 항체(프로테인테크사, 카탈로그 번호 66005-1-Ig)를 0.1M 카보네이트 버퍼(pH 9.4)로 3 μg/mL로 희석하고, 96 Well ELISA용 플레이트(눙크사 제조)에 1 웰 당 50 μL씩 분주하여, 4℃에서 밤새 정치함으로써, 항체의 고정화를 행한 플레이트를 제작했다. 이어서, 플레이트를 정제수로 1배 농도로 희석한 Tris Buffered Saline with Tween 20(산타크루즈사, 카탈로그 번호 sc-24953)(이하, 세정 용액이라고 기재한다)로 세정한 후, 소혈청 알부민(와코쥰야쿠사, 카탈로그 번호 017-22231)을 종농도 3%가 되도록 희석한 세정 용액(이하, 블로킹 용액이라고 기재한다)을 1 웰 당 200 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 희석한 번역 반응 용액을 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 이때, 서열 번호 539에 나타내는 번역 산물 폴리펩티드 표품(코스모바이오사 제조)을 마찬가지로 블로킹 용액으로 각 농도로 희석하여 플레이트에 분주했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 10,000배로 희석한 Monoclonal ANTI-FLAG M2-Peroxidase(HRP) Ab produced in mouse(SIGMA사 제조, 카탈로그 항체 A8592-1MG)를 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 1-Step Ultra TMB-ELISA(서모피셔사이엔티픽사 제조, 카탈로그 번호 34028)를 1 웰 당 50 μL씩 분주하여, 실온에서 수분 정치했다. 그 후, 0.5M 황산(와코쥰야쿠고교사 제조)을 1 웰 당 50 μL씩 분주하여 반응을 정지시킨 후, 흡광광도계(바이오라드사 제조)를 이용하여, 측정 파장 450 nm, 참조 파장 570 nm의 흡광도를 측정했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 당부 수식을 갖지 않는 R18을 1로 했을 때의 상대 번역 산물량을 하기 표에 기재했다.
번역 산물 폴리펩티드 표품: NH2-MDYKDDDDKIIDYKDDDDKGGDYKDDDDKHHHHHH-COOH (서열 번호 539)
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상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 화합물은, Hela 세포 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
시험예 7
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro 에서의 번역 활성을 평가했다. 우선, 10% 소태아 혈청을 포함하는 RPMI 배지(나카라이테스크사 제조)로 현탁한 Hela 세포를 1 웰 당 세포수 10,000 cells/100 μL가 되도록 96 웰 접착 세포용 배양 플레이트에 파종하여, 37℃, 5% CO2 조건 하에서 밤새 배양했다. 밤새 배양 후의 세포로부터 배양 상청을 제거하여, 1 웰 당 40 μL의 10% 소태아 혈청을 포함하는 RPMI 배지를 첨가한 후, 각 화합물의 종농도가 0.1 μM가 되도록 각 화합물과 종농도 0.3%의 Lipofectamin Messenger MAX Transfection Reagent(서모피셔사이엔티픽사 제조, 카탈로그 번호: LMRNA008)를 옵티멤(서모피셔사이엔티픽사 제조, 카탈로그 번호: 31985-070)으로 희석하여 혼합하고, 혼합액을 1 웰 당 10 μL가 되도록 각각의 배양 플레이트에 첨가하여, 37℃, 5% CO2 조건 하에서 5시간 배양했다. 5시간 배양 후의 세포로부터 배양 상청을 제거하고, 빙냉한 D-PBS(-)(나카라이테스크사 제조)로 한 번 세정한 후, 표 103에 관해서는 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 NP-40(인비트로젠사, FNN0021)을 1 웰 당 20 μL 가하고, 30초간 격하게 침투하여 세포를 용해했다. 표 104 및 표 105에 관해서는 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 iScript RT-qPCR Sample Preparation Reagent(바이오라드사, 1708898)를 1 웰 당 20 μL 가하고, 30초간 격하게 침투하여 세포를 용해했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법과 같은 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM)를 표에 기재했다.
Figure pct00129
Figure pct00130
Figure pct00131
Figure pct00132
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA는, Hela 세포에 첨가 후, 유전자 서열로 코드된 폴리펩티드를 산생하고, 그 활성은 당부 수식을 갖지 않는 mRNA와 동등 이상이었다.
시험예 8
(mRNA 샘플의 마우스 초대 간세포를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, 마우스 초대 간세포(서모피셔사이엔티픽사 제조, 카탈로그 번호 MSCP10)를 이용하여 in vitro에서의 번역 활성을 평가했다. 우선, Primary Hepatocyte Thawing and Plating Supplements(서모피셔사이엔티픽사 제조, 카탈로그 번호 CM3000)를 포함하는 William's E Medium, no phenol red(서모피셔사이엔티픽사 제조, 카탈로그 번호 A1217601)에 현탁시킨 마우스 초대 간세포를 1 웰 당 세포수 10,000 cells/100 μL가 되도록 96 웰 콜라겐 I 코트 배양 플레이트(코닝사 제조, 카탈로그 번호: 356407)에 파종하여, 37℃, 5% CO2 조건 하에서 5시간 배양했다. 배양 후의 세포로부터 배양 상청을 제거하여, Primary Hepatocyte Maintenance Supplements(서모피셔사이엔티픽사 제조, 카탈로그 번호 CM4000)를 포함하는 William's E Medium, no phenol red를 1 웰 당 100 μL가 되도록 첨가하고, 또한 37℃, 5% CO2 조건 하에서 5시간 배양했다. 밤새 배양 후의 세포로부터 배양 상청을 제거하고, Primary Hepatocyte Maintenance Supplements를 포함하는 William's E Medium, no phenol red를 1 웰 당 40 μL 첨가한 후, 각 화합물의 종농도가 0.1 μM가 되도록 각 화합물과 종농도 0.3%의 Lipofectamin Messenger MAX Transfection Reagent를 옵티멤으로 희석하여 혼합하고, 혼합액을 1 웰 당 10 μL가 되도록 각각의 배양 플레이트에 첨가하여, 37℃, 5% CO2 조건 하에서 5시간 배양했다. 5시간 배양 후의 세포로부터 배양 상청을 제거하고, Primary Hepatocyte Maintenance Supplements를 포함하는 William's E Medium, no phenol red를 1 웰 당 100 μL 첨가한 후, 또 37℃, 5% CO2 조건 하에서 1시간 배양했다. 1시간 배양 후의 세포로부터 배양 상청을 제거하고, 빙냉한 D-PBS(-)(나카라이테스크사 제조)로 한 번 세정한 후, 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 NP-40(인비트로젠사, FNN0021)을 1 웰 당 20 μL 가하고, 30초간 격하게 침투하여 세포를 용해했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법과 같은 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM)를 이하의 표에 기재했다.
Figure pct00133
Figure pct00134
Figure pct00135
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA는, 마우스 간세포에 첨가 후, 유전자 서열로 코드된 폴리펩티드를 산생하고, 그 활성은 당부 수식을 갖지 않는 mRNA와 동등 이상이었다.
시험예 9
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro 에서의 번역 활성을 평가했다.
우선, 각 화합물을 20 μM가 되도록 THE RNA Storage Solution(서모피셔사이엔티픽사 제조, 카탈로그 번호 AM7000)으로 희석했다. Hela 세포주는 SE Cell Line 96-well Nucleofector kit(Lonza사 제조, 카탈로그 번호 V4SC-1096) 부속의 SE Cell Line Nucleofector Solution 및 Supplement 1의 혼합액으로 200,000 cells/19 μL가 되도록 현탁. 조제한 핵산 용액과 Hela 세포 현탁액을 체적비 1:19로 혼합한 후, Nucleofector(tm) 96-well Shuttl 시스템(Lonza사 제조)을 이용하여, 펄스 조건 FF-137로 엘렉트로포레이션을 실시했다. 엘렉트로포레이션 10분 후의 세포를 10% 소태아 혈청을 포함하는 RPMI 배지(나카라이테스크사 제조)에 현탁하고, 1 웰 당 세포수 50,000 cells/145 μL가 되도록 96 웰 접착 세포용 배양 플레이트에 파종하여, 37℃, 5% CO2 조건 하에서 3시간 배양했다. 3시간 배양 후의 세포로부터 배양 상청을 제거하고, 빙냉한 D-PBS(-)(나카라이테스크사 제조)로 한 번 세정한 후, 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 iScript RT-qPCR Sample Preparation Reagent(바이오라드사, 1708898)를 1 웰 당 20 μL 가하고, 30초간 격하게 침투하여 세포를 용해했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법과 같은 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM)를 이하의 표에 기재했다.
Figure pct00136
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 mRNA는 Hela 세포에 엘렉트로포레이션 후, 유전자 서열로 코드된 폴리펩티드를 산생하고, 그 활성은 번역 영역에 당부 수식을 갖지 않는 mRNA와 비교하여 우수했다.
시험예 10
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, 1-Step Human Coupled IVT Kit(서모피셔사이엔티픽사 제조, 카탈로그 번호 88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)와 같은 방법으로, 핵산 농도가 종농도 1 μM가 되는 조건으로 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 번역 산물 폴리펩티드 표품으로서 서열 번호 540에 나타내는 펩티드(코스모바이오사 제조)를 이용하는 것 이외에는 같은 방법으로 실시했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 번역 영역에 당부 수식을 갖지 않는 표에서의 각 화합물을 1로 했을 때의 상대 번역 산물량을 이하의 표에 기재했다.
번역 산물 폴리펩티드 표품: NH2-MDYKDDDDKGGHHHHHH-COOH (서열 번호 540)
Figure pct00137
Figure pct00138
Figure pct00139
Figure pct00140
Figure pct00141
Figure pct00142
Figure pct00143
Figure pct00144
Figure pct00145
Figure pct00146
Figure pct00147
Figure pct00148
상기 시험 결과로부터 분명한 것과 같이, 각 mRNA 화합물은, Hela 세포 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
시험예 11
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro 에서의 번역 활성을 평가했다. 세포주에의 각 화합물의 트랜스펙션과 세포 용해액의 조제는 시험예 7(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)과 같은 방법으로 실시하고, 세포의 용해는 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 iScript RT-qPCR Sample Preparation Reagent를 이용하여 실시했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 10(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법과 같은 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM)를 이하의 표에 기재했다.
Figure pct00149
시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA는, Hela 세포에 첨가 후, 유전자 서열로 코드된 폴리펩티드를 산생하고, 그 활성은 번역 영역에 당부 수식을 갖지 않는 mRNA와 비교하여 우수했다.
시험예 12
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, 1-Step Human Coupled IVT Kit(서모피셔사이엔티픽사 제조, 카탈로그 번호 88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)와 같은 조건으로, 핵산 농도가 종농도 1 μM가 되는 조건으로 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 번역 산물 폴리펩티드 표품으로서 서열 번호 541에 나타내는 펩티드(코스모바이오사 제조)를 이용하는 것 이외에는 같은 방법으로 실시했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 번역 영역에 당부 수식을 갖지 않는 E82를 1로 했을 때의 상대 번역 산물량을 표 124∼133에 기재했다.
번역 산물 폴리펩티드 표품: NH2-MDYKDDDDKGGDYKDDDDKHHHHHH-COOH (서열 번호 541)
Figure pct00150
Figure pct00151
Figure pct00152
Figure pct00153
Figure pct00154
Figure pct00155
Figure pct00156
Figure pct00157
Figure pct00158
Figure pct00159
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, Hela 세포 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 폴리펩티드를 산생했다.
시험예 13
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro 에서의 번역 활성을 평가했다. 세포주에의 각 화합물의 트랜스펙션과 세포 용해액의 조제는 시험예 7(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)과 같은 방법으로 실시하고, 세포의 용해는 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 iScript RT-qPCR Sample Preparation Reagent를 이용하여 실시했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 12(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법과 같은 방법으로 실시했다. 측정 결과, 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM)을 이하의 표에 기재했다.
Figure pct00160
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA는, Hela 세포에 첨가 후, 유전자 서열로 코드된 폴리펩티드를 산생하고, 그 활성은 당부 수식을 갖지 않는 mRNA와 비교하여 우수했다.
시험예 14
(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Rabbit-Reticulocyte-Lysate-System-Nuclease-Treated 키트를 이용하여 진핵세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)와 같은 방법으로 실시했다.
번역 반응 후의 반응 용액 중의 번역 산물은 이하에 기재한 샌드위치 ELISA법에 의해 검출했다. 우선, Anti-Human EGF 항체(Peprotech사 제조, 카탈로그 번호 500-P45)를 0.1M 카보네이트 버퍼(pH 9.4)로 3 μg/mL로 희석하고, 96 Well ELISA 용 플레이트(눙크사 제조)에 1 웰 당 50 μL씩 분주하여, 4℃에서 밤새 정치함으로써, 항체의 고정화를 행한 플레이트를 제작했다. 이어서, 플레이트를 정제수로 1배 농도로 희석한 Tris Buffered Saline with Tween 20(이하, 세정 용액이라고 기재한다)로 세정한 후, 소혈청 알부민을 종농도 3%가 되도록 희석한 세정 용액(이하, 블로킹 용액이라고 기재한다)을 1 웰 당 200 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 100배 희석한 번역 반응 용액을 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 블로킹 용액으로 10,000배로 희석한 Monoclonal ANTI-FLAG M2-Peroxidase(HRP) Ab produced in mouse(SIGMA사 제조, 카탈로그 항체 A8592-1MG)를 1 웰 당 50 μL씩 분주하여, 실온에서 1시간 정치했다. 플레이트를 세정 용액으로 세정한 후, 1-Step Ultra TMB-ELISA(서모피셔사이엔티픽사 제조, 카탈로그 번호 34028)를 1 웰 당 50 μL씩 분주하여, 실온에서 수분 정치했다. 그 후, 0.5M 황산(와코쥰야쿠고교사 제조)을 1 웰 당 50 μL씩 분주하고, 반응을 정지시킨 후, 흡광광도계(바이오라드사 제조)를 이용하여, 측정 파장 450 nm, 참조 파장 570 nm의 흡광도를 측정했다. 각 번역 반응 용액을 측정했을 때의 흡광도(측정 파장의 흡광도로부터 참조 파장의 흡광도를 뺀 것)를 이하의 표에 기재했다.
Figure pct00161
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, 토끼 적혈구 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 FLAG-EGF 펩티드를 산생했다.
시험예 15
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, 1-Step Human Coupled IVT Kit(서모피셔사이엔티픽사 제조, 카탈로그 번호 88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)와 같은 조건으로, 핵산 농도가 종농도 1 μM가 되는 조건으로 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 14(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 번역 반응액을 블로킹 용액으로 20배로 희석하는 것 이외에는 같은 방법으로 실시했다. 각 번역 반응 용액을 측정했을 때의 흡광도(측정 파장의 흡광도로부터 참조 파장의 흡광도를 뺀 것)를 이하의 표에 기재했다.
Figure pct00162
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, Hela 세포 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 FLAG-EGF 펩티드를 산생했다.
시험예 16
(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Hela 세포주를 이용하여 in vitro 에서의 번역 활성을 평가했다. 세포주에의 각 화합물의 트랜스펙션과 세포 용해액의 조제는 시험예 7(mRNA 샘플의 Hela 세포주를 이용한 in vitro 번역 반응 시험)과 같은 방법으로 실시하고, 세포의 용해는 2%의 프로테아제 저해제 칵테일(동물세포 추출물용)을 포함하는 iScript RT-qPCR Sample Preparation Reagent를 이용하여 실시했다.
얻어진 세포 용해액 중의 번역 산물은, 시험예 14(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 세포 용해액을 블로킹 용액으로 30배로 희석하는 것 이외에는 같은 방법으로 실시했다. 각 세포 용해액을 측정했을 때의 흡광도(측정 파장의 흡광도로부터 참조 파장의 흡광도를 뺀 것)를 이하의 표에 기재했다.
Figure pct00163
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, Hela 세포에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 FLAG-EGF 펩티드를 산생하고, 그 활성은 당부 수식을 갖지 않는 mRNA와 비교하여 우수했다.
시험예 17
(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, Rabbit-Reticulocyte-Lysate-System-Nuclease-Treated 키트를 이용하여 진핵세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)와 같은 방법으로 실시했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 6(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 번역 산물 폴리펩티드 표품으로서 서열 번호 542에 나타내는 펩티드(코스모바이오사 제조)를 이용하는 것 이외에는 같은 방법으로 실시했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 번역 영역에 당부 수식을 갖지 않는 E6을 1로 했을 때의 상대 번역 산물량을 이하의 표에 기재했다.
번역 산물 폴리펩티드 표품: NH2-MDYKDDDDKIIDYKDDDDKGGDYKDDDDKSIINFEKLHHHHHH-COOH (서열 번호 542)
Figure pct00164
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, 토끼 적혈구 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 펩티드를 산생했다.
시험예 18
(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)
표 21∼56에 기재한 각 화합물에 관해서, 1-Step Human Coupled IVT Kit(서모피셔사이엔티픽사 제조, 카탈로그 번호 88882)를 이용하여 인간세포계에 있어서의 번역 활성을 평가했다. 번역 반응은 시험예 2(mRNA 샘플의 Hela 세포주 라이세이트를 이용한 번역 반응 시험)와 같은 조건으로, 핵산 농도가 종농도 1 μM가 되는 조건으로 행했다.
번역 반응 후의 반응 용액 중의 번역 산물은, 시험예 17(진핵세포계에 있어서의 번역 반응; 토끼 적혈구 라이세이트를 이용한 번역 반응 시험)에 기재한 샌드위치 ELISA법의 방법에 따라서, 번역 반응액을 블로킹 용액으로 10배로 희석하는 것 이외에는 같은 방법으로 실시했다. 폴리펩티드 표품의 흡광도를 바탕으로 작성한 검량선을 이용하여 정량한, 각 번역 반응 용액 중의 번역 산물 농도(nM) 및 번역 영역에 당부 수식을 갖지 않는 E6을 1로 했을 때의 상대 번역 산물량을 이하의 표에 기재했다.
Figure pct00165
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 각 mRNA 화합물은, Hela 세포 라이세이트에 첨가 후, 진핵세포의 번역계에 의해서 유전자 서열로 코드된 펩티드를 산생했다.
시험예 19
(mRNA 샘플의 혈청 중 안정성 시험)
표 21∼56에 기재한 각 화합물에 관해서, 시판 마우스 혈청(다카라바이오, 카탈로그 번호 2311B, lot 번호 AJ10759A)을 이용하여 혈청 중 핵산 안정성을 평가했다. 우선, 마우스 혈청을 Ultra Pure(tm) DNase/RNase-Free Distilled Water(DW)(Invitrogen, 카탈로그 번호 10977-015)로 15배 희석하여, 희석 혈청 용액을 조제했다. 각 화합물은 종농도가 5 μM가 되도록 THE RNA storage solution(서모피셔사이엔티픽사, 카탈로그 번호 AM7001)로 희석했다.
효소 미반응(0 min)용으로서 별도의 96 well PCR 플레이트에 희석 혈청 용액 8 μL, 6 U/μL Ribonuclease Inhibitor(다카라바이오, 카탈로그 번호 2311B) 2.5 μL의 혼합 용액 10.5 μL 및 5 μM mRNA 2 μL를 첨가하여 -30℃에서 보존했다. 효소 반응용으로서, 또 별도의 96 well PCR 플레이트에 희석 혈청 용액 28 μL와 5 μM mRNA7 μL를 첨가하여 잘 혼합했다. 이것을 10 μL씩 새로운 96 well PCR 플레이트 4장에 분주하여, 각 플레이트 소정 시간(5 min, 15 min, 30 min, 60 min) 37℃에서 반응시킨 후, 6 U/μL Rnase inhibitor를 2.5 μL 첨가하여 측정까지 -30℃에서 보존했다.
효소 반응 후의 반응 용액 중의 잔존 mRNA량은 이하에 기재한 RT-qPCR법에 의해 검출했다. 우선, 검량선에는 표 140에 관해서는 화합물 R18을, 표 141에 관해서는 각각 대응하는 화합물을 사용하고, THE RNA storage solution에 의해서 4 μM부터 4배 희석으로 11점 농도를 취하여, 희석 계열을 제작했다. 검량선 및 효소 반응 후의 샘플 2.5 μL는 Ribonuclease Inhibitor를 종농도 0.2 U/mL로 가한 DW를 이용하여 1071배 희석했다. 이 희석한 시료 5 μL 및 2 μM RT primer(시그마알드리치사) 1 μL를 이용하여 TaqMan Micro RNART kit(서모피셔사이엔티픽, 카탈로그 번호 4366597)에 의해 역전사 산물 cDNA를 제작했다. 반응 온도는 16℃ 30 min→42℃ 30 min→85℃ 5 min으로 실시했다. cDNA 5 μL, TaqMan Gene Expression Master Mix 10 μL, Fw primer(시그마알드리치사) 0.28 μL, Rv primer(시그마알드리치사) 0.33 μL, TaqMan MGB Probe(서모피셔사이엔티픽사, 카탈로그 번호 4316033) 0.38 μL 및 증류수 4. 01 μL를 혼합하여, qPCR 측정을 행했다. 기기는 Quantstudio 12K Flex(Applied Biosystems)를 사용했다. 또한, 사용한 Primer 및 Taqman MGB Probe의 DNA 서열은 이하와 같다. 측정 결과, 표품의 CT 값을 바탕으로 검량선을 이용하여, 각 시료 중의 각 화합물의 농도를 정량하고, 효소미 반응(0분)에 대한 상대 잔존량으로서 산출한 것을 이하의 표에 기재했다.
RT primer: 5'-TCAGTGGTGGTGGTGGTGGTGTTTG-3' (서열 번호 75)
Fw primer: 5'-ATCTTGTCGTCGTCGTCCTT-3' (서열 번호 76)
Rv primer: 5'-GAATACAAGCTACTTGTTCTTTT-3' (서열 번호 77)
Taqman MGB Probe: 5'-CAGCCACCATG-3' (서열 번호 78)
Figure pct00166
Figure pct00167
상기 시험 결과로부터 분명한 것과 같이, 당부 수식을 갖는 mRNA는 당부 수식을 갖지 않는 mRNA와 비교하여 혈청 내에서의 분해 내성이 향상되었다.
시험예 20
(VEGF 단백질의 번역 반응)
<비교 화합물 RN의 합성>
VEGF 단백질로 번역되는 비교 화합물 RN의 합성에 이용한 재료(폴리뉴클레오티드)의 서열 정보를 나타낸다. 표에서의 각 뉴클레오티드 N은 RNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를, dN은 DNA를 나타낸다.
Figure pct00168
이하의 일련의 조작에 의해 비교 화합물 RN을 얻었다.
(PCR 반응에 의한 이중쇄 DNA의 조제와 In vitro transcriotion에 의한 3' 말단 측 폴리뉴클레오티드 단편의 조제)
플라스미드 DNA는 시판되는 pUC19 벡터의 Sma I 사이트에, 상술한 서열 번호 546에 나타내는 인공 합성 유전자 서열 GN을 삽입한 것을 이용했다(가부시키가이샤파스막사 제조).
플라스미드 DNA, FW 프라이머 및 RV 프라이머를 이용하여 PCR을 행했다. PCR 용액의 종농도는 이하와 같다; 주형 DNA 0.2 ng/μL, dNTP 250 μM, 프라이머 0.3 μM, Prime STARHS DNA Polymerase(Takara) 0.025 U/μL, Prime STAR Buffer(Mg2+ plus)(Takara) 1x. 온도 사이클은 이하와 같다; 94 oC 5 min, [98 oC 10 sec, 55 oC 30 sec, 72 oC 60 sec] x 30 사이클. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제(粗精製)를 행했다. 이어서, DpnI 처리에 의해, 주형 plasmid의 분해 제거를 행했다. 반응액의 종농도는, PCR 산물 3.43 μg/μL, Dpn I(Takara) 1 U/μL, T buffer(Takara) 1x로, 37도에서 1시간 인큐베이트를 행했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행했다.
이어서, T7 RNA polymerase에 의한 전사 반응을 행했다. 반응액의 종농도는 이하와 같다; DNA 10 ng/μL, DTT 5 mM, ATP, CTP, UTP 각 2 mM, GMP 2 mM, GTP 0.5 mM, T7 RNA polymerase(Takara) 2.5 U/μL, T7 RNA Polymerese buffer(Takara) 1x, RNase Inhibitor, Murine(NEB) 0.2 U/μL. 37도에서 2시간 인큐베이트를 행했다. 이어서 DNase(recombinant, RNase-free, Takara)를 종농도 0.1 U/μL만큼을 첨가하여, 37도에서 30분 인큐베이트를 행했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행하여, 3' 말단 측 폴리뉴클레오티드 단편 RN-2를 얻었다.
(RNA 라이게이션에 의한 RNA 연결 산물의 조제)
정해진 규칙에 따라서 화학 합성에 의해 얻어진 3' 말단 측 폴리뉴클레오티드 단편 RN-1 및 in vitro transcription에 의해 얻어진 RNA 단편 RN-2, 템플레이트 DNA-A를 이용하여, RNA ligase 2에 의한 연결 반응을 행했다. 종농도는, RN-1 2 μM, RN-2 2 μM, DNAN 4 μM, PEG8000 10%(v/v), T4 RNA ligase 2(NEB) 1 U/μL, T4 RNA ligase 2 buffer(NEB) 1x, RNase inhibitor Murine(NEB) 1 U/μL. 튜브에 PEG8000, T4 RNA ligase 2, RNase inhibitor 이외의 기질·시약을 가한 후, 90도 3분 가열하여, 실온까지 자연 방열했다. 나머지 시약·효소를 첨가하여, 45도에서 1시간 인큐베이트했다. DNase를 종농도 0.33 U/μL만큼 첨가하여, 37도에서 15분 인큐베이트했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행하여, 연결 RNA를 얻었다. 반응 샘플은, dPAGE(5% 아크릴아미드, 7M 우레아)로 해석했다. 겔 정제를 이하와 같이 행했다. dPAGE(6% 아크릴아미드, 7.5M 우레아, 25% 포름아미드)로 영동 후, 해당 밴드를 잘라내어, MQ수로 12시간 추출을 행했다. 아미콘 10K(Merck Millipore) 처리, 이소프로판올 침전에 의해 겔 추출 산물을 얻었다.
(RNA 연결 산물의 연결부 서열 해석)
이하의 일련의 조작에 의해, Smarter RACE 5' 3' Kit(Takara Bio사 제조, 카탈로그 번호 634859)를 이용하여 RNA 연결 산물 RN의 연결부의 서열을 분석했다. 우선, 100 ng/μL로 조제한 RN을 1 μL 취하고, 5' CDS Primer A 1 μL 및 Nuclease-free water 9 μL와 혼합하여, 72℃에서 4분간 가열하고, 4℃에서 2분간 냉각했다. 반응액에 1 μL의 SMARTER II A Oligo,4 μL의 5x First Strand Buffer, 0.5 μL의 100 mM DTT, 1 μL의 20 mM dNTPs, 0.5 μL의 40 U/μL RNase Inhibitor, 2 μL의 SMART Scribe Reverse Trancriptase를 혼합하고, 42℃에서 90분간, 72℃에서 10분간 가열하여, 4℃에서 냉각한 후, 240 μL의 TE Buffer를 첨가하여 혼합함으로써, 주형 cDNA를 합성했다. 이어서, 얻어진 주형 cDNA를 이용하여 이하와 같이 PCR 반응을 실시했다. 구체적으로는 2.5 μL의 주형 cDNA, 5 μL의 10xUPM, 0.1 μL의 100 μM RV 프라이머 2(서열 번호 548), 25 μL의 SeqAmp Buffer, 1 μL의 SeqAmp DNA polymerase, 16.4 μL의 Nuclease-free water를 혼합하고, 서멀 사이클러를 이용하여 94℃에서 30초간 가열하고, 그 후 68℃ 30초간, 72℃ 60초간 가열을 20회 반복하고, 그 후 4℃에서 냉각했다. 얻어진 PCR 산물을 1.5% 아가로오스-TAE 겔로 전기 영동하여, 상기 밴드를 잘라내고, QIA quick Gel Extraction Kit(QIAGEN사 제조, 카탈로그 번호 28704)로 PCR 산물을 정제했다. 얻어진 PCR 산물 1 μL를 Zero Blunt TOPO PCR Cloning Kit for Sequencing(Invitrogen사 제조, 카탈로그 번호 45-0031)에 포함되는 TOPO vector 0.5 μL, Salt solution 0.5 μL, Nuclease-free water 1 μL와 혼합하여, 실온에서 5분간 반응시켰다. 얻어진 반응물을 Competent Quick DH5α(도요보사 제조, 카탈로그 번호 DNA-913)로 형질 전환하여, 100 μg/mL의 암피실린을 포함하는 LB 한천 배지 플레이트에 파종하고, 37℃에서 밤새 배양함으로써 싱글 콜로니를 얻었다. 싱글 콜로니를 100 μg/mL의 암피실린을 포함하는 LB 액체 배지에 식균하여 37℃에서 밤새 배양하고, 얻어진 대장균으로부터 Pure Yield Plasmid Miniprep System(프로메가사 제조, 카탈로그 번호 A1222)을 이용하여 플라스미드 DNA를 추출했다.
얻어진 플라스미드 DNA 500 ng를 6.4 pmol의 시퀀스 프라이머(M13FW 또는 M13RV, 각각 서열 번호 549, 550)와 혼합하여 Nuclease-free water로 14 μL로 조제하고, 파스막사에 의뢰함으로써 생거법에 기초한 캐피럴리 시퀀스 해석을 실시했다. 독립된 3개의 싱글 콜로니로부터의 시퀀스 해석 결과, RNA 연결 산물 RN의 연결부의 서열이 서열 번호 546에 나타내는 유전자 서열의 상기 부위와 일치하고 있는 것이 확인되었다.
RV 프라이머 2: 5'-GATTACGCCAAGCTTTGGCTTGAAGATGTACTCGATCTCATCAGG3'···서열 번호 548
시퀀스 프라이머 M13FW: 5'-CTCGATCTCATCAGG3'···서열 번호 549
시퀀스 프라이머 M13RV: 5'-CAGGAAACAGCTATGAC-3'···서열 번호 550
<비교 화합물 RN'의 합성>
VEGF 단백질로 번역되는 비교 화합물 RN'의 합성에 이용한 재료(폴리뉴클레오티드)의 서열 정보를 나타낸다. 표에서의 각 뉴클레오티드 N은 RNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를, dN은 DNA를 나타낸다.
Figure pct00169
이하의 일련의 조작에 의해 비교 화합물 RN'을 얻었다.
(선형화 플라스미드 DNA의 조제와 In vitro transcriotion에 의한 RNA 단편의 조제)
플라스미드 DNA는 시판되는 pUC19 벡터의 EcoRV 사이트 및 XbaI 사이트에, 서열 번호 552에 나타내는 인공 합성 유전자 서열 GN'을 삽입한 것을 이용했다(가부시키가이샤진위즈 제조). 플라스미드 DNA를 제한 효소 XbaI를 이용하여 직쇄화를 행했다. 반응액의 종농도는, 플라스미드 DNA 20 ng/μL, XbaI(Takara) 0.75 U/μL, M buffer(Takara) 1x, BSA 0.01%로 37도에서 1시간 인큐베이트했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행했다. 얻어진 직쇄화 DNA를 이용하여 전사 반응을 행했다. 반응액의 종농도는 이하와 같다; DNA 10 ng/μL, DTT 5 mM, ATP, CTP, UTP 각 2 mM, GMP 2 mM, GTP 0.5 mM, T7 RNA polymerase(Takara) 2.5 U/μL, T7 RNA Polymerese buffer(Takara) 1x, RNase Inhibitor, Murine(NEB) 0.2 U/μL. 37도에서 2시간 인큐베이트를 행했다. 이어서 DNase(recombinant, RNase-free, Takara)를 종농도 0.1 U/μL만큼을 첨가하여, 37도에서 30분 인큐베이트를 행했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행하여, 3' 말단 측 폴리뉴클레오티드 단편 RN'-2를 얻었다.
(RNA 라이게이션에 의한 RNA 연결 산물의 조제)
정해진 규칙에 따라서 화학 합성에 의해 얻어진 5' 말단 측 폴리뉴클레오티드 단편 RN'-1 및 in vitro transcription에 의해 얻어진 3' 말단 측 폴리뉴클레오티드 단편 RN'-2, 템플레이트 DNA-B를 이용하여, RNA ligase 2에 의한 연결 반응을 행했다. 종농도는, RN-1 2 μM, RN-2 2 μM, DNAN 4 μM, PEG8000 10%(v/v), T4 RNA ligase 2(NEB) 1 U/μL, T4 RNA ligase 2 buffer(NEB) 1x, RNase inhibitor Murine(NEB) 1 U/μL. 튜브에 PEG8000, T4 RNA ligase 2, RNase inhibitor 이외의 기질·시약을 가한 후, 90도 3분 가열하여, 실온까지 자연 방열했다. 나머지 시약·효소를 첨가하여, 45도에서 1시간 인큐베이트했다. DNase를 종농도 0.33 U/μL만큼 첨가하여, 37도에서 15분 인큐베이트했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행하여, 연결 RNA를 얻었다. 반응 샘플은 dPAGE(5% 아크릴아미드, 7M 우레아)로 해석했다. 겔 정제를 이하와 같이 행했다. dPAGE(6% 아크릴아미드, 7.5M 우레아, 25% 포름아미드)로 영동 후, 상기 밴드를 잘라내고, MQ수로 12시간 추출을 행했다. 아미콘 10K(Merck Millipore) 처리, 이소프로판올 침전에 의해 겔 추출 산물을 얻었다.
<당부 수식을 갖는 화합물 EN의 합성>
VEGF 단백질로 번역되는 화합물 EN의 합성에 이용한 재료(폴리뉴클레오티드)의 서열 정보를 나타낸다. 표에서의 각 뉴클레오티드 N은 RNA를, N(M)은 2'-O-메틸 수식 RNA를, N(F)은 2'-F화 수식 RNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를, dN은 DNA를 나타낸다.
Figure pct00170
이하의 일련의 조작에 의해 당부 수식을 갖는 화합물 EN을 얻었다.
(선형화 플라스미드 DNA의 조제와 In vitro transcriotion에 의한 RNA 단편의 조제)
3' 측의 단편은 상기 RN'-2 조제법과 같은 방법으로 실시했다.
(RNA 라이게이션에 의한 RNA 연결 산물의 조제)
화학 합성에 의해 얻어진 RNA 단편 EN-1 및 RNA 단편 RN'-2, 템플레이트 DNA-C를 이용하여, RNA ligase 2에 의한 연결 반응을 행했다. 종농도는 EN-1 2 μM, RN'-2 2 μM, 템플레이트 DNA 4 μM, PEG8000 10%(v/v), T4 RNA ligase 2(NEB) 1 U/μL, T4 RNA ligase 2 buffer(NEB) 1x, RNase inhibitor Murine(NEB) 1 U/μL.튜브에 PEG8000, T4 RNA ligase 2, RNase inhibitor 이외의 기질·시약을 가한 후, 90도 3분 가열하여, 실온까지 자연 방열했다. 나머지 시약·효소를 첨가하여, 45도에서 1시간 인큐베이트했다. DNase(recombinant, RNase-free, Takara)를 종농도 0.33 U/μL만큼 첨가하여, 37도에서 15분 인큐베이트했다. 페놀클로로포름 추출, 이소프로판올 침전에 의해 조정제를 행하여, 연결 RNA를 얻었다. 반응 샘플은 dPAGE(5% 아크릴아미드, 7M 우레아)로 해석했다. 겔 정제를 이하와 같이 행했다. dPAGE(6% 아크릴아미드, 7.5M 우레아, 25% 포름아미드)로 영동 후, 상기 밴드를 잘라내어, MQ수로 12시간 추출을 행했다. 아미콘 10K(Merck Millipore) 처리, 이소프로판올 침전에 의해 겔 추출 산물을 얻었다.
(mRNA 샘플의 번역 반응)
상기에서 얻어진 RN, RN' 및 EN의 서열 정보를 표 145에 나타낸다. 표 145에서, 각 뉴클레오티드 N(대문자)는 RNA를, 각 뉴클레오티드 N(F)는 2'-F화 수식 RNA를, N(MOE)은 2'-O-메톡시에틸 수식 RNA를 나타낸다.
Figure pct00171
RN, RN', EN에 관해서, Hela 세포주를 이용하여 in vitro에서의 번역 활성을 평가했다. 우선, 10% 소태아 혈청을 포함하는 RPMI 배지(나카라이테스크사 제조)로 현탁한 Hela 세포를 1 웰 당 세포수 10,000 cells/100 μL가 되도록 96 웰 접착 세포용 배양 플레이트에 파종하여, 37℃, 5% CO2 조건 하에서 밤새 배양했다. 밤새 배양 후의 세포로부터 배양 상청을 제거하고, 1 웰 당 40 μL의 10% 소태아 혈청을 포함하는 RPMI 배지를 첨가한 후, 각 화합물의 종농도가 0.3, 1, 3 및 10 nM가 되도록 각 화합물과 종농도 0.3%의 Lipofectamin Messenger MAX Transfection Reagent(서모피셔사이엔티픽사 제조, 카탈로그 번호: LMRNA008)를 옵티멤(서모피셔사이엔티픽사 제조, 카탈로그 번호: 31985-070)으로 희석하여 혼합하고, 혼합액을 1 웰 당 10 μL가 되도록 각각의 배양 플레이트에 첨가하여, 37℃, 5% CO2 조건 하에서 4시간 배양했다. 4시간 배양 후의 세포로부터 배양 상청을 회수하고, 10% 소태아 혈청을 포함하는 RPMI 배지를 1 웰 당 50 μL가 되도록 첨가하여, 37℃, 5% CO2 조건 하에서 또 밤새 배양했다. 24시간 배양 후의 세포로부터 배양 상청을 회수했다.
얻어진 배양 상청 중의 VEGF 단백질량은, Human VEGE Quantikine ELISA(R&D사 제조, 카탈로그 번호 DVE00)를 이용하여, 키트 부속의 메뉴얼에 따라서 측정했다. 측정 결과 정량된 각 배양 상청 중의 VEGF 단백질 농도(ng/mL)를 이하의 표에 기재했다.
Figure pct00172
상기 평가 결과로부터 분명한 것과 같이, 당부 수식을 갖는 EN은, Hela 세포에 첨가 후, 유전자 서열로 코드된 VEGF 단백질을 산생하고, 그 효율은 당부 수식을 갖지 않는 RN 및 RN'와 비교하여 우수했다.
서열 번호 1: 화합물 E1
서열 번호 2: 화합물 E1-1
서열 번호 3: 화합물 E1-2
서열 번호 4: 템플레이트 DNA1
서열 번호 5: 화합물 E2
서열 번호 6: 화합물 E2-1
서열 번호 7: 화합물 E2-2
서열 번호 8: 화합물 E3
서열 번호 9: 화합물 E3-1
서열 번호 10: 화합물 E3-2
서열 번호 11: 화합물 E4
서열 번호 12: 화합물 E4-1
서열 번호 13: 화합물 E4-2
서열 번호 14: 화합물 R1
서열 번호 15: 화합물 R1-1
서열 번호 16: 화합물 R1-2
서열 번호 17: 템플레이트 DNA2
서열 번호 18: 화합물 R2
서열 번호 19: 화합물 R2-1
서열 번호 20: 화합물 R2-2
서열 번호 21: 화합물 R3
서열 번호 22: 화합물 R3-1
서열 번호 23: 화합물 R3-2
서열 번호 24: 템플레이트 DNA3
서열 번호 25: 화합물 R4
서열 번호 26: 화합물 R4-1
서열 번호 27: 화합물 R4-2
서열 번호 28: 화합물 R4-3
서열 번호 29: 템플레이트 DNA4
서열 번호 30: 화합물 R5
서열 번호 31: 화합물 R5-1
서열 번호 32: 화합물 R5-2
서열 번호 33: 화합물 R6
서열 번호 34: 화합물 R6-1
서열 번호 35: 화합물 R6-2
서열 번호 36: 화합물 R7
서열 번호 37: 화합물 R7-1
서열 번호 38: 화합물 R7-2
서열 번호 39: 화합물 R8
서열 번호 40: 화합물 R8-1
서열 번호 41: 화합물 R8-2
서열 번호 42: 화합물 R9
서열 번호 43: 화합물 R9-1
서열 번호 44: 화합물 R9-2
서열 번호 45: 화합물 R10
서열 번호 46: 화합물 R10-1
서열 번호 47: 화합물 R10-2
서열 번호 48: 화합물 R11
서열 번호 49: 화합물 R11-1
서열 번호 50: 화합물 R11-2
서열 번호 51: 화합물 R12
서열 번호 52: 화합물 R12-1
서열 번호 53: 화합물 R12-2
서열 번호 54: 화합물 R13
서열 번호 55: 화합물 R13-1
서열 번호 56: 화합물 R13-2
서열 번호 57: 화합물 R14
서열 번호 58: 화합물 R14-1
서열 번호 59: 화합물 R14-2
서열 번호 60: 화합물 R15
서열 번호 61: 화합물 R15-1
서열 번호 62: 화합물 R15-2
서열 번호 63: 화합물 R16
서열 번호 64: 화합물 R16-1
서열 번호 65: 화합물 R16-2
서열 번호 66: 화합물 R17
서열 번호 67: 화합물 R17-1
서열 번호 68: 화합물 R17-2
서열 번호 69: 화합물 R17-3
서열 번호 70: 템플레이트 DNA5
서열 번호 71: 템플레이트 DNA6
서열 번호 72: 화합물 R18
서열 번호 73: 화합물 R18-1
서열 번호 74: 화합물 R18-2
서열 번호 75: RT primer
서열 번호 76: Fw primer
서열 번호 77: Rv primer
서열 번호 78: Taqman MGB Probe
서열 번호 79∼538: 화합물 E5∼E248-1
서열 번호 539∼542: 번역 산물 폴리펩티드 표품
서열 번호 543: FW 프라이머
서열 번호 544: RV 프라이머 1
서열 번호 545: 5' 말단 폴리뉴클레오티드 서열 RN-1
서열 번호 546: 인공 합성 유전자 서열 GN
서열 번호 547: 템플레이트 DNA-A
서열 번호 548: RV 프라이머 2
서열 번호 549: 시퀀스 프라이머 M13FW
서열 번호 550: 시퀀스 프라이머 M13RV
서열 번호 551: 5' 말단 폴리뉴클레오티드 서열 RN'-1
서열 번호 552: 인공 합성 유전자 서열 GN'
서열 번호 553: 템플레이트 DNA-B
서열 번호 554: EN-1
서열 번호 555: 템플레이트 DNA-C
서열 번호 556: 화합물 RN 및 RN'
서열 번호 557: 화합물 EN
SEQUENCE LISTING <110> National University Corporation Tokai National Higher Education and Research System <110> KYOWA KIRIN CO., LTD. <120> POLYNUCLEOTIDE AND PHARMACEUTICAL COMPOSITION <130> K1635ALP0001 <150> JP 2019-236399 <151> 2019-12-26 <160> 557 <170> PatentIn version 3.5 <210> 1 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E1 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <400> 1 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 2 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E1-1 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 2 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 3 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E1-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 3 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 4 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 1 <400> 4 cctttatcgt cgtcgtcttt atagtcgatg 30 <210> 5 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E2 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <400> 5 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 6 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E2-1 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 6 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 7 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E2-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (84)..(84) <223> 2'-deoxy-2'-fluoroadenosine <400> 7 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 8 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E3 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <400> 8 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 9 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E3-1 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 9 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 10 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E3-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 10 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 11 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E4 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 11 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 12 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E4-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 12 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 13 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E4-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 13 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 14 <211> 126 <212> RNA <213> Artificial Sequence <220> <223> R1 <220> <221> misc_feature <222> (70)..(71) <223> phosphoryl amide bond <400> 14 auuauuaagg agauauaucc gaugauuauu gacuacaagg acgacgauga caaaauuauu 60 gacuacaagg acgacgauga caaacugcug auuauugacu acaaggacga cgaugacaaa 120 auuauu 126 <210> 15 <211> 70 <212> RNA <213> Artificial Sequence <220> <223> R1-1 <220> <221> misc_feature <222> (70)..(70) <223> 3'-hydroxyl group is substituted by amino group <400> 15 auuauuaagg agauauaucc gaugauuauu gacuacaagg acgacgauga caaaauuauu 60 gacuacaagg 70 <210> 16 <211> 56 <212> RNA <213> Artificial Sequence <220> <223> R1-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 16 acgacgauga caaacugcug auuauugacu acaaggacga cgaugacaaa auuauu 56 <210> 17 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 2 <400> 17 cagcagtttg tcatcgtcgt ccttgtagtc aataattttg 40 <210> 18 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R2 <220> <221> misc_feature <222> (80)..(81) <223> phosphoryl amide bond <400> 18 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 19 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R2-1 <220> <221> misc_feature <222> (80)..(80) <223> 3'-hydroxyl group is substituted by amino group <400> 19 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 20 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R2-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 20 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 21 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R3 <220> <221> misc_feature <222> (49)..(50) <223> phosphoryl amide bond <400> 21 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 22 <211> 49 <212> RNA <213> Artificial Sequence <220> <223> R3-1 <220> <221> misc_feature <222> (49)..(49) <223> 3'-hydroxyl group is substituted by amino group <400> 22 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaag 49 <210> 23 <211> 96 <212> RNA <213> Artificial Sequence <220> <223> R3-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 23 gacgacgacg acaagaucau cgacuauaaa gacgacgacg auaaaggugg cgacuauaag 60 gacgacgacg acaaacacca ccaccaccac cacuga 96 <210> 24 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 3 <400> 24 gtcgtcgtcg tccttgtagt ccat 24 <210> 25 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R4 <220> <221> misc_feature <222> (29)..(30) <223> phosphoryl amide bond <220> <221> misc_feature <222> (80)..(81) <223> phosphoryl amide bond <400> 25 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 26 <211> 29 <212> RNA <213> Artificial Sequence <220> <223> R4-1 <220> <221> misc_feature <222> (29)..(29) <223> 3'-hydroxyl group is substituted by amino group <400> 26 gggagaauac aagcuacuug uucuuuuug 29 <210> 27 <211> 51 <212> RNA <213> Artificial Sequence <220> <223> R4-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (51)..(51) <223> 3'-hydroxyl group is substituted by amino group <400> 27 cagccaccau ggacuacaag gacgacgacg acaagaucau cgacuauaaa g 51 <210> 28 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R4-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 28 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 29 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 4 <400> 29 gtccatggtg gctgcaaaaa gaacaagt 28 <210> 30 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R5 <220> <221> misc_feature <222> (80)..(81) <223> -NHC(O)-CH2-S-P(O)(OH)-O- bond <400> 30 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 31 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R5-1 <220> <221> misc_feature <222> (80)..(80) <223> 3'-hydroxyl group is substituted by amino group <400> 31 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 32 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R5-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorothioated <400> 32 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 33 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> R6 <400> 33 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 34 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R6-1 <400> 34 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 35 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> R6-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 35 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 36 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R7 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <400> 36 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 37 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R7-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <400> 37 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 38 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R7-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 38 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 39 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R8 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyluridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyluridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyluridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methyluridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyluridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <400> 39 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 40 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R8-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyluridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyluridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyluridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methyluridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyluridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <400> 40 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 41 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R8-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 41 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 42 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R9 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <400> 42 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 43 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R9-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <400> 43 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 44 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R9-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 44 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 45 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R10 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyluridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyluridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyluridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methyluridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyluridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (37)..(37) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (38)..(38) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-O-methyluridine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (44)..(44) <223> 2'-O-methyluridine <220> <221> modified_base <222> (45)..(45) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (51)..(51) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-O-methyluridine <220> <221> modified_base <222> (70)..(70) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (72)..(72) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-O-methyluridine <220> <221> modified_base <222> (75)..(75) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <220> <221> modified_base <222> (77)..(77) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (89)..(89) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (90)..(90) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methyluridine <220> <221> modified_base <222> (92)..(92) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (93)..(93) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (94)..(94) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (96)..(96) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (97)..(97) <223> 2'-O-methyluridine <220> <221> modified_base <222> (98)..(98) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (99)..(99) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (100)..(100) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (101)..(101) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (102)..(102) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (103)..(103) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (104)..(104) <223> 2'-O-methyluridine <220> <221> modified_base <222> (105)..(105) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (106)..(106) <223> 2'-O-methyluridine <220> <221> modified_base <222> (107)..(107) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (108)..(108) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (109)..(109) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (111)..(111) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (113)..(113) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (114)..(114) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (115)..(115) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (116)..(116) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (117)..(117) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (118)..(118) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (119)..(119) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (120)..(120) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (121)..(121) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (122)..(122) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (123)..(123) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (124)..(124) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (126)..(126) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (127)..(127) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (129)..(129) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (130)..(130) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (132)..(132) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (133)..(133) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (135)..(135) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (136)..(136) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (138)..(138) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (139)..(139) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (141)..(141) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (142)..(142) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 45 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 46 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R10-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyluridine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyluridine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyluridine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyluridine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyluridine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyluridine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methyluridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyluridine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyluridine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (37)..(37) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (38)..(38) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-O-methyluridine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (44)..(44) <223> 2'-O-methyluridine <220> <221> modified_base <222> (45)..(45) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (51)..(51) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-O-methyluridine <220> <221> modified_base <222> (70)..(70) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (72)..(72) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-O-methyluridine <220> <221> modified_base <222> (75)..(75) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <220> <221> modified_base <222> (77)..(77) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-O-methyladenosine <400> 46 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 47 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R10-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyluridine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyluridine <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyluridine <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (34)..(34) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (36)..(36) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (37)..(37) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (39)..(39) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (42)..(42) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 47 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 48 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R11 <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (80)..(81) <223> phosphoryl amide bond <400> 48 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 49 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R11-1 <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (80)..(80) <223> 3'-phosphorylated <400> 49 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 50 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R11-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-hydroxyl group is substituted by amino group <400> 50 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 51 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R12 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 51 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 52 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R12-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <400> 52 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 53 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R12-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 53 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 54 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R13 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-deoxy-2'-fluoroadenosine <400> 54 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 55 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R13-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <400> 55 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 56 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R13-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <400> 56 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 57 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R14 <220> <221> misc_feature <222> (1)..(1) <223> LNA <220> <221> misc_feature <222> (2)..(2) <223> LNA <220> <221> misc_feature <222> (3)..(3) <223> LNA <220> <221> misc_feature <222> (143)..(143) <223> LNA <220> <221> misc_feature <222> (144)..(144) <223> LNA <220> <221> misc_feature <222> (145)..(145) <223> LNA <400> 57 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 58 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R14-1 <220> <221> misc_feature <222> (1)..(1) <223> LNA <220> <221> misc_feature <222> (2)..(2) <223> LNA <220> <221> misc_feature <222> (3)..(3) <223> LNA <400> 58 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 59 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R14-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (63)..(63) <223> LNA <220> <221> misc_feature <222> (64)..(64) <223> LNA <220> <221> misc_feature <222> (65)..(65) <223> LNA <400> 59 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 60 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R15 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 60 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 61 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R15-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <400> 61 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 62 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R15-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 62 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 63 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R16 <220> <221> modified_base <222> (4)..(4) <223> 6-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> 6-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 6-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 6-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 6-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 6-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 6-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> 6-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> 6-methyladenosine <220> <221> modified_base <222> (38)..(38) <223> 6-methyladenosine <400> 63 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 64 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R16-1 <220> <221> modified_base <222> (4)..(4) <223> 6-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> 6-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 6-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 6-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 6-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 6-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 6-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> 6-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> 6-methyladenosine <220> <221> modified_base <222> (38)..(38) <223> 6-methyladenosine <400> 64 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 65 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R16-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 65 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 66 <211> 126 <212> RNA <213> Artificial Sequence <220> <223> R17 <400> 66 auuauuaagg agauauaucc gaugauuauu gacuacaagg acgacgauga caaaauuauu 60 gacuacaagg acgacgauga caaacugcug auuauugacu acaaggacga cgaugacaaa 120 auuauu 126 <210> 67 <211> 40 <212> RNA <213> Artificial Sequence <220> <223> R17-1 <400> 67 auuauuaagg agauauaucc gaugauuauu gacuacaagg 40 <210> 68 <211> 44 <212> RNA <213> Artificial Sequence <220> <223> R17-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 68 acgacgauga caaaauuauu gacuacaagg acgacgauga caaa 44 <210> 69 <211> 42 <212> RNA <213> Artificial Sequence <220> <223> R17-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 69 cugcugauua uugacuacaa ggacgacgau gacaaaauua uu 42 <210> 70 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 5 <400> 70 gtcatcgtcg tccttgtagt c 21 <210> 71 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Template DNA 6 <400> 71 caataatcag cagtttgtca tcg 23 <210> 72 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> R18 <400> 72 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 73 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> R18-1 <400> 73 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 74 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> R18-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 74 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 75 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> RT primer <400> 75 tcagtggtgg tggtggtggt gtttg 25 <210> 76 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> forward primer <400> 76 atcttgtcgt cgtcgtcctt 20 <210> 77 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> reverse primer <400> 77 gaatacaagc tacttgttct ttt 23 <210> 78 <211> 11 <212> DNA <213> Artificial Sequence <220> <223> TaqMan MGB probe <400> 78 cagccaccat g 11 <210> 79 <211> 264 <212> RNA <213> Artificial Sequence <220> <223> E5 <400> 79 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gccu 264 <210> 80 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E5-1 <400> 80 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 81 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E5-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 81 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 82 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E5-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 82 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgccu 85 <210> 83 <211> 169 <212> RNA <213> Artificial Sequence <220> <223> E6 <400> 83 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaaaguaua auaaacuuug aaaaacugca ccaccaccac caccacuga 169 <210> 84 <211> 89 <212> RNA <213> Artificial Sequence <220> <223> E6-1 <400> 84 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacg 89 <210> 85 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E6-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 85 auaaaggugg cgacuauaag gacgacgacg acaaaaguau aauaaacuuu gaaaaacugc 60 accaccacca ccaccacuga 80 <210> 86 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E7 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <400> 86 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 87 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E7-1 <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 87 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 88 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E7-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 88 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 89 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E8 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <400> 89 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 90 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E8-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 90 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 91 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E8-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 91 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 92 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E9 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 92 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 93 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E9-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 93 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 94 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E9-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (45)..(45) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 94 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 95 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E10 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (77)..(77) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (92)..(92) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (122)..(122) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 95 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 96 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E10-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (77)..(77) <223> 2'-O-methyladenosine <400> 96 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 97 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E10-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 97 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 98 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E11 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (109)..(109) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 98 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 99 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E11-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <400> 99 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 100 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E11-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 100 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 101 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E12 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methyluridine <220> <221> modified_base <222> (97)..(97) <223> 2'-O-methyluridine <220> <221> modified_base <222> (106)..(106) <223> 2'-O-methyluridine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 101 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 102 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E12-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <400> 102 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 103 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E12-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyluridine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyluridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 103 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 104 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E13 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (103)..(103) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (112)..(112) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (115)..(115) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (118)..(118) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (121)..(121) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 104 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 105 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E13-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <400> 105 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 106 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E13-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (38)..(38) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 106 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 107 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E14 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methyluridine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 107 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 108 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E14-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 108 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 109 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E14-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 109 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 110 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E15 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 110 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 111 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E15-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <400> 111 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 112 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E15-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 112 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 113 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E16 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 113 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 114 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E16-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 114 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 115 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E16-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 115 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 116 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E17 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 116 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 117 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E17-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 117 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 118 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E17-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 118 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 119 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E18 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 119 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 120 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E18-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <400> 120 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 121 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E18-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 121 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 122 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E19 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 122 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 123 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E19-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <400> 123 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 124 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E19-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 124 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 125 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E20 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (88)..(88) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (91)..(91) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (94)..(94) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (97)..(97) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (100)..(100) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (103)..(103) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (106)..(106) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (109)..(109) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (115)..(115) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (118)..(118) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (121)..(121) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (124)..(124) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (127)..(127) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (130)..(130) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (133)..(133) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (136)..(136) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (139)..(139) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (142)..(142) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 125 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 126 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E20-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroadenosine <400> 126 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 127 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E20-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 127 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 128 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E21 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (94)..(94) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (97)..(97) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (100)..(100) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (103)..(103) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (106)..(106) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (109)..(109) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (115)..(115) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (118)..(118) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (121)..(121) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (124)..(124) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (127)..(127) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (130)..(130) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (133)..(133) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (136)..(136) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (139)..(139) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (142)..(142) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 128 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 129 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E21-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroadenosine <400> 129 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 130 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E21-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 130 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 131 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E22 <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methyladenosine <400> 131 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 132 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E22-1 <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methyladenosine <400> 132 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 133 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E22-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 133 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 134 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E23 <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <400> 134 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 135 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E23-1 <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <400> 135 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 136 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E23-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 136 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 137 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E24 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 137 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 138 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E24-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 138 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 139 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E24-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 139 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 140 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E25 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (115)..(115) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 140 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 141 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E25-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 141 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 142 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E25-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 142 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 143 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E26 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 143 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 144 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E26-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 144 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 145 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E26-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 145 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 146 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E27 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 146 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 147 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E27-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 147 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 148 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E27-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 148 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 149 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E28 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 149 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 150 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E28-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 150 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 151 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E28-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 151 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 152 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E29 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 152 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 153 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E29-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 153 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 154 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E29-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 154 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 155 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E30 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 155 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 156 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E30-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 156 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 157 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E30-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 157 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 158 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E31 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 158 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 159 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E31-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 159 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 160 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E31-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 160 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 161 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E32 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (110)..(110) <223> LNA <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 161 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 162 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E32-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 162 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 163 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E32-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (30)..(30) <223> LNA <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 163 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 164 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E33 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (110)..(110) <223> LNA <220> <221> misc_feature <222> (113)..(113) <223> LNA <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 164 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 165 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E33-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 165 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 166 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E33-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (30)..(30) <223> LNA <220> <221> misc_feature <222> (33)..(33) <223> LNA <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 166 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 167 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E34 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (112)..(112) <223> LNA <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 167 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 168 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E34-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 168 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 169 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E34-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (32)..(32) <223> LNA <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 169 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 170 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E35 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (112)..(112) <223> LNA <220> <221> misc_feature <222> (115)..(115) <223> LNA <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 170 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 171 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E35-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 171 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 172 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E35-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (32)..(32) <223> LNA <220> <221> misc_feature <222> (35)..(35) <223> LNA <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 172 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 173 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E36 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (111)..(111) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 173 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 174 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E36-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 174 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 175 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E36-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 175 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 176 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E37 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (111)..(111) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 176 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 177 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E37-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 177 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 178 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E37-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 178 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 179 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E38 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 179 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 180 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E38-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 180 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 181 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E38-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 181 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 182 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E39 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 182 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 183 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E39-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 183 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 184 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E39-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 184 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 185 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E40 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 185 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 186 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E40-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 186 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 187 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E40-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 187 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 188 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E41 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (115)..(115) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 188 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 189 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E41-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 189 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 190 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E41-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 190 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 191 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E42 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 191 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 192 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E42-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 192 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 193 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E42-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 193 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 194 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E43 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 194 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 195 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E43-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 195 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 196 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E43-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 196 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 197 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E44 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 197 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 198 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E44-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 198 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 199 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E44-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 199 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 200 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E45 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (112)..(112) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (115)..(115) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 200 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 201 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E45-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 201 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 202 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E45-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 202 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 203 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E46 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 203 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 204 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E46-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 204 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 205 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E46-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 205 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 206 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E47 <220> <221> misc_feature <222> (1)..(1) <223> LNA <220> <221> misc_feature <222> (2)..(2) <223> LNA <220> <221> misc_feature <222> (3)..(3) <223> LNA <220> <221> misc_feature <222> (4)..(4) <223> LNA <220> <221> misc_feature <222> (5)..(5) <223> LNA <220> <221> misc_feature <222> (6)..(6) <223> LNA <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(143) <223> LNA <220> <221> misc_feature <222> (144)..(144) <223> LNA <220> <221> misc_feature <222> (145)..(145) <223> LNA <400> 206 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 207 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E47-1 <220> <221> misc_feature <222> (1)..(1) <223> LNA <220> <221> misc_feature <222> (2)..(2) <223> LNA <220> <221> misc_feature <222> (3)..(3) <223> LNA <220> <221> misc_feature <222> (4)..(4) <223> LNA <220> <221> misc_feature <222> (5)..(5) <223> LNA <220> <221> misc_feature <222> (6)..(6) <223> LNA <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 207 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 208 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E47-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(63) <223> LNA <220> <221> misc_feature <222> (64)..(64) <223> LNA <220> <221> misc_feature <222> (65)..(65) <223> LNA <400> 208 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 209 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E48 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 209 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 210 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E48-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 210 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 211 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E48-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 211 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 212 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E49 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 212 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 213 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E49-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 213 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 214 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E49-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 214 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 215 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E50 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (163)..(163) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (164)..(164) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (165)..(165) <223> 2'-O-methoxyethyladenosine <400> 215 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 216 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E50-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 216 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 217 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E50-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethyladenosine <400> 217 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 218 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E51 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (163)..(163) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (164)..(164) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (165)..(165) <223> 2'-O-methoxyethyladenosine <400> 218 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 219 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E51-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 219 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 220 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E51-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethyladenosine <400> 220 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 221 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E52 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (163)..(164) <223> 5'-phosphonothioate <220> <221> modified_base <222> (163)..(163) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (164)..(165) <223> 5'-phosphonothioate <220> <221> modified_base <222> (164)..(164) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (165)..(165) <223> 2'-O-methoxyethyladenosine <400> 221 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 222 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E52-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 222 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 223 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E52-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (84)..(85) <223> 5'-phosphonothioate <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethyladenosine <400> 223 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 224 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E53 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (163)..(164) <223> 5'-phosphonothioate <220> <221> modified_base <222> (163)..(163) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (164)..(165) <223> 5'-phosphonothioate <220> <221> modified_base <222> (164)..(164) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (165)..(165) <223> 2'-O-methoxyethyladenosine <400> 224 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 225 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E53-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 225 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 226 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E53-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (84)..(85) <223> 5'-phosphonothioate <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethyladenosine <400> 226 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 227 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E54 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 227 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 228 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E54-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 228 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 229 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E54-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 229 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 230 <211> 143 <212> RNA <213> Artificial Sequence <220> <223> E55 <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-O-methyladenosine <400> 230 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaac gacgacgaua aagguggcga cuauaaggac gacgacgaca 120 aacaccacca ccaccaccac uga 143 <210> 231 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E55-1 <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-O-methyladenosine <400> 231 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 232 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E55-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 232 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 233 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E56 <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <400> 233 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 234 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E56-1 <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <400> 234 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 235 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E56-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 235 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 236 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E57 <220> <221> modified_base <222> (4)..(4) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-ethy-2'-O-methyladenosine <400> 236 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 237 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E57-1 <220> <221> modified_base <222> (4)..(4) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-ethy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-ethy-2'-O-methyladenosine <400> 237 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 238 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E57-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 238 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 239 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E58 N6-ethy- <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <400> 239 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 240 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E58-1 N6-ethy- <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluoroadenosineN6-ethy- <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <400> 240 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 241 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E58-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <400> 241 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 242 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E59 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 242 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 243 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E59-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 243 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 244 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E59-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 244 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 245 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E60 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 245 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 246 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E60-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (7)..(7) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (11)..(11) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (31)..(31) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (35)..(35) <223> N6-methy-2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 246 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 247 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E60-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 247 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 248 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E61 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 248 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc guggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 249 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E61-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 249 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 250 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E61-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 250 acgacgacga uaaagguggc guggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 251 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E62 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 251 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc guggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 252 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E62-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 252 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 253 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E62-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 253 acgacgacga uaaagguggc guggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 254 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E63 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 254 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc cccgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 255 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E63-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 255 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 256 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E63-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 256 acgacgacga uaaagguggc cccgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 257 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E64 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 257 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc cccgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 258 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E64-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 258 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 259 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E64-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 259 acgacgacga uaaagguggc cccgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 260 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E65 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 260 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc accgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 261 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E65-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 261 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 262 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E65-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 262 acgacgacga uaaagguggc accgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 263 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E66 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 263 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc accgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 264 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E66-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 264 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 265 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E66-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 265 acgacgacga uaaagguggc accgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 266 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E67 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 266 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gccgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 267 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E67-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 267 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 268 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E67-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 268 acgacgacga uaaagguggc gccgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 269 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E68 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 269 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gccgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 270 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E68-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 270 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 271 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E68-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 271 acgacgacga uaaagguggc gccgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 272 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E69 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 272 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc caggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 273 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E69-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 273 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 274 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E69-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 274 acgacgacga uaaagguggc caggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 275 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E70 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 275 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc caggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 276 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E70-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 276 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 277 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E70-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 277 acgacgacga uaaagguggc caggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 278 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E71 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 278 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ugcgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 279 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E71-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 279 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 280 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E71-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 280 acgacgacga uaaagguggc ugcgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 281 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E72 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 281 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ugcgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 282 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E72-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 282 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 283 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E72-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 283 acgacgacga uaaagguggc ugcgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 284 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E73 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 284 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc agagacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 285 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E73-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 285 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 286 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E73-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 286 acgacgacga uaaagguggc agagacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 287 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E74 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 287 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc agagacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 288 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E74-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 288 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 289 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E74-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 289 acgacgacga uaaagguggc agagacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 290 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E75 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 290 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ugggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 291 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E75-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 291 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 292 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E75-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 292 acgacgacga uaaagguggc ugggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 293 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E76 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 293 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ugggacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 294 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E76-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 294 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 295 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E76-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 295 acgacgacga uaaagguggc ugggacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 296 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E77 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 296 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ggcgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 297 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E77-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 297 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 298 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E77-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 298 acgacgacga uaaagguggc ggcgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 299 <211> 148 <212> RNA <213> Artificial Sequence <220> <223> E78 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-O-methyluridine <220> <221> modified_base <222> (147)..(147) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (148)..(148) <223> 2'-O-methyladenosine <400> 299 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc ggcgacuaua aggacgacga 120 cgacaaacac caccaccacc accacuga 148 <210> 300 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E78-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 300 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 301 <211> 68 <212> RNA <213> Artificial Sequence <220> <223> E78-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyluridine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methyladenosine <400> 301 acgacgacga uaaagguggc ggcgacuaua aggacgacga cgacaaacac caccaccacc 60 accacuga 68 <210> 302 <211> 91 <212> RNA <213> Artificial Sequence <220> <223> E79 <400> 302 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc caccaccacc accaccacug a 91 <210> 303 <211> 91 <212> RNA <213> Artificial Sequence <220> <223> E80 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (89)..(89) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (90)..(90) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methoxyethyladenosine <400> 303 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc caccaccacc accaccacug a 91 <210> 304 <211> 91 <212> RNA <213> Artificial Sequence <220> <223> E81 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (89)..(90) <223> 5'-phosphonothioate <220> <221> modified_base <222> (89)..(89) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (90)..(91) <223> 5'-phosphonothioate <220> <221> modified_base <222> (90)..(90) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methyladenosine <400> 304 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc caccaccacc accaccacug a 91 <210> 305 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E82 <400> 305 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 306 <211> 64 <212> RNA <213> Artificial Sequence <220> <223> E83 <400> 306 gggagccacc auggacuaua aggacgacga cgacaaaggu ggccaccacc accaccacca 60 cuga 64 <210> 307 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E84 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 307 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 308 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E85 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (86)..(87) <223> 5'-phosphonothioate <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (87)..(88) <223> 5'-phosphonothioate <220> <221> modified_base <222> (87)..(87) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methyladenosine <400> 308 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 309 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E86 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 309 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 310 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E86-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <400> 310 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 311 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E86-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 311 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 312 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E87 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-deoxy-2'-fluoroadenosine <400> 312 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 313 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E87-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 313 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 314 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E87-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <400> 314 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 315 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E88 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (109)..(109) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 315 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 316 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E88-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 316 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 317 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E88-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 317 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 318 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E89 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (109)..(109) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 318 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 319 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E89-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <400> 319 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 320 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E89-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 320 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 321 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E90 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 321 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 322 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E90-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <400> 322 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 323 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E90-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 323 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 324 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E91 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (103)..(103) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (121)..(121) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 324 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 325 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E91-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <400> 325 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 326 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E91-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 326 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 327 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E92 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methyluridine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (97)..(97) <223> 2'-O-methyluridine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (106)..(106) <223> 2'-O-methyluridine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 327 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 328 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E92-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <400> 328 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 329 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E92-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyluridine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyluridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 329 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 330 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E93 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (97)..(97) <223> 2'-O-methyluridine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (106)..(106) <223> 2'-O-methyluridine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 330 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 331 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E93-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methyluridine <400> 331 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 332 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E93-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyluridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 332 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 333 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E94 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 333 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 334 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E94-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-O-methylguanosine <400> 334 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 335 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E94-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 335 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 336 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E95 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (110)..(110) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 336 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 337 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E95-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylguanosine <400> 337 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 338 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E95-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 338 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 339 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E96 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (41)..(41) <223> LNA <220> <221> misc_feature <222> (59)..(59) <223> LNA <220> <221> misc_feature <222> (71)..(71) <223> LNA <220> <221> misc_feature <222> (86)..(86) <223> LNA <220> <221> misc_feature <222> (101)..(101) <223> LNA <220> <221> misc_feature <222> (119)..(119) <223> LNA <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 339 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 340 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E96-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (41)..(41) <223> LNA <220> <221> misc_feature <222> (59)..(59) <223> LNA <220> <221> misc_feature <222> (71)..(71) <223> LNA <400> 340 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 341 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E96-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (6)..(6) <223> LNA <220> <221> misc_feature <222> (21)..(21) <223> LNA <220> <221> misc_feature <222> (39)..(39) <223> LNA <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 341 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 342 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E97 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 342 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 343 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E97-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 343 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 344 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E97-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 344 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 345 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E98 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 345 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 346 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E98-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 346 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 347 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E98-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 347 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 348 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E99 <220> <221> misc_feature <222> (1)..(1) <223> BNA <220> <221> misc_feature <222> (2)..(2) <223> BNA <220> <221> misc_feature <222> (3)..(3) <223> BNA <220> <221> misc_feature <222> (4)..(4) <223> BNA <220> <221> misc_feature <222> (5)..(5) <223> BNA <220> <221> misc_feature <222> (6)..(6) <223> BNA <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(143) <223> BNA <220> <221> misc_feature <222> (144)..(144) <223> BNA <220> <221> misc_feature <222> (145)..(145) <223> BNA <400> 348 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 349 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E99-1 <220> <221> misc_feature <222> (1)..(1) <223> BNA <220> <221> misc_feature <222> (2)..(2) <223> BNA <220> <221> misc_feature <222> (3)..(3) <223> BNA <220> <221> misc_feature <222> (4)..(4) <223> BNA <220> <221> misc_feature <222> (5)..(5) <223> BNA <220> <221> misc_feature <222> (6)..(6) <223> BNA <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 349 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 350 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E99-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(63) <223> BNA <220> <221> misc_feature <222> (64)..(64) <223> BNA <220> <221> misc_feature <222> (65)..(65) <223> BNA <400> 350 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 351 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E100 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (5)..(6) <223> 5'-phosphonothioate <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 351 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 352 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E100-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (5)..(6) <223> 5'-phosphonothioate <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 352 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 353 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E100-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 353 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 354 <211> 265 <212> RNA <213> Artificial Sequence <220> <223> E101 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (167)..(167) <223> 2'-deoxy-2'-fluorouridine <400> 354 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gcuga 265 <210> 355 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E101-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <400> 355 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 356 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E101-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (37)..(37) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (82)..(82) <223> 2'-deoxy-2'-fluoroguanosine <400> 356 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 357 <211> 86 <212> RNA <213> Artificial Sequence <220> <223> E101-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methyluridine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyladenosine <400> 357 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgcuga 86 <210> 358 <211> 265 <212> RNA <213> Artificial Sequence <220> <223> E102 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (167)..(167) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (170)..(170) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (173)..(173) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (176)..(176) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (185)..(185) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (188)..(188) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (191)..(191) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (194)..(194) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (197)..(197) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (200)..(200) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (203)..(203) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (206)..(206) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (209)..(209) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (212)..(212) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (215)..(215) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (218)..(218) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (221)..(221) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (224)..(224) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (227)..(227) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (230)..(230) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (233)..(233) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (236)..(236) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (239)..(239) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (242)..(242) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (245)..(245) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (248)..(248) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (251)..(251) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (254)..(254) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (257)..(257) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (260)..(260) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (263)..(264) <223> 5'-phosphonothioate <220> <221> modified_base <222> (263)..(263) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (264)..(265) <223> 5'-phosphonothioate <220> <221> modified_base <222> (264)..(264) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (265)..(265) <223> 2'-O-methoxyethyladenosine <400> 358 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gcuga 265 <210> 359 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E102-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <400> 359 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 360 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E102-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (37)..(37) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (82)..(82) <223> 2'-deoxy-2'-fluoroguanosine <400> 360 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 361 <211> 86 <212> RNA <213> Artificial Sequence <220> <223> E102-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (84)..(85) <223> 5'-phosphonothioate <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (85)..(86) <223> 5'-phosphonothioate <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethyladenosine <400> 361 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgcuga 86 <210> 362 <211> 265 <212> RNA <213> Artificial Sequence <220> <223> E103 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (167)..(167) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (170)..(170) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (173)..(173) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (176)..(176) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (185)..(185) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (188)..(188) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (191)..(191) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (194)..(194) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (197)..(197) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (200)..(200) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (203)..(203) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (206)..(206) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (209)..(209) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (212)..(212) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (215)..(215) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (218)..(218) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (221)..(221) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (224)..(224) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (227)..(227) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (230)..(230) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (233)..(233) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (236)..(236) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (239)..(239) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (242)..(242) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (245)..(245) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (248)..(248) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (251)..(251) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (254)..(254) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (257)..(257) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (260)..(260) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (263)..(264) <223> 5'-phosphonothioate <220> <221> modified_base <222> (263)..(263) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (264)..(265) <223> 5'-phosphonothioate <220> <221> modified_base <222> (264)..(264) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (265)..(265) <223> 2'-O-methyladenosine <400> 362 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gcuga 265 <210> 363 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E103-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <400> 363 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 364 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E103-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (37)..(37) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (82)..(82) <223> 2'-deoxy-2'-fluoroguanosine <400> 364 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 365 <211> 86 <212> RNA <213> Artificial Sequence <220> <223> E103-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (84)..(85) <223> 5'-phosphonothioate <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (85)..(86) <223> 5'-phosphonothioate <220> <221> modified_base <222> (85)..(85) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyladenosine <400> 365 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgcuga 86 <210> 366 <211> 265 <212> RNA <213> Artificial Sequence <220> <223> E104 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (167)..(167) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (170)..(170) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (173)..(173) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (176)..(176) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (185)..(185) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (188)..(188) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (191)..(191) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (194)..(194) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (197)..(197) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (200)..(200) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (203)..(203) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (206)..(206) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (209)..(209) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (212)..(212) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (215)..(215) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (218)..(218) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (221)..(221) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (224)..(224) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (227)..(227) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (230)..(230) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (233)..(233) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (236)..(236) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (239)..(239) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (242)..(242) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (245)..(245) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (248)..(248) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (251)..(251) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (254)..(254) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (257)..(257) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (260)..(260) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (263)..(263) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (264)..(264) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (265)..(265) <223> 2'-O-methoxyethyladenosine <400> 366 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gcuga 265 <210> 367 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E104-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <400> 367 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 368 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E104-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (37)..(37) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (82)..(82) <223> 2'-deoxy-2'-fluoroguanosine <400> 368 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 369 <211> 86 <212> RNA <213> Artificial Sequence <220> <223> E104-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethyladenosine <400> 369 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgcuga 86 <210> 370 <211> 265 <212> RNA <213> Artificial Sequence <220> <223> E105 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (167)..(167) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (170)..(170) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (173)..(173) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (176)..(176) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (185)..(185) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (188)..(188) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (191)..(191) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (194)..(194) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (197)..(197) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (200)..(200) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (203)..(203) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (206)..(206) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (209)..(209) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (212)..(212) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (215)..(215) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (218)..(218) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (221)..(221) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (224)..(224) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (227)..(227) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (230)..(230) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (233)..(233) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (236)..(236) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (239)..(239) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (242)..(242) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (245)..(245) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (248)..(248) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (251)..(251) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (254)..(254) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (257)..(257) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (260)..(260) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (263)..(263) <223> 2'-O-methyluridine <220> <221> modified_base <222> (264)..(264) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (265)..(265) <223> 2'-O-methyladenosine <400> 370 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgacaaagcc auuaauagug acucugagug 120 uccccugucc cacgacgggu acugccucca cgacggugug ugcauguaua uugaagcauu 180 ggacaaguac gccugcaacu guguuguugg cuacaucggg gagcgcuguc aguaccgaga 240 ccugaagugg ugggaacugc gcuga 265 <210> 371 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E105-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroguanosine <400> 371 gggagccacc auggacuaca aggacgacga cgacaagauc aucgacuaua aagacgacga 60 cgauaaaggu ggcgacuaua aggacgacga cgac 94 <210> 372 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E105-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (7)..(7) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (10)..(10) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (19)..(19) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (22)..(22) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (25)..(25) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (28)..(28) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (31)..(31) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (34)..(34) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (37)..(37) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (52)..(52) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (70)..(70) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (73)..(73) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (76)..(76) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (82)..(82) <223> 2'-deoxy-2'-fluoroguanosine <400> 372 aaagccauua auagugacuc ugaguguccc cugucccacg acggguacug ccuccacgac 60 ggugugugca uguauauuga agcau 85 <210> 373 <211> 86 <212> RNA <213> Artificial Sequence <220> <223> E105-3 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (78)..(78) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (81)..(81) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methyluridine <220> <221> modified_base <222> (85)..(85) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyladenosine <400> 373 uggacaagua cgccugcaac uguguuguug gcuacaucgg ggagcgcugu caguaccgag 60 accugaagug gugggaacug cgcuga 86 <210> 374 <211> 169 <212> RNA <213> Artificial Sequence <220> <223> E106 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (167)..(167) <223> 2'-O-methyluridine <220> <221> modified_base <222> (168)..(168) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (169)..(169) <223> 2'-O-methyladenosine <400> 374 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaaaguaua auaaacuuug aaaaacugca ccaccaccac caccacuga 169 <210> 375 <211> 89 <212> RNA <213> Artificial Sequence <220> <223> E106-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <400> 375 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacg 89 <210> 376 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E106-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyluridine <220> <221> modified_base <222> (79)..(79) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (80)..(80) <223> 2'-O-methyladenosine <400> 376 auaaaggugg cgacuauaag gacgacgacg acaaaaguau aauaaacuuu gaaaaacugc 60 accaccacca ccaccacuga 80 <210> 377 <211> 169 <212> RNA <213> Artificial Sequence <220> <223> E107 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (167)..(168) <223> 5'-phosphonothioate <220> <221> modified_base <222> (167)..(167) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (168)..(169) <223> 5'-phosphonothioate <220> <221> modified_base <222> (168)..(168) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (169)..(169) <223> 2'-O-methoxyethyladenosine <400> 377 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaaaguaua auaaacuuug aaaaacugca ccaccaccac caccacuga 169 <210> 378 <211> 89 <212> RNA <213> Artificial Sequence <220> <223> E107-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <400> 378 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacg 89 <210> 379 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E107-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (78)..(79) <223> 5'-phosphonothioate <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (79)..(80) <223> 5'-phosphonothioate <220> <221> modified_base <222> (79)..(79) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (80)..(80) <223> 2'-O-methoxyethyladenosine <400> 379 auaaaggugg cgacuauaag gacgacgacg acaaaaguau aauaaacuuu gaaaaacugc 60 accaccacca ccaccacuga 80 <210> 380 <211> 169 <212> RNA <213> Artificial Sequence <220> <223> E108 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (167)..(168) <223> 5'-phosphonothioate <220> <221> modified_base <222> (167)..(167) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (168)..(169) <223> 5'-phosphonothioate <220> <221> modified_base <222> (168)..(168) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (169)..(169) <223> 2'-O-methyladenosine <400> 380 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaaaguaua auaaacuuug aaaaacugca ccaccaccac caccacuga 169 <210> 381 <211> 89 <212> RNA <213> Artificial Sequence <220> <223> E108-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <400> 381 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacg 89 <210> 382 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E108-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (78)..(79) <223> 5'-phosphonothioate <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (79)..(80) <223> 5'-phosphonothioate <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (80)..(80) <223> 2'-O-methyladenosine <400> 382 auaaaggugg cgacuauaag gacgacgacg acaaaaguau aauaaacuuu gaaaaacugc 60 accaccacca ccaccacuga 80 <210> 383 <211> 169 <212> RNA <213> Artificial Sequence <220> <223> E109 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (143)..(143) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (146)..(146) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (149)..(149) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (152)..(152) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (155)..(155) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (158)..(158) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (161)..(161) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (164)..(164) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (167)..(167) <223> 2'-O-methyluridine <220> <221> modified_base <222> (168)..(168) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (169)..(169) <223> 2'-O-methyladenosine <400> 383 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaaaguaua auaaacuuug aaaaacugca ccaccaccac caccacuga 169 <210> 384 <211> 89 <212> RNA <213> Artificial Sequence <220> <223> E109-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <400> 384 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacg 89 <210> 385 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E109-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (69)..(69) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (72)..(72) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (75)..(75) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyluridine <220> <221> modified_base <222> (79)..(79) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (80)..(80) <223> 2'-O-methyladenosine <400> 385 auaaaggugg cgacuauaag gacgacgacg acaaaaguau aauaaacuuu gaaaaacugc 60 accaccacca ccaccacuga 80 <210> 386 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E110 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (5)..(6) <223> 5'-phosphonothioate <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 386 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 387 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E110-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> misc_feature <222> (5)..(6) <223> 5'-phosphonothioate <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 387 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 388 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E110-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethyluridine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 388 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 389 <211> 165 <212> RNA <213> Artificial Sequence <220> <223> E111 <220> <221> misc_feature <222> (1)..(1) <223> artificial danglingend <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 389 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acugaaaaaa aaaaaaaaaa aaaaa 165 <210> 390 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E111-1 <220> <221> misc_feature <222> (1)..(1) <223> artificial danglingend <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 390 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 391 <211> 85 <212> RNA <213> Artificial Sequence <220> <223> E111-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 391 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acugaaaaaa aaaaaaaaaa aaaaa 85 <210> 392 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E112 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 392 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 393 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E112-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 393 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 394 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E112-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 394 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 395 <211> 185 <212> DNA <213> Artificial Sequence <220> <223> E113 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 395 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc actgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 180 aaaaa 185 <210> 396 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E113-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 396 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 397 <211> 105 <212> DNA <213> Artificial Sequence <220> <223> E113-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 397 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 actgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 105 <210> 398 <211> 185 <212> DNA <213> Artificial Sequence <220> <223> E114 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (92)..(92) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (95)..(95) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (98)..(98) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (101)..(101) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (104)..(104) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (107)..(107) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (110)..(110) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (113)..(113) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (116)..(116) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (119)..(119) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (122)..(122) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (125)..(125) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (128)..(128) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (131)..(131) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (134)..(134) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (137)..(137) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (140)..(140) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methoxyethylthymine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methoxyethyladenosine <400> 398 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc actgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 180 aaaaa 185 <210> 399 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E114-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluoroadenosine <400> 399 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 400 <211> 105 <212> DNA <213> Artificial Sequence <220> <223> E114-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (6)..(6) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethylthymine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyladenosine <400> 400 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 actgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 105 <210> 401 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E115 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 401 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 402 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E116 <400> 402 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc agccaccacc accaccacca cuga 94 <210> 403 <211> 67 <212> RNA <213> Artificial Sequence <220> <223> E117 <400> 403 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccacuga 67 <210> 404 <211> 64 <212> RNA <213> Artificial Sequence <220> <223> E118 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethyladenosine <400> 404 gggagccacc auggacuaua aggacgacga cgacaaaggu ggccaccacc accaccacca 60 cuga 64 <210> 405 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E119 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (92)..(92) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (93)..(93) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (94)..(94) <223> 2'-O-methoxyethyladenosine <400> 405 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc agccaccacc accaccacca cuga 94 <210> 406 <211> 67 <212> RNA <213> Artificial Sequence <220> <223> E120 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 406 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccacuga 67 <210> 407 <211> 91 <212> RNA <213> Artificial Sequence <220> <223> E121 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (89)..(89) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (90)..(90) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methoxyethyladenosine <400> 407 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc caccaccacc accaccacug a 91 <210> 408 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E122 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 408 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 409 <211> 64 <212> RNA <213> Artificial Sequence <220> <223> E123 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methoxyethyladenosine <400> 409 gggagccacc auggacuaua aggacgacga cgacaaaggu ggccaccacc accaccacca 60 cuga 64 <210> 410 <211> 94 <212> RNA <213> Artificial Sequence <220> <223> E124 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (89)..(89) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (92)..(92) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (93)..(93) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (94)..(94) <223> 2'-O-methoxyethyladenosine <400> 410 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc agccaccacc accaccacca cuga 94 <210> 411 <211> 67 <212> RNA <213> Artificial Sequence <220> <223> E125 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 411 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccacuga 67 <210> 412 <211> 91 <212> RNA <213> Artificial Sequence <220> <223> E126 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (89)..(89) <223> 2'-O-methoxyethyluridine <220> <221> modified_base <222> (90)..(90) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (91)..(91) <223> 2'-O-methoxyethyladenosine <400> 412 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuauaagg acgacgacga 60 caaagguggc caccaccacc accaccacug a 91 <210> 413 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E127 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 413 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 414 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E128 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 414 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 415 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E129 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 415 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 416 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E130 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 416 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 417 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E131 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 417 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 418 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E132 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 418 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 419 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E133 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 419 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 420 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E134 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 420 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 421 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E135 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 421 gggagccacc atggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 422 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E136 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 422 gggagccacc atggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 423 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E137 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 423 gggagccacc atggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 424 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E138 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 424 gggagccacc atggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 425 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E139 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 425 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 426 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E140 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 426 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 427 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E141 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 427 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 428 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E142 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 428 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 429 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E143 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 429 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 430 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E144 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 430 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 431 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E145 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 431 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 432 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E146 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 432 gggagccacc auggacuaua aagacgacga cgauaaaggc ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 433 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E147 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 433 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 434 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E148 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 434 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 435 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E149 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methyluridine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 435 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 436 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E150 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (40)..(40) <223> LNA <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (43)..(43) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 436 gggagccacc auggacuaua aagacgacga cgauaaaggt ggtgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 437 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E151 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 437 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 438 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E152 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methyluridine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 438 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 439 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E153 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 439 gggagccacc auggacuaua aagacgacga cgauaaaggu ggugacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 440 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E154 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 440 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 441 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E155 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 441 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacau caucaucauc aucautga 88 <210> 442 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E156 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 442 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacau caucaucauc aucautga 88 <210> 443 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E157 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 443 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 444 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E158 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (58)..(58) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (61)..(61) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 444 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 445 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E159 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 445 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 446 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E160 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 446 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 447 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E161 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 447 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 448 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E162 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 448 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 449 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E163 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 449 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggatgauga 60 ugauaaacac caccaccacc accactga 88 <210> 450 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E164 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (55)..(55) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 450 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggatgauga 60 ugauaaacac caccaccacc accactga 88 <210> 451 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E165 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 451 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 452 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E166 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 452 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 453 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E167 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 453 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 454 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E168 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 454 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 455 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E169 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methyluridine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 455 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 456 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E170 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (55)..(55) <223> LNA <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (58)..(58) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 456 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggatgatga 60 ugauaaacac caccaccacc accactga 88 <210> 457 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E171 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 457 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 458 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E172 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methyluridine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 458 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 459 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E173 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 459 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 460 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E174 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 460 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 461 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E175 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 461 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 462 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E176 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 462 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 463 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E177 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 463 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgauuaua aggaugauga 60 ugauaaacac caccaccacc accactga 88 <210> 464 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E178 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 464 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 465 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E179 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methyluridine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 465 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 466 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E180 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> misc_feature <222> (49)..(49) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 466 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuata aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 467 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E181 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 467 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 468 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E182 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 468 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaagcac caccaccacc accactga 88 <210> 469 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E183 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 469 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaagcac caccaccacc accactga 88 <210> 470 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E184 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 470 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaagcac caccaccacc accactga 88 <210> 471 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E185 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (52)..(52) <223> LNA <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (67)..(67) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 471 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaagcac caccaccacc accactga 88 <210> 472 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E186 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (66)..(66) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 472 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaagcac caccaccacc accactga 88 <210> 473 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E187 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 473 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 474 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E188 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 474 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 475 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E189 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 475 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 476 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E190 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 476 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 477 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E191 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 477 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 478 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E192 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 478 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 479 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E193 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 479 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagccacc accaccacca 60 ccactga 67 <210> 480 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E194 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 480 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagucacc accaccacca 60 ccactga 67 <210> 481 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E195 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 481 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagucacc accaccacca 60 ccactga 67 <210> 482 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E196 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methyluridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 482 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagucacc accaccacca 60 ccactga 67 <210> 483 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E197 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 483 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagtcacc accaccacca 60 ccactga 67 <210> 484 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E198 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 484 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagucacc accaccacca 60 ccactga 67 <210> 485 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E199 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 485 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcagucacc accaccacca 60 ccactga 67 <210> 486 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E200 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 486 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcuggcacc accaccacca 60 ccactga 67 <210> 487 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E201 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 487 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcuggcacc accaccacca 60 ccactga 67 <210> 488 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E202 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 488 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcuggcacc accaccacca 60 ccactga 67 <210> 489 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E203 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 489 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcuggcacc accaccacca 60 ccactga 67 <210> 490 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E204 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 490 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcuggcacc accaccacca 60 ccactga 67 <210> 491 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E205 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 491 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugucacc accaccacca 60 ccactga 67 <210> 492 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E206 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 492 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugucacc accaccacca 60 ccactga 67 <210> 493 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E207 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methyluridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 493 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugucacc accaccacca 60 ccactga 67 <210> 494 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E208 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 494 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugucacc accaccacca 60 ccactga 67 <210> 495 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E209 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 495 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugucacc accaccacca 60 ccactga 67 <210> 496 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E210 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 496 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugccacc accaccacca 60 ccactga 67 <210> 497 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E211 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 497 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugccacc accaccacca 60 ccactga 67 <210> 498 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E212 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 498 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugccacc accaccacca 60 ccactga 67 <210> 499 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E213 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 499 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugccacc accaccacca 60 ccactga 67 <210> 500 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E214 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 500 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcugccacc accaccacca 60 ccactga 67 <210> 501 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E215 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 501 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 502 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E216 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 502 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 503 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E217 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 503 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 504 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E218 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 504 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 505 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E219 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 505 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 506 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E220 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 506 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauccacc accaccacca 60 ccactga 67 <210> 507 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E221 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 507 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 508 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E222 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 508 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 509 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E223 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methyluridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 509 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 510 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E224 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 510 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcautcacc accaccacca 60 ccactga 67 <210> 511 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E225 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 511 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 512 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E226 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methyluridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 512 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 513 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E227 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 513 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcauucacc accaccacca 60 ccactga 67 <210> 514 <211> 67 <212> DNA <213> Artificial Sequence <220> <223> E228 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methoxyethyladenosine <400> 514 gggagccacc auggacuaua aggacgacga cgacaaaggu ggcatucacc accaccacca 60 ccactga 67 <210> 515 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E229 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 515 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 516 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E230 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 516 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 517 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E231 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 517 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 518 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E232 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 518 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 519 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E233 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 519 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 520 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E234 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 520 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 521 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E235 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 521 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 522 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E236 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (54)..(54) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 522 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 523 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E237 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (54)..(54) <223> LNA <220> <221> misc_feature <222> (57)..(57) <223> LNA <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 523 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 524 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E238 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 524 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 525 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E239 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 525 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 526 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E240 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (14)..(15) <223> 5'-phosphonothioate <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (23)..(24) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (26)..(27) <223> 5'-phosphonothioate <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (29)..(30) <223> 5'-phosphonothioate <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (44)..(45) <223> 5'-phosphonothioate <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (59)..(60) <223> 5'-phosphonothioate <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 526 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 527 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E241 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (14)..(15) <223> 5'-phosphonothioate <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (29)..(30) <223> 5'-phosphonothioate <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (44)..(45) <223> 5'-phosphonothioate <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (59)..(60) <223> 5'-phosphonothioate <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 527 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 528 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E242 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (23)..(24) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (26)..(27) <223> 5'-phosphonothioate <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 528 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 529 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E243 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (68)..(69) <223> 5'-phosphonothioate <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (71)..(72) <223> 5'-phosphonothioate <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (74)..(75) <223> 5'-phosphonothioate <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (77)..(78) <223> 5'-phosphonothioate <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (80)..(81) <223> 5'-phosphonothioate <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 529 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 530 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E244 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (11)..(12) <223> 5'-phosphonothioate <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (14)..(15) <223> 5'-phosphonothioate <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (17)..(18) <223> 5'-phosphonothioate <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> misc_feature <222> (20)..(21) <223> 5'-phosphonothioate <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (23)..(24) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (26)..(27) <223> 5'-phosphonothioate <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (29)..(30) <223> 5'-phosphonothioate <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (32)..(33) <223> 5'-phosphonothioate <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (35)..(36) <223> 5'-phosphonothioate <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (38)..(39) <223> 5'-phosphonothioate <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (41)..(42) <223> 5'-phosphonothioate <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (44)..(45) <223> 5'-phosphonothioate <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (47)..(48) <223> 5'-phosphonothioate <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> misc_feature <222> (50)..(51) <223> 5'-phosphonothioate <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (59)..(60) <223> 5'-phosphonothioate <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (62)..(63) <223> 5'-phosphonothioate <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (65)..(66) <223> 5'-phosphonothioate <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (68)..(69) <223> 5'-phosphonothioate <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (71)..(72) <223> 5'-phosphonothioate <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (74)..(75) <223> 5'-phosphonothioate <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (77)..(78) <223> 5'-phosphonothioate <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (80)..(81) <223> 5'-phosphonothioate <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyluridine <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methyladenosine <400> 530 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 531 <211> 88 <212> DNA <213> Artificial Sequence <220> <223> E245 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> misc_feature <222> (11)..(12) <223> 5'-phosphonothioate <220> <221> modified_base <222> (11)..(11) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (14)..(15) <223> 5'-phosphonothioate <220> <221> modified_base <222> (14)..(14) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (17)..(18) <223> 5'-phosphonothioate <220> <221> modified_base <222> (17)..(17) <223> 2'-deoxy-2'-fluorouridine <220> <221> misc_feature <222> (20)..(21) <223> 5'-phosphonothioate <220> <221> modified_base <222> (20)..(20) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (23)..(24) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (26)..(27) <223> 5'-phosphonothioate <220> <221> modified_base <222> (26)..(26) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (29)..(30) <223> 5'-phosphonothioate <220> <221> modified_base <222> (29)..(29) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (32)..(33) <223> 5'-phosphonothioate <220> <221> modified_base <222> (32)..(32) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (35)..(36) <223> 5'-phosphonothioate <220> <221> modified_base <222> (35)..(35) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (38)..(39) <223> 5'-phosphonothioate <220> <221> modified_base <222> (38)..(38) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (41)..(42) <223> 5'-phosphonothioate <220> <221> modified_base <222> (41)..(41) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (44)..(45) <223> 5'-phosphonothioate <220> <221> modified_base <222> (44)..(44) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (47)..(48) <223> 5'-phosphonothioate <220> <221> modified_base <222> (47)..(47) <223> 2'-deoxy-2'-fluorouridine <220> <221> misc_feature <222> (50)..(51) <223> 5'-phosphonothioate <220> <221> modified_base <222> (50)..(50) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (59)..(60) <223> 5'-phosphonothioate <220> <221> modified_base <222> (59)..(59) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (62)..(63) <223> 5'-phosphonothioate <220> <221> modified_base <222> (62)..(62) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (65)..(66) <223> 5'-phosphonothioate <220> <221> modified_base <222> (65)..(65) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> misc_feature <222> (68)..(69) <223> 5'-phosphonothioate <220> <221> modified_base <222> (68)..(68) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (71)..(72) <223> 5'-phosphonothioate <220> <221> modified_base <222> (71)..(71) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (74)..(75) <223> 5'-phosphonothioate <220> <221> modified_base <222> (74)..(74) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (77)..(78) <223> 5'-phosphonothioate <220> <221> modified_base <222> (77)..(77) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (80)..(81) <223> 5'-phosphonothioate <220> <221> modified_base <222> (80)..(80) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-deoxy-2'-fluorocytidine <220> <221> misc_feature <222> (86)..(87) <223> 5'-phosphonothioate <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methoxyethylthymine <220> <221> misc_feature <222> (87)..(88) <223> 5'-phosphonothioate <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (88)..(88) <223> 2'-O-methoxyethyladenosine <400> 531 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accactga 88 <210> 532 <211> 88 <212> RNA <213> Artificial Sequence <220> <223> E246 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (5)..(6) <223> 5'-phosphonothioate <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (6)..(7) <223> 5'-phosphonothioate <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (7)..(8) <223> 5'-phosphonothioate <220> <221> modified_base <222> (7)..(7) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (8)..(9) <223> 5'-phosphonothioate <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (9)..(10) <223> 5'-phosphonothioate <220> <221> modified_base <222> (9)..(9) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (10)..(11) <223> 5'-phosphonothioate <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (11)..(12) <223> 5'-phosphonothioate <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (12)..(13) <223> 5'-phosphonothioate <220> <221> modified_base <222> (12)..(12) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (13)..(14) <223> 5'-phosphonothioate <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (14)..(15) <223> 5'-phosphonothioate <220> <221> modified_base <222> (14)..(14) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (15)..(16) <223> 5'-phosphonothioate <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (16)..(17) <223> 5'-phosphonothioate <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (17)..(18) <223> 5'-phosphonothioate <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (18)..(19) <223> 5'-phosphonothioate <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (19)..(20) <223> 5'-phosphonothioate <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (20)..(21) <223> 5'-phosphonothioate <220> <221> modified_base <222> (20)..(20) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (21)..(22) <223> 5'-phosphonothioate <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (23)..(24) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (24)..(25) <223> 5'-phosphonothioate <220> <221> modified_base <222> (24)..(24) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (25)..(26) <223> 5'-phosphonothioate <220> <221> modified_base <222> (25)..(25) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (26)..(27) <223> 5'-phosphonothioate <220> <221> modified_base <222> (26)..(26) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (27)..(28) <223> 5'-phosphonothioate <220> <221> modified_base <222> (27)..(27) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (28)..(29) <223> 5'-phosphonothioate <220> <221> modified_base <222> (28)..(28) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (29)..(30) <223> 5'-phosphonothioate <220> <221> modified_base <222> (29)..(29) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (30)..(31) <223> 5'-phosphonothioate <220> <221> modified_base <222> (30)..(30) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (31)..(32) <223> 5'-phosphonothioate <220> <221> modified_base <222> (31)..(31) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (32)..(33) <223> 5'-phosphonothioate <220> <221> modified_base <222> (32)..(32) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (33)..(34) <223> 5'-phosphonothioate <220> <221> modified_base <222> (33)..(33) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (34)..(35) <223> 5'-phosphonothioate <220> <221> modified_base <222> (34)..(34) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (35)..(36) <223> 5'-phosphonothioate <220> <221> modified_base <222> (35)..(35) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (36)..(37) <223> 5'-phosphonothioate <220> <221> modified_base <222> (36)..(36) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (37)..(38) <223> 5'-phosphonothioate <220> <221> modified_base <222> (37)..(37) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (38)..(39) <223> 5'-phosphonothioate <220> <221> modified_base <222> (38)..(38) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (39)..(40) <223> 5'-phosphonothioate <220> <221> modified_base <222> (39)..(39) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (40)..(41) <223> 5'-phosphonothioate <220> <221> modified_base <222> (40)..(40) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (41)..(42) <223> 5'-phosphonothioate <220> <221> modified_base <222> (41)..(41) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (42)..(43) <223> 5'-phosphonothioate <220> <221> modified_base <222> (42)..(42) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (43)..(44) <223> 5'-phosphonothioate <220> <221> modified_base <222> (43)..(43) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (44)..(45) <223> 5'-phosphonothioate <220> <221> modified_base <222> (44)..(44) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (45)..(46) <223> 5'-phosphonothioate <220> <221> modified_base <222> (45)..(45) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (46)..(47) <223> 5'-phosphonothioate <220> <221> modified_base <222> (46)..(46) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (47)..(48) <223> 5'-phosphonothioate <220> <221> modified_base <222> (47)..(47) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (48)..(49) <223> 5'-phosphonothioate <220> <221> modified_base <222> (48)..(48) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (49)..(50) <223> 5'-phosphonothioate <220> <221> modified_base <222> (49)..(49) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (50)..(51) <223> 5'-phosphonothioate <220> <221> modified_base <222> (50)..(50) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (51)..(52) <223> 5'-phosphonothioate <220> <221> modified_base <222> (51)..(51) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (52)..(53) <223> 5'-phosphonothioate <220> <221> modified_base <222> (52)..(52) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (53)..(54) <223> 5'-phosphonothioate <220> <221> modified_base <222> (53)..(53) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (54)..(55) <223> 5'-phosphonothioate <220> <221> modified_base <222> (54)..(54) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (55)..(56) <223> 5'-phosphonothioate <220> <221> modified_base <222> (55)..(55) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (56)..(57) <223> 5'-phosphonothioate <220> <221> modified_base <222> (56)..(56) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (57)..(58) <223> 5'-phosphonothioate <220> <221> modified_base <222> (57)..(57) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (58)..(59) <223> 5'-phosphonothioate <220> <221> modified_base <222> (58)..(58) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (59)..(60) <223> 5'-phosphonothioate <220> <221> modified_base <222> (59)..(59) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (60)..(61) <223> 5'-phosphonothioate <220> <221> modified_base <222> (60)..(60) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (61)..(62) <223> 5'-phosphonothioate <220> <221> modified_base <222> (61)..(61) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (62)..(63) <223> 5'-phosphonothioate <220> <221> modified_base <222> (62)..(62) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (65)..(66) <223> 5'-phosphonothioate <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (66)..(67) <223> 5'-phosphonothioate <220> <221> modified_base <222> (66)..(66) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (67)..(68) <223> 5'-phosphonothioate <220> <221> modified_base <222> (67)..(67) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (68)..(69) <223> 5'-phosphonothioate <220> <221> modified_base <222> (68)..(68) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (69)..(70) <223> 5'-phosphonothioate <220> <221> modified_base <222> (69)..(69) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (70)..(71) <223> 5'-phosphonothioate <220> <221> modified_base <222> (70)..(70) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (71)..(72) <223> 5'-phosphonothioate <220> <221> modified_base <222> (71)..(71) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (72)..(73) <223> 5'-phosphonothioate <220> <221> modified_base <222> (72)..(72) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (73)..(74) <223> 5'-phosphonothioate <220> <221> modified_base <222> (73)..(73) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (74)..(75) <223> 5'-phosphonothioate <220> <221> modified_base <222> (74)..(74) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (75)..(76) <223> 5'-phosphonothioate <220> <221> modified_base <222> (75)..(75) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (76)..(77) <223> 5'-phosphonothioate <220> <221> modified_base <222> (76)..(76) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (77)..(78) <223> 5'-phosphonothioate <220> <221> modified_base <222> (77)..(77) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (78)..(79) <223> 5'-phosphonothioate <220> <221> modified_base <222> (78)..(78) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (79)..(80) <223> 5'-phosphonothioate <220> <221> modified_base <222> (79)..(79) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (80)..(81) <223> 5'-phosphonothioate <220> <221> modified_base <222> (80)..(80) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (81)..(82) <223> 5'-phosphonothioate <220> <221> modified_base <222> (81)..(81) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (82)..(83) <223> 5'-phosphonothioate <220> <221> modified_base <222> (82)..(82) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (83)..(84) <223> 5'-phosphonothioate <220> <221> modified_base <222> (83)..(83) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (84)..(85) <223> 5'-phosphonothioate <220> <221> modified_base <222> (84)..(84) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (85)..(86) <223> 5'-phosphonothioate <220> <221> modified_base <222> (85)..(85) <223> 2'-O-methylcytidine <220> <221> misc_feature <222> (86)..(87) <223> 5'-phosphonothioate <220> <221> modified_base <222> (86)..(86) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (87)..(88) <223> 5'-phosphonothioate <220> <221> modified_base <222> (87)..(87) <223> 2'-O-methylguanosine <400> 532 gggagccacc auggacuaua aagacgacga cgauaaaggu ggcgacuaua aggacgacga 60 cgacaaacac caccaccacc accacuga 88 <210> 533 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E247 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> misc_feature <222> (143)..(144) <223> 5'-phosphonothioate <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (144)..(145) <223> 5'-phosphonothioate <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 533 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 534 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E247-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 534 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 535 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E247-2 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> misc_feature <222> (63)..(64) <223> 5'-phosphonothioate <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> misc_feature <222> (64)..(65) <223> 5'-phosphonothioate <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 535 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 536 <211> 145 <212> RNA <213> Artificial Sequence <220> <223> E248 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (143)..(143) <223> 2'-O-methyluridine <220> <221> modified_base <222> (144)..(144) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (145)..(145) <223> 2'-O-methyladenosine <400> 536 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag acgacgacga uaaagguggc gacuauaagg acgacgacga 120 caaacaccac caccaccacc acuga 145 <210> 537 <211> 80 <212> RNA <213> Artificial Sequence <220> <223> E248-1 <220> <221> misc_feature <222> (1)..(2) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methylguanosine <220> <221> misc_feature <222> (3)..(4) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> misc_feature <222> (4)..(5) <223> 5'-phosphonothioate <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <400> 537 gggagaauac aagcuacuug uucuuuuugc agccaccaug gacuacaagg acgacgacga 60 caagaucauc gacuauaaag 80 <210> 538 <211> 65 <212> RNA <213> Artificial Sequence <220> <223> E248-1 <220> <221> misc_feature <222> (1)..(1) <223> 5'-phosphorylated <220> <221> modified_base <222> (63)..(63) <223> 2'-O-methyluridine <220> <221> modified_base <222> (64)..(64) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (65)..(65) <223> 2'-O-methyladenosine <400> 538 acgacgacga uaaagguggc gacuauaagg acgacgacga caaacaccac caccaccacc 60 acuga 65 <210> 539 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide sample <400> 539 Met Asp Tyr Lys Asp Asp Asp Asp Lys Ile Ile Asp Tyr Lys Asp Asp 1 5 10 15 Asp Asp Lys Gly Gly Asp Tyr Lys Asp Asp Asp Asp Lys His His His 20 25 30 His His His 35 <210> 540 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide sample <400> 540 Met Asp Tyr Lys Asp Asp Asp Asp Lys Gly Gly His His His His His 1 5 10 15 His <210> 541 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide sample <400> 541 Met Asp Tyr Lys Asp Asp Asp Asp Lys Gly Gly Asp Tyr Lys Asp Asp 1 5 10 15 Asp Asp Lys His His His His His His 20 25 <210> 542 <211> 43 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide sample <400> 542 Met Asp Tyr Lys Asp Asp Asp Asp Lys Ile Ile Asp Tyr Lys Asp Asp 1 5 10 15 Asp Asp Lys Gly Gly Asp Tyr Lys Asp Asp Asp Asp Lys Ser Ile Ile 20 25 30 Asn Phe Glu Lys Leu His His His His His His 35 40 <210> 543 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> FW primer <400> 543 aagctaatac gactcactat agggtgcatt ggagccttgc cttgctgctc 50 <210> 544 <211> 134 <212> DNA <213> Artificial Sequence <220> <223> RV primer 1 <400> 544 ctagattttt tttttttttt tttttttttt tttttttttt tttttttttt tttttttttt 60 tttttttttt tttttttttt tttttttttt tttttttttt tttttgccgc ccactcagac 120 tttattcaaa gacc 134 <210> 545 <211> 66 <212> RNA <213> Artificial Sequence <220> <223> RN-1 <400> 545 gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccaccaug aacuuucugc 60 ugucuu 66 <210> 546 <211> 767 <212> DNA <213> Artificial Sequence <220> <223> GN <400> 546 ttggaccctc gtacagaagc taatacgact cactataggg aaataagaga gaaaagaaga 60 gtaagaagaa atataagagc caccatgaac tttctgctgt cttgggtgca ttggagcctt 120 gccttgctgc tctacctcca ccatgccaag tggtcccagg ctgcacccat ggcagaagga 180 ggagggcaga atcatcacga agtggtgaag ttcatggatg tctatcagcg cagctactgc 240 catccaatcg agaccctggt ggacatcttc caggagtacc ctgatgagat cgagtacatc 300 ttcaagccat cctgtgtgcc cctgatgcga tgcgggggct gctgcaatga cgagggcctg 360 gagtgtgtgc ccactgagga gtccaacatc accatgcaga ttatgcggat caaacctcac 420 caaggccagc acataggaga gatgagcttc ctacagcaca acaaatgtga atgcagacca 480 aagaaagata gagcaagaca agaaaatccc tgtgggcctt gctcagagcg gagaaagcat 540 ttgtttgtac aagatccgca gacgtgtaaa tgttcctgca aaaacacaga ctcgcgttgc 600 aaggcgaggc agcttgagtt aaacgaacgt acttgcagat gtgacaagcc gaggcggtga 660 taataggctg gagcctcggt ggccatgctt cttgcccctt gggcctcccc ccagcccctc 720 ctccccttcc tgcacccgta cccccgtggt ctttgaataa agtctga 767 <210> 547 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Template DNA-A <400> 547 ggctccaatg cacccaagac agcagaaagt 30 <210> 548 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> RV primer 2 <400> 548 gattacgcca agctttggct tgaagatgta ctcgatctca tcagg 45 <210> 549 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Sequence primer M13FW <400> 549 ctcgatctca tcagg 15 <210> 550 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> Sequence primer M13RV <400> 550 caggaaacag ctatgac 17 <210> 551 <211> 66 <212> RNA <213> Artificial Sequence <220> <223> RN-1 <400> 551 gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccaccaug aacuuucugc 60 ugucuu 66 <210> 552 <211> 802 <212> DNA <213> Artificial Sequence <220> <223> GN' <400> 552 aattcagtac ttaatacgac tcactatagg gtgcattgga gccttgcctt gctgctctac 60 ctccaccatg ccaagtggtc ccaggctgca cccatggcag aaggaggagg gcagaatcat 120 cacgaagtgg tgaagttcat ggatgtctat cagcgcagct actgccatcc aatcgagacc 180 ctggtggaca tcttccagga gtaccctgat gagatcgagt acatcttcaa gccatcctgt 240 gtgcccctga tgcgatgcgg gggctgctgc aatgacgagg gcctggagtg tgtgcccact 300 gaggagtcca acatcaccat gcagattatg cggatcaaac ctcaccaagg ccagcacata 360 ggagagatga gcttcctaca gcacaacaaa tgtgaatgca gaccaaagaa agatagagca 420 agacaagaaa atccctgtgg gccttgctca gagcggagaa agcatttgtt tgtacaagat 480 ccgcagacgt gtaaatgttc ctgcaaaaac acagactcgc gttgcaaggc gaggcagctt 540 gagttaaacg aacgtacttg cagatgtgac aagccgaggc ggtgataata ggctggagcc 600 tcggtggcca tgcttcttgc cccttgggcc tccccccagc ccctcctccc cttcctgcac 660 ccgtaccccc gtggtctttg aataaagtct gagtgggcgg caaaaaaaaa aaaaaaaaaa 720 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 780 aaaaaaaaaa aaaaaaaaaa at 802 <210> 553 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Template DNA-B <400> 553 ggctccaatg cacccaagac agcagaaagt 30 <210> 554 <211> 66 <212> RNA <213> Artificial Sequence <220> <223> EN-1 <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 554 gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccaccaug aacuuucugc 60 ugucuu 66 <210> 555 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Template DNA-C <400> 555 ggctccaatg cacccaagac agcagaaagt 30 <210> 556 <211> 844 <212> RNA <213> Artificial Sequence <220> <223> RN and RN' <400> 556 gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccaccaug aacuuucugc 60 ugucuugggu gcauuggagc cuugccuugc ugcucuaccu ccaccaugcc aagugguccc 120 aggcugcacc cauggcagaa ggaggagggc agaaucauca cgaaguggug aaguucaugg 180 augucuauca gcgcagcuac ugccauccaa ucgagacccu gguggacauc uuccaggagu 240 acccugauga gaucgaguac aucuucaagc cauccugugu gccccugaug cgaugcgggg 300 gcugcugcaa ugacgagggc cuggagugug ugcccacuga ggaguccaac aucaccaugc 360 agauuaugcg gaucaaaccu caccaaggcc agcacauagg agagaugagc uuccuacagc 420 acaacaaaug ugaaugcaga ccaaagaaag auagagcaag acaagaaaau cccugugggc 480 cuugcucaga gcggagaaag cauuuguuug uacaagaucc gcagacgugu aaauguuccu 540 gcaaaaacac agacucgcgu ugcaaggcga ggcagcuuga guuaaacgaa cguacuugca 600 gaugugacaa gccgaggcgg ugauaauagg cuggagccuc gguggccaug cuucuugccc 660 cuugggccuc cccccagccc cuccuccccu uccugcaccc guacccccgu ggucuuugaa 720 uaaagucuga gugggcggca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 780 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaau 840 cuag 844 <210> 557 <211> 844 <212> RNA <213> Artificial Sequence <220> <223> EN <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methoxyethylguanosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methoxyethyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (15)..(15) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (21)..(21) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (24)..(24) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (27)..(27) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (30)..(30) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (33)..(33) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (36)..(36) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (39)..(39) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (42)..(42) <223> 2'-deoxy-2'-fluoroguanosine <220> <221> modified_base <222> (45)..(45) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (48)..(48) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (51)..(51) <223> 2'-deoxy-2'-fluoroadenosine <220> <221> modified_base <222> (54)..(54) <223> 2'-deoxy-2'-fluorouridine <220> <221> modified_base <222> (57)..(57) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (60)..(60) <223> 2'-deoxy-2'-fluorocytidine <220> <221> modified_base <222> (63)..(63) <223> 2'-deoxy-2'-fluorouridine <400> 557 gggaaauaag agagaaaaga agaguaagaa gaaauauaag agccaccaug aacuuucugc 60 ugucuugggu gcauuggagc cuugccuugc ugcucuaccu ccaccaugcc aagugguccc 120 aggcugcacc cauggcagaa ggaggagggc agaaucauca cgaaguggug aaguucaugg 180 augucuauca gcgcagcuac ugccauccaa ucgagacccu gguggacauc uuccaggagu 240 acccugauga gaucgaguac aucuucaagc cauccugugu gccccugaug cgaugcgggg 300 gcugcugcaa ugacgagggc cuggagugug ugcccacuga ggaguccaac aucaccaugc 360 agauuaugcg gaucaaaccu caccaaggcc agcacauagg agagaugagc uuccuacagc 420 acaacaaaug ugaaugcaga ccaaagaaag auagagcaag acaagaaaau cccugugggc 480 cuugcucaga gcggagaaag cauuuguuug uacaagaucc gcagacgugu aaauguuccu 540 gcaaaaacac agacucgcgu ugcaaggcga ggcagcuuga guuaaacgaa cguacuugca 600 gaugugacaa gccgaggcgg ugauaauagg cuggagccuc gguggccaug cuucuugccc 660 cuugggccuc cccccagccc cuccuccccu uccugcaccc guacccccgu ggucuuugaa 720 uaaagucuga gugggcggca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 780 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaau 840 cuag 844

Claims (25)

  1. 개시 코돈에서부터 종지 코돈까지의 번역 영역을 포함하며,
    상기 번역 영역이 n개의 코돈을 포함하고, 상기 n이 2 이상의 양의 정수이며,
    상기 n개의 코돈이 각각 1번째, 2번째 및 3번째의 뉴클레오티드를 포함하고,
    상기 n개의 코돈 중 적어도 2개의 코돈에 있어서의 1번째의 뉴클레오티드가 당부 수식(sugar-modified) 뉴클레오티드인 폴리뉴클레오티드.
  2. 제1항에 있어서, 상기 당부 수식 뉴클레오티드가, 적어도 2' 위치가 수식된 당부를 포함하는 것인 폴리뉴클레오티드.
  3. 제2항에 있어서, 상기 적어도 2' 위치가 수식된 당부가 이하에서 선택되는 것인 폴리뉴클레오티드:
    Figure pct00173
    .
  4. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 당부 수식 뉴클레오티드가 아데닌, 구아닌, 시토신 및 우라실로 이루어지는 군에서 선택되는 염기에 대응하는 염기부를 포함하고,
    상기 염기의 종류가 적어도 2종류인 폴리뉴클레오티드.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서, 상기 당부 수식 뉴클레오티드의 적어도 1개가 수식 염기부를 포함하는 것인 폴리뉴클레오티드.
  6. 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 n개의 코돈 전부에 있어서의 1번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  7. 제1항 내지 제6항 중 어느 한 항에 있어서, 상기 종지 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  8. 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 개시 코돈의 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  9. 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 2번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  10. 제1항 내지 제9항 중 어느 한 항에 있어서, 상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  11. 제1항 내지 제10항 중 어느 한 항에 있어서, 상기 n이 2∼2000의 정수인 폴리뉴클레오티드.
  12. 제1항 내지 제11항 중 어느 한 항에 있어서, 5' 측 비번역 영역을 더 포함하는 폴리뉴클레오티드.
  13. 제12항에 있어서, 상기 5' 측 비번역 영역이, 이하의 염기부를 포함하는 염기부 수식 뉴클레오티드를 포함하는 것인 폴리뉴클레오티드:
    Figure pct00174

    [식 중, R은 탄소수 1∼6의 알킬기이다.]
  14. 제12항 또는 제13항에 있어서, 상기 5' 측 비번역 영역의 5' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  15. 제12항 내지 제14항 중 어느 한 항에 있어서, 5' 캡 구조를 더 포함하는 폴리뉴클레오티드.
  16. 제1항 내지 제15항 중 어느 한 항에 있어서, 3' 측 비번역 영역을 더 포함하는 폴리뉴클레오티드.
  17. 제16항에 있어서, 상기 3' 측 비번역 영역이 폴리A쇄를 포함하는 것인 폴리뉴클레오티드.
  18. 제16항 또는 제17항에 있어서, 상기 3' 측 비번역 영역의 3' 말단에서부터 1번째, 2번째 및 3번째의 뉴클레오티드가 당부 수식 뉴클레오티드인 폴리뉴클레오티드.
  19. 제12항 내지 제18항 중 어느 한 항에 있어서, 5' 측 비번역 영역 및/또는 3' 측 비번역 영역이 당부 수식 뉴클레오티드를 포함하는 것인 폴리뉴클레오티드.
  20. 제1항 내지 제19항 중 어느 한 항에 있어서, 이하의 구조를 포함하는 폴리뉴클레오티드:
    Figure pct00175

    [식 중,
    R1 및 R2는 각각 독립적으로 H, OH, F 또는 OCH3을 나타내고,
    B1 및 B2는 각각 독립적으로 염기부를 나타내며,
    X1은 O, S 또는 NH를 나타내고,
    X2는 O, S, NH 또는 이하의 구조를 나타내며,
    Figure pct00176

    X3은 OH, SH 또는 이들의 염을 나타내고,
    단, X1 및 X2는 동시에 O은 아니다.]
  21. 제1항 내지 제20항 중 어느 한 항에 있어서, 포스포로티오에이트 구조를 포함하는 폴리뉴클레오티드.
  22. 제1항 내지 제21항 중 어느 한 항에 있어서, 상기 n개의 코돈 중 적어도 1개의 코돈에 있어서의 1번째의 뉴클레오티드와 2번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 것인 폴리뉴클레오티드.
  23. 제1항 내지 제22항 중 어느 한 항에 있어서, 상기 5' 측 비번역 영역의 5' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 것인 폴리뉴클레오티드.
  24. 제1항 내지 제23항 중 어느 한 항에 있어서, 상기 3' 측 비번역 영역의 3' 말단에서부터 1∼2번째의 뉴클레오티드, 1∼3번째의 뉴클레오티드, 1∼4번째의 뉴클레오티드 또는 1∼5번째의 뉴클레오티드가 포스포로티오에이트에 의해서 연결되어 있는 것인 폴리뉴클레오티드.
  25. 제1항 내지 제24항 중 어느 한 항에 기재한 폴리뉴클레오티드를 포함하는 의약 조성물.
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