KR20210098477A - 핵산 복합체 - Google Patents

핵산 복합체 Download PDF

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KR20210098477A
KR20210098477A KR1020217019004A KR20217019004A KR20210098477A KR 20210098477 A KR20210098477 A KR 20210098477A KR 1020217019004 A KR1020217019004 A KR 1020217019004A KR 20217019004 A KR20217019004 A KR 20217019004A KR 20210098477 A KR20210098477 A KR 20210098477A
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히로토 이와이
다카시 이마에다
히로유키 아리야마
다쿠야 무라카미
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쿄와 기린 가부시키가이샤
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Abstract

본 발명은 하기 식 1로 표시되는 핵산 복합체를 제공한다.
식 1:
Figure pct00265

(식 1 중, X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이고, 상기 이중 사슬 핵산은, 상기 안티센스 사슬 중의, 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이고, 상기 센스 사슬의 3' 말단 또는 5' 말단은 S3에 결합하고, L1 및 L2는 각각 독립적으로 당 리간드이고, S1, S2 및 S3은 각각 독립적으로 링커이다.)

Description

핵산 복합체
본 발명은 핵산 복합체 및 이 핵산 복합체를 포함하는 의약 조성물 등에 관한 것이다.
핵산 의약으로서 압타머, 안티센스, 디코이 핵산, 리보자임, siRNA, miRNA 및 antimiRNA 등이 알려져 있다. 핵산 의약은 세포 내의 온갖 유전자를 제어할 수 있는 범용성이 높기 때문에, 지금까지 치료가 어렵다고 여겨져 온 다양한 질환에 대한 임상 응용이 기대되고 있다.
또한, 핵산 의약은 세포 내에 있어서의 표적 선택성과 활성이 높기 때문에, 항체, 저분자 의약에 이어지는 차세대 의약으로서 기대되고 있다.
그러나, 핵산 의약의 문제점으로서 표적 조직에의 송달이 곤란하다는 것을 들 수 있다.
인비보에 있어서의 효과적인 핵산 의약의 송달법의 하나로서, 표적화 화합물과 핵산의 핵산 복합체(콘쥬게이트)를 이용하는 것이 보고되어 있다. 표적화 화합물로서, 세포 밖으로 발현되는 수용체에 결합할 수 있는 리간드를 들 수 있다. 그 중에서도 특히 간세포에 매우 고발현인 아시알로당단백질 수용체(ASGPR)에 결합 가능한 리간드로서, N-아세틸-D-갈락토사민(GalNAc) 등을 이용한 핵산 복합체가 여러 개 보고되어 있다. 최근에는 이들 리간드와 siRNA류를 결합한 핵산 복합체가 간세포에 효율적으로 송달되는 것이 보고되어 있다(비특허문헌 1).
표적화 화합물과 올리고뉴클레오티드의 복합체로서, 예컨대 특허문헌 1 및 2에는 이하에 나타내는 핵산 복합체가 개시되어 있다.
Figure pct00001
(식 중, Ac는 아세틸기를 나타낸다. 이하, 본 명세서에 있어서 마찬가지다.)
또한, 특허문헌 3에는 특허문헌 1 및 2에 개시되는 핵산 복합체와 같은 당(糖) 리간드 테더 유닛을 갖는 이하에 나타내는 구조를 갖는 핵산 복합체가 개시되어 있다.
Figure pct00002
또한, 특허문헌 4에는 당 리간드 테더 유닛으로서 이하에 나타내는 구조를 갖는 핵산 복합체가 개시되어 있다.
Figure pct00003
APCS(amyloid P component, serum)(별칭 혈청 아밀로이드 P, SAP 혹은 펜트락신(Pentraxin)-2라고도 한다)는 223 아미노산으로 구성되는 당단백질의 5량체 구조를 갖는다. APCS는 간에서 생성되는 당 단백질이며, 혈중에 30∼50 μg/mL라는 비교적 고농도로 존재한다.
또한, APCS는 칼슘 의존적으로 모든 종류의 아밀로이드 섬유에 결합하는 생화학적 특성을 가지고, 아밀로이드를 갖는 환자의 아밀로이드 내에도 20,000 mg이나 되는 다량의 APCS가 포함되어 있는 것이 알려져 있다(비특허문헌 2).
APCS는 모든 아밀로이드 관련 질환 환자에게 있어서의 아밀로이드 내에 존재하므로, 아밀로이드 관련 질환 환자에게 있어서의 진단 마커로서 이용되고 있다(비특허문헌 3).
아밀로이드 관련 질환은, 아밀로이드 섬유로서 알려져 있는 이상한 불용성 단백질 섬유가 조직에 침착(沈着)되어 장기 장해가 야기되는 질환이다.
APCS가 아밀로이드에 결합함으로써 프로테아제에 의한 분해 내성이나 면역 세포에 의한 탐식에 대한 내성을 유도함으로써, APCS가 결합한 아밀로이드를 안정화할 수 있다는 것이 밝혀져 있고, 또한 APCS의 아밀로이드에의 결합을 저해함으로써, 장기에의 아밀로이드 침착 및 그것에 동반되는 조직 장해를 경감할 수 있다는 것이, 동물 모델을 이용한 연구 및 임상 연구로부터 강하게 시사되어 있다(비특허문헌 4 및 5).
APCS의 발현을 특이적으로 억제함으로써, 아밀로이드 관련 질환을 예방 또는 치료할 수 있다고 기대할 수 있지만, APCS의 발현을 특이적으로 억제하는 의약품은 지금까지 보고되지 않았다.
[특허문헌 1] 국제공개 제2009/073809호 [특허문헌 2] 국제공개 제2013/075035호 [특허문헌 3] 국제공개 제2015/105083호 [특허문헌 4] 국제공개 제2014/179620호
[비특허문헌 1] 저널 오브 아메리칸 케미컬 소사이어티(Journal of American Chemical Society), 2014년, 제136권, p 16958-16961 [비특허문헌 2] 아밀로이드(Amyloid) 1997년, 제4: 4권, p 274-295 [비특허문헌 3] 뉴잉글랜드 저널 오브 메디신(N. Engl. J. Med.) 1990년, 제323권, p 508-13 [비특허문헌 4] 네이처(Nature) 2010년, 제468권, p 93-97 [비특허문헌 5] 뉴잉글랜드 저널 오브 메디신(N. Engl. J. Med.) 2015년, 제373권, p 1106-1114
본 발명의 목적은 APCS의 발현을 억제할 수 있는 핵산 복합체를 제공하는 데에 있다.
본 발명은 이하에 관한 것이다.
[1]
하기 식 1로 표시되는 핵산 복합체.
식 1:
Figure pct00004
(식 1 중,
X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이고,
상기 이중 사슬 핵산은, 상기 안티센스 사슬 중의 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이고,
상기 센스 사슬의 3' 말단 또는 5' 말단은 S3에 결합하고,
L1 및 L2는 각각 독립적으로 당 리간드이고,
S1, S2 및 S3은 각각 독립적으로 링커이다.)
[2]
하기 식 2로 표시되는 구조를 갖는 [1]에 기재한 핵산 복합체.
식 2:
Figure pct00005
(식 2 중,
X, L1, L2 및 S3은 각각 상기와 동의이고,
P1, P2, P3, P4, P5 및 P6, 그리고 T1 및 T2는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q1, Q2, Q3 및 Q4는 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n-CH2CH2-이며, n은 0∼99의 정수이고,
B1 및 B2는 각각 독립적으로 결합수(結合手)이거나 또는 하기 식 2-1로 표시되는 어느 하나의 구조이고, 각 구조에 있어서의 말단의 둥근 흑점은 각각 P2 또는 P3 혹은 P5 또는 P6과의 결합점이며, m1, m2, m3 및 m4는 각각 독립적으로 0∼10의 정수이고,
식 2-1:
Figure pct00006
p1 및 p2는 각각 독립적으로 1, 2 또는 3의 정수이고,
q1, q2, q3 및 q4는 각각 독립적으로 0∼10의 정수이고,
단, p1 및 p2가 각각 2 또는 3의 정수일 때, 각각의 P3 및 P6, Q2 및 Q4, T1 및 T2, 그리고 L1 및 L2는 동일하거나 또는 다르더라도 좋으며, q1∼q4가 2∼10일 때, 각각의 -[P2-Q1]-, -[Q2-P3]-, -[P5-Q3]-, -[Q4-P6]-의 조합은 동일하거나 또는 다르더라도 좋다.)
[3]
P1 및 P4가 각각 독립적으로 -CO-NH-, -NH-CO- 또는 -O-인 [2]에 기재한 핵산 복합체.
[4]
-[P2-Q1]q1- 및 -[P5-Q3]q3-이 각각 독립적으로 존재하지 않거나 또는 하기 식 3-1∼식 3-3으로 표시되는 어느 하나의 구조인 [2] 또는 [3]에 기재한 핵산 복합체.
식 3-1:
Figure pct00007
식 3-2:
Figure pct00008
식 3-3:
Figure pct00009
(식 3-1∼식 3-3 중,
m5 및 m6은 각각 독립적으로 0∼10의 정수이고, 식 3-1∼식 3-3의 구조에 있어서의 말단의 둥근 흑점은 각각 B1 또는 B2 혹은 P1 또는 P4와의 결합점이다.)
[5]
하기 식 4-1∼식 4-9로 표시되는 어느 하나의 구조를 갖는 [2]∼[4]의 어느 한 항에 기재한 핵산 복합체.
식 4-1:
Figure pct00010
식 4-2:
Figure pct00011
식 4-3:
Figure pct00012
식 4-4:
Figure pct00013
식 4-5:
Figure pct00014
식 4-6:
Figure pct00015
식 4-7:
Figure pct00016
식 4-8:
Figure pct00017
식 4-9:
Figure pct00018
(식 4-1∼4-9 중,
X, L1, L2, S3, P3, P6, T1, T2, Q2, Q4, q2 및 q4는 각각 상기와 동의이다.)
[6]
하기 식 5로 표시되는 구조를 갖는 [1]에 기재한 핵산 복합체.
식 5:
Figure pct00019
(식 5 중,
X, S3, P1, P2, P3, Q1, Q2, B1, T1, L1, p1, q1 및 q2는 각각 상기와 동의이다.)
[7]
P1이 -CO-NH-, -NH-CO- 또는 -O-인 [6]에 기재한 핵산 복합체.
[8]
하기 식 6-1∼식 6-9로 표시되는 어느 하나의 구조를 갖는 [6] 또는 [7]에 기재한 핵산 복합체.
식 6-1:
Figure pct00020
식 6-2:
Figure pct00021
식 6-3:
Figure pct00022
식 6-4:
Figure pct00023
식 6-5:
Figure pct00024
식 6-6:
Figure pct00025
식 6-7:
Figure pct00026
식 6-8:
Figure pct00027
식 6-9:
Figure pct00028
(식 6-1∼6-9 중,
X, S3, P3, Q2, T1, L1 및 q2는 각각 상기와 동의이다.)
[9]
하기 식 7-1∼식 7-9로 표시되는 어느 하나의 구조를 갖는 [2]∼[5]의 어느 한 항에 기재한 핵산 복합체.
식 7-1:
Figure pct00029
식 7-2:
Figure pct00030
식 7-3:
Figure pct00031
식 7-4:
Figure pct00032
식 7-5:
Figure pct00033
식 7-6:
Figure pct00034
식 7-7:
Figure pct00035
식 7-8:
Figure pct00036
식 7-9:
Figure pct00037
(식 7-1∼7-9 중,
X, S3, L1 및 L2는 각각 상기와 동의이다.)
[10]
상기 당 리간드가 N-아세틸갈락토사민인 [1]∼[9]의 어느 한 항에 기재한 핵산 복합체.
[11]
상기 이중 사슬 핵산이 수식 뉴클레오티드를 포함하는 [1]∼[10]의 어느 한 항에 기재한 핵산 복합체.
[12]
센스 사슬의 3' 말단 및 안티센스 사슬의 5' 말단은 평활(平滑) 말단을 형성하는 [1]∼[11]의 어느 한 항에 기재한 핵산 복합체.
[13]
상기 이중 사슬 핵산이 당부(糖部) 수식 뉴클레오티드를 포함하는 [11]에 기재한 핵산 복합체.
[14]
하기 식 7-8-1로 표시되는 구조를 갖는 [1]∼[13]의 어느 한 항에 기재한 핵산 복합체.
식 7-8-1:
Figure pct00038
(식 7-8-1 중, X는 상기와 동의이다.)
[15]
X가 표 1-1∼표 1-13에 기재한 센스 사슬/안티센스 사슬로 이루어지는 군에서 선택되는 한 쌍의 센스 사슬/안티센스 사슬인 [1]∼[14]의 어느 한 항에 기재한 핵산 복합체.
[16]
X가 표 M1-1∼표 M1-3 및 표 R-1∼표 R-4에 기재한 센스 사슬/안티센스 사슬로 이루어지는 군에서 선택되는 한 쌍의 센스 사슬/안티센스 사슬인 [1]∼[14]의 어느 한 항에 기재한 핵산 복합체.
[16-A1]
X가 3' 말단이 S3에 결합하는 센스 사슬과 서열 번호 2126, 2144, 2146의 어느 하나의 안티센스 사슬을 포함하는 한 쌍의 센스 사슬/안티센스 사슬인 [1]∼[14]의 어느 한 항에 기재한 핵산 복합체.
[16-A2]
하기 식 6-1∼식 6-9로 표시되는 구조를 갖는 [16-A1]에 기재한 핵산 복합체.
식 6-7:
Figure pct00039
(식 6-7 중,
X, S3, P3, Q2, T1, L1 및 q2는 각각 상기와 동의이다.)
[16-A3]
하기 식 7-8로 표시되는 구조를 갖는 [16-A1]에 기재한 핵산 복합체.
식 7-8:
Figure pct00040
(식 7-8 중,
X, S3, L1 및 L2는 각각 상기와 동의이다.)
[16-A4]
하기 식 7-8-1로 표시되는 구조를 갖는 [16-A1]에 기재한 핵산 복합체.
식 7-8-1:
Figure pct00041
(식 7-8-1 중, X는 상기와 동의이다.)
[16-B1]
X가 서열 번호 2083의 센스 사슬과 서열 번호 2126의 안티센스 사슬, 서열 번호 2101의 센스 사슬과 서열 번호 2144의 안티센스 사슬, 또는 서열 번호 2103의 센스 사슬과 서열 번호 2146의 안티센스 사슬을 포함하는 한 쌍의 센스 사슬/안티센스 사슬인 [1]∼[14]의 어느 한 항에 기재한 핵산 복합체.
[16-B2]
하기 식 6-1∼식 6-9로 표시되는 구조를 갖는 [16-B1]에 기재한 핵산 복합체.
식 6-7:
Figure pct00042
(식 6-7 중,
X, S3, P3, Q2, T1, L1 및 q2는 각각 상기와 동의이다.)
[16-B3]
하기 식 7-8로 표시되는 구조를 갖는 [16-B1]에 기재한 핵산 복합체.
식 7-8:
Figure pct00043
(식 7-8 중,
X, S3, L1 및 L2는 각각 상기와 동의이다.)
[16-B4]
하기 식 7-8-1로 표시되는 구조를 갖는 [16-B1]에 기재한 핵산 복합체.
식 7-8-1:
Figure pct00044
(식 7-8-1 중, X는 상기와 동의이다.)
[17]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체를 포함하는 의약 조성물.
[18]
세포 내에 도입하기 위한 [17]에 기재한 의약 조성물.
[19]
정맥내 투여 또는 피하 투여되는 [17] 또는 [18]에 기재한 의약 조성물.
[20]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체 또는 [17]∼[19]의 어느 한 항에 기재한 의약 조성물을, 그것을 필요로 하는 환자에게 투여하는 것을 포함하는, 질환의 치료 또는 예방 방법.
[21]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체 또는 [17]∼[19]의 어느 한 항에 기재한 의약 조성물을 이용하여 이중 사슬 핵산을 세포 내에 도입하는 것을 포함하는, APCS 유전자의 발현을 억제하는 방법.
[22]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체 또는 [17]∼[19]의 어느 한 항에 기재한 의약 조성물을 포유동물에게 투여하는 것을 포함하는, 아밀로이드 관련 질환의 치료 방법.
[23]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체 또는 [17]∼[19]의 어느 한 항에 기재한 의약 조성물을 포함하는, 아밀로이드 관련 질환의 치료에 이용하기 위한 의약.
[24]
[1]∼[16]의 어느 한 항에 기재한 핵산 복합체 또는 [17]∼[19]의 어느 한 항에 기재한 의약 조성물을 포함하는, 아밀로이드 관련 질환의 치료제.
[25]
아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 [22]에 기재한 치료 방법.
[26]
아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 [23]에 기재한 의약.
[27]
아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 [24]에 기재한 치료제.
예컨대 본 발명의 핵산 복합체를 포함하는 의약 조성물을 포유동물에게 투여하여 생체 내에 있어서 각종 관련 질환을 치료할 수 있다.
도 1은 시험예 2에 있어서의 각 마우스군의 혈중 인간 APCS 농도의 추이를 도시하는 도면이다. 도면에서 Day0의 APCS 농도는 투여 6일 전의 값을 나타내고, 첫회 투여일을 Day0으로 했다. 횡축은 첫회 투여일을 0일째로 한 경과 일수, 종축은 혈중 인간 APCS 농도(μg/mL)를 나타낸다. ○는 컨트롤군, ▲은 화합물 5-2의 10 mg/kg 투여군을 나타낸다. 도면의 에러 바는 표준편차(SD)를 나타낸다.
본 발명의 핵산 복합체는 하기 식 1로 표시되는 핵산 복합체이다.
식 1:
Figure pct00045
식 1 중,
X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이고,
상기 이중 사슬 핵산은, 상기 안티센스 사슬 중의, 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이고,
상기 센스 사슬의 3' 말단 또는 5' 말단은 S3에 결합하고,
L1 및 L2는 각각 독립적으로 당 리간드이고,
S1, S2 및 S3은 각각 독립적으로 링커이다.
본 발명에 있어서, S1 및 S2는 S3의 벤젠환 상의 치환 위치에 대하여 각각 오르토 위치, 메타 위치, 파라 위치에서 벤젠환과 결합할 수 있지만, 하기 식 1-1로 표시되는 핵산 복합체인 것이 적합하다. 식 1에 있어서의 S1 및 S2의 벤젠환에의 결합수는, 벤젠환 상의 S3의 치환 위치 이외에 임의의 위치일 수 있다는 것을 의미한다.
식 1-1:
Figure pct00046
식 1-1 중,
X, L1, L2, S1, S2 및 S3은 각각 상기와 동의이다.
본 명세서에 있어서, 상기와 동의란, 식 1-1을 예시하여 설명하면, 식 1-1 중의 X, L1, L2, S1 및 S2 각각에 관해서, 식 1에 있어서 상기한 X, L1, L2, S1 및 S2 각각에 관한 정의와 같은 기일 수 있다는 것을 의미하고 있다.
본 발명에 있어서, X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이다.
또한, 상기 이중 사슬 핵산은, 상기 안티센스 사슬 중의, 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 후술하는 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이다.
또한, 상기 센스 사슬의 3' 말단 또는 5' 말단은 S3에 결합한다.
L1 및 L2는 각각 독립적으로 당 리간드이다.
본 발명에 있어서, 당 리간드란, 표적 세포에서 발현된 수용체에 결합할 수 있는 당류(단당, 이당, 삼당 및 다당 등)에서 유래하는 기를 의미한다. 또한, 본 발명에 있어서, 당 리간드가 O- 결합에 의해 S1 및 S2의 링커에 결합하고 있는 경우에는, 당 리간드란, 그것을 구성하는 당류의 결합에 관여하는 수산기를 제외한 부분이 당류에서 유래하는 기를 의미한다.
본 발명에서는, 올리고뉴클레오티드의 표적이 되는 당 리간드를 선택하면 된다.
단당으로서는, 예컨대 알로오스, 알토오스, 아라비노오스, 클라디노오스, 에리트로오스, 에리트룰로오스, 프럭토오스, D-푸시톨, L-푸시톨, 푸코사민, 푸코오스, 푸쿨로오스, 갈락토사민, D-갈락토사미니톨, N-아세틸-갈락토사민, 갈락토오스, 글루코사민, N-아세틸-글루코사민, 글루코사미니톨, 글루코오스, 글루코오스-6-인산, 글로오스, 글리세르알데히드, L-글리세로-D-만노-헵토오스, 글리세롤, 글리세론, 글로오스, 이도오스, 릭소오스, 만노사민, 만노오스, 만노오스-6-인산, 피시코오스, 퀴노보오스, 퀴노보사민, 람니톨, 람노사민, 람노오스, 리보오스, 리불로오스, 세도헵툴로오스, 소르보오스, 타가토오스, 타로오스, 타르타르산, 트레오스, 자일로오스 및 자일룰로오스 등을 들 수 있다.
이당, 삼당, 다당으로서는, 예컨대 아베크오스, 아클라보오스, 아미세토오스, 아밀로펙틴, 아밀로오스, 아피오스, 아르카노오스, 아스칼릴로오스, 아스코르빈산, 보이비노오스, 셀로비오스, 셀로트리오스, 셀룰로오스, 카코트리오스, 칼루코오스, 키틴, 코리토오스, 시클로덱스트린, 시마로오스, 덱스트린, 2-데옥시리보오스, 2-데옥시글루코오스, 디기노오스, 디기탈로오스, 디기톡소오스, 에발로오스, 에베미트로오스(evemitrose), 프럭토올리고당, 갈락토올리고당(galto-oligosaccharide, 겐티아노오스, 겐티오비오스, 글루칸, 글리코겐, 하마멜로오스, 헤파린, 이눌린, 이소레보글루코세논, 이소말토오스, 이소말토트리오스, 이소파노오스, 코지비오스, 락토오스, 락토사민, 락토오스디아민, 라미나라비오스, 레보글루코산, 레보글루코세논, β-말토스, 말토리오스, 만난올리고당, 만니노트리오스, 멜레치토오스, 멜리비오스, 무람산, 미카로오스, 미시노오스, 뉴라민산, 시알산 함유 당쇄, 니겔로오스, 노디리미신, 노비오스, 올레안드로오스, 파노오스, 파라토오스, 플란테오스, 프리메베로오스, 라피노오스, 로디노오스, 루티노오스, 사르멘토오스, 세도헵툴로오스, 세도헵툴로산, 솔라트리오스, 소포로오스, 스타키오스, 스트렙토오스, 수크로오스, α,α-트레할로오스, 트라할로사민, 투라노오스, 티벨로오스, 자일로비오스, 움벨리페로오스 등을 들 수 있다.
당류에 있어서의 각 단당은 D체 또는 L체라도 좋고, D체와 L체의 임의 비율에 의한 혼합물이라도 좋다.
당류는, 데옥시당(알코올히드록시기를 수소 원자로 치환한 것), 아미노당(알코올히드록시기를 아미노기로 치환한 것), 티오당(알코올히드록시기를 티올로 치환한 것, 또는 C=O를 C=S로 치환한 것, 또는 고리 산소를 황으로 치환한 것), 셀레노당, 텔룰로당, 아자당(고리 탄소를 질소로 치환한 것), 이미노당(고리 산소를 질소로 치환한 것), 포스파노당(고리 산소를 인으로 치환한 것), 포스파당(고리 탄소를 인으로 치환한 것), C- 치환 단당(비말단 탄소 원자에 있어서의 수소 원자를 탄소 원자로 치환한 것), 불포화 단당, 알디톨(카르보닐기를 CHOH기로 치환한 것), 알돈산(알데히드기를 카르복시기로 치환한 것), 케토알돈산, 우론산, 알다르산 등을 포함하고 있어도 좋다.
단당인 아미노당으로서, 갈락토사민, 글루코사민, 만노사민, 푸코사민, 퀴노보사민, 뉴라민산, 무라민산, 락토오스디아민, 아코사민, 바실로사민, 다우노사민, 데소사민, 포로사민, 가로사민, 카노사민, 칸소사민(kansosamine), 미카미노오스, 미코사민, 페로사민, 푸노이모사민, 푸르푸로사민(purpurosamine), 로도사민 등을 들 수 있다. 또한, 아미노당의 아미노기는 아세틸기 등으로 치환되어 있어도 좋다.
시알산 함유 당쇄로서는, NeuAc을 당쇄 비환원 말단에 함유하는 당쇄를 들 수 있고, 구체적으로는 NeuAc-Gal-GlcNAc을 함유하는 당쇄나 Neu5Acα(2-6)Galβ(1-3)GlcNAc 등을 들 수 있다.
당류에 있어서의 각 단당은, 표적 세포에 발현된 수용체에 결합 가능한 것을 한도로 하여, 치환기로 치환되어 있어도 좋으며, 예컨대 수산기가 치환되어 있어도 좋고, 각 단당에 있어서의 수소 원자가 아지드 및/또는 치환되어 있어도 좋은 아릴기로 하나∼복수 치환되어 있어도 좋다.
당 리간드로서는, 표적으로 하는 각 장기에 대응하여 표적 세포의 표면에 발현되는 수용체에 결합하는 당 리간드를 선택하는 것이 바람직하다. 예컨대 표적 세포가 간세포인 경우, 간세포 표면에 발현되는 수용체에 대한 당 리간드가 바람직하고, 아시알로당 단백질 수용체(ASGPR)에 대한 당 리간드가 보다 바람직하다.
ASGPR에 대한 당 리간드로서는, 만노오스 또는 N-아세틸갈락토사민이 바람직하고, N-아세틸갈락토사민이 보다 바람직하다.
ASGPR에 대하여 보다 친화성이 높은 당 리간드로서, 예컨대 Bioorganic Medicinal Chemistry, 17,7254(2009) 및 Journal of American Chemical Society, 134, 1978(2012) 등에 기재된 당 유도체가 알려져 있으며, 이들을 이용하여도 좋다.
본 발명에 있어서, S1, S2 및 S3은 링커이다.
S1과 S2는 당 리간드인 L1과 L2와 벤젠환을 연결하는 구조라면 특별히 한정되는 것은 아니며, 핵산 복합체에 있어서 이용되는 공지된 구조를 채용하여도 좋다. S1과 S2는 동일하더라도 좋고 다르더라도 좋다.
당 리간드인 L1과 L2는 S1 및 S2와 글리코시드 결합에 의해 연결되어 있는 것이 바람직하다. S1 및 S2는 벤젠환과 예컨대 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH- 결합에 의해 각각 연결되어 있어도 좋다.
S3은 이중 사슬 핵산인 X와 벤젠환을 연결하는 구조라면 특별히 한정되는 것은 아니며, 핵산 복합체에 있어서 이용되는 공지된 구조를 채용하여도 좋다.
올리고뉴클레오티드인 X는 S3과 포스포디에스테르 결합에 의해 연결되어 있는 것이 바람직하다. S3은 벤젠환과 예컨대 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH- 결합에 의해 연결되어 있어도 좋다.
S1, S2 및 S3의 링커는 예컨대 국제공개 제2009/073809호, 국제공개 제2013/075035호, 국제공개 제2015/105083호, 국제공개 제2014/179620호, 국제공개 제2015/006740호에 개시되는 구조를 채용하여도 좋다.
본 발명에 있어서, 핵산 복합체는 하기 식 2로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 2:
Figure pct00047
식 2 중,
X, L1, L2 및 S3은 각각 상기와 동의이고,
P1, P2, P3, P4, P5 및 P6, 그리고 T1 및 T2는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q1, Q2, Q3 및 Q4는 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n-CH2CH2-이며, n은 0∼99의 정수이다.
P1 및 P4는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, -O-, -O-CO-, -NH-CO- 또는 -CO-NH-인 것이 바람직하고, -O-, -NH-CO- 또는 -CO-NH-인 것이 보다 바람직하고, -NH-CO-인 것이 더욱 바람직하다.
P1 또는 P4가 예컨대 -NH-CO-인 경우, -NH-CO- 벤젠환이라는 부분 구조를 갖는다.
Q1, Q2, Q3 및 Q4는 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n-CH2CH2-이고, n은 0∼99의 정수이지만, 치환 혹은 무치환의 탄소수 1∼12의 알킬렌인 것이 바람직하고, 무치환의 탄소수 1∼12의 알킬렌인 것이 보다 바람직하고, 무치환의 탄소수 1∼6의 알킬렌인 것이 더욱 바람직하고, 무치환의 탄소수 1∼4의 알킬렌인 것이 보다 더욱 바람직하다.
P2 및 P5는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, 존재하지 않거나 -CO-O- 또는 -CO-NH-인 것이 바람직하고, 존재하지 않거나 -CO-NH-인 것이 보다 바람직하다. P2 및 P5가 예컨대 -CO-NH-인 경우, B1-CO-NH-Q1 및 B2-CO-NH-Q3이라는 부분 구조를 갖는다.
-[P2-Q1]q1- 및 -[P5-Q3]q3-이 각각 독립적으로 존재하지 않거나 또는 하기 식 3-1∼식 3-3으로 표시되는 어느 하나의 구조인 것이 적합하다.
식 3-1:
Figure pct00048
식 3-2:
Figure pct00049
식 3-3:
Figure pct00050
식 3-1∼3-3 중,
m5 및 m6은 각각 독립적으로 0∼10의 정수이고, 식 3-1∼식 3-3의 구조에 있어서의 말단의 둥근 흑점은 각각 B1 또는 B2 혹은 P1 또는 P4와의 결합점이다.
B1 및 B2는 각각 독립적으로 결합수이거나 또는 하기 식으로 표시되는 어느 하나의 구조이고, 각 구조에 있어서의 말단의 둥근 흑점은 각각 P2 또는 P3 혹은 P5 또는 P6과의 결합점이며, m1, m2, m3 및 m4는 각각 독립적으로 0∼10의 정수이다.
Figure pct00051
B1 및 B2는, 글루타민산, 아스파라긴산, 리신, 이미노이아세트산 등의 비천연 아미노산을 포함하는 아미노산, 또는 2-아미노-1,3-프로판디올 등의 아미노알코올에서 유래하는 기인 것이 바람직하고, B1 및 B2가 글루타민산 및 아스파라긴산에서 유래하는 기인 경우, 글루타민산 및 아스파라긴산의 아미노기가 각각 결합하며, P2 및 P5로서 -NH-CO- 결합인 것이 바람직하고, B1 및 B2가 리신에서 유래하는 기인 경우, 리신의 카르복실기가 각각 결합하며, P2 및 P5로서 -CO-NH- 결합인 것이 바람직하고, B1 및 B2가 이미노이아세트산에서 유래하는 기인 경우, 이미노이아세트산의 아미노기가 각각 결합하며, P2 및 P5로서 -CO- 결합이 되는 것이 바람직하다. B1 및 B2는 구체적으로는 이하의 구조를 갖는 것이 바람직하다.
Figure pct00052
p1 및 p2가 각각 2 또는 3의 정수일 때, 각각의 P3 및 P6, Q2 및 Q4, T1 및 T2, 그리고 L1 및 L2는 동일하더라도 또는 다르더라도 좋다.
q1∼q4가 2∼10일 때, 각각의 -[P2-Q1]-, -[Q2-P3]-, -[P5-Q3]-, -[Q4-P6]-의 조합은 동일하더라도 또는 다르더라도 좋다. 각각의 -[P2-Q1]-, -[Q2-P3]-, -[P5-Q3]- 및 -[Q4-P6]-의 조합이 동일하거나 또는 다르다는 것은 -[P2-Q1]-, -[Q2-P3]-, -[P5-Q3]- 및 -[Q4-P6]-으로 표시되는 각 2∼10의 단위가 동일한 경우와 다른 경우가 있다는 것을 의미한다.
본 발명에 있어서, 핵산 복합체는 하기 식 4-1∼4-9로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 4-1:
Figure pct00053
식 4-2:
Figure pct00054
식 4-3:
Figure pct00055
식 4-4:
Figure pct00056
식 4-5:
Figure pct00057
식 4-6:
Figure pct00058
식 4-7:
Figure pct00059
식 4-8:
Figure pct00060
식 4-9:
Figure pct00061
식 4-1∼4-9 중,
X, L1, L2, S3, P3, P6, T1, T2, Q2, Q4, q2 및 q4는 각각 상기와 동의이다.
P3 및 P6은 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, -O-CO- 또는 -NH-CO-인 것이 바람직하고, -NH-CO-인 것이 보다 바람직하다. P3 및 P6이 예컨대 -NH-CO-인 경우, 각각 B1-NH-CO-Q2 및 B2-NH-CO-Q4라는 부분 구조를 갖는다.
T1 및 T2는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, -O- 또는 -S-인 것이 바람직하고, -O-인 것이 보다 바람직하다.
본 발명에 있어서, 핵산 복합체는 하기 식 5로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 5에서는, 식 2에 있어서의 P1과 P4, P2와 P5, P3과 P6, Q1과 Q3, Q2와 Q4, B1과 B2, T1과 T2, L1과 L2, p1과 p2, q1과 q3 및 q2와 q4가 각각 동일하다.
식 5:
Figure pct00062
식 5 중,
X, S3, P1, P2, P3, Q1, Q2, B1, T1, L1, p1, q1 및 q2는 각각 상기와 동의이다.
또한, 식 5에 있어서의 X, S3, P1, P2, P3, Q1, Q2, B1, T1, L1, p1, q1 및 q2는 각각 상술한 적합한 기라도 좋지만, P1이 -CO-NH-, -NH-CO- 또는 -O-인 것이 바람직하다.
식 5에 있어서의 -(P2-Q1)q1-은 존재하지 않거나 또는 상기 식 3-1∼식 3-3으로 표시되는 어느 하나의 구조인 것이 적합하다.
본 발명에 있어서, 핵산 복합체는 하기 식 6-1∼6-9로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 6-1:
Figure pct00063
식 6-2:
Figure pct00064
식 6-3:
Figure pct00065
식 6-4:
Figure pct00066
식 6-5:
Figure pct00067
식 6-6:
Figure pct00068
식 6-7:
Figure pct00069
식 6-8:
Figure pct00070
식 6-9:
Figure pct00071
식 6-1∼식 6-9 중,
X, S3, P3, Q2, T1, L1 및 q2는 각각 상기와 동의이다.
본 발명에 있어서, 핵산 복합체는 하기 식 7-1∼식 7-9의 어느 하나로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 7-1:
Figure pct00072
식 7-2:
Figure pct00073
식 7-3:
Figure pct00074
식 7-4:
Figure pct00075
식 7-5:
Figure pct00076
식 7-6:
Figure pct00077
식 7-7:
Figure pct00078
식 7-8:
Figure pct00079
식 7-9:
Figure pct00080
식 7-1∼식 7-9 중,
X, L1, L2 및 S3은 각각 상기와 동의이다. L1과 L2는 동일하더라도 좋고, 다르더라도 좋으며, 동일한 것이 적합하다.
식 7-1∼식 7-9에 있어서, 각 알킬렌기 부분을 사슬 길이가 다른 알킬렌 사슬을 도입함으로써, 또한 아미드 결합 등을 다른 결합으로 치환함으로써, 식 7-1∼식 7-9로 표시되는 구조를 갖는 핵산 복합체 이외의 핵산 유도체를 제조할 수도 있다.
본 발명에 있어서, 핵산 복합체는 하기 식 11로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 11:
Figure pct00081
식 11 중,
L1, L2, S1, S2 및 X는 각각 상기와 동의이고,
P7 및 P8은 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q5, Q6 및 Q7은 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n8-CH2CH2-이며, n8은 0∼99의 정수이고,
B3은 본 명세서 내에서는 블랜처 유닛이라고 불리며, 하기 식 11-1로 표시되는 어느 하나의 구조이고, 파선은 각각 Q5 및 Q6과의 결합수를 의미한다.
식 11-1:
Figure pct00082
식 11-1 중, 트리아졸환을 갖는 기에 있어서의 치환은, 상기 트리아졸환의 1 위치 및 3 위치의 질소 원자의 어느 하나이다.
q5 및 q6은 각각 독립적으로 0∼10의 정수이다.
P7은 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, -O-, -NH-CO- 또는 -CO-NH-인 것이 바람직하고, -O- 또는 -NH-CO-인 것이 보다 바람직하다. P7이 예컨대 -O-인 경우, 벤젠환-O-라는 부분 구조를 갖는다.
P8은 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이지만, 존재하는 경우, -CO-O- 또는 -CO-NH-인 것이 바람직하고, -CO-NH-인 것이 보다 바람직하다. P8이 예컨대 -CO-NH-인 경우, Q6-CO-NH-라는 부분 구조를 갖는다.
Q5, Q6 및 Q7은 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n8-CH2CH2-이며, n8은 0∼99의 정수이지만, 치환 혹은 무치환의 탄소수 1∼12의 알킬렌인 것이 바람직하고, 무치환의 탄소수 1∼12의 알킬렌인 것이 보다 바람직하고, 무치환의 탄소수 1∼6의 알킬렌인 것이 더욱 바람직하고, 무치환의 탄소수 1∼4의 알킬렌인 것이 보다 더욱 바람직하다.
-(P7-Q5)q5-는 -O-(CH2)m15-NH- 및 -NH-CO-(CH2)m16-NH이고, m15 및 m16은 각각 독립적으로 1∼10의 정수인 것이 적합하다.
본 발명에 있어서, 핵산 복합체는 하기 식 12-1∼식 12-12의 어느 하나로 표시되는 구조를 갖는 핵산 복합체인 것이 적합하다.
식 12-1:
Figure pct00083
식 12-2:
Figure pct00084
식 12-3:
Figure pct00085
식 12-4:
Figure pct00086
식 12-5:
Figure pct00087
식 12-6:
Figure pct00088
식 12-7:
Figure pct00089
식 12-8:
Figure pct00090
식 12-9:
Figure pct00091
식 12-10:
Figure pct00092
식 12-11:
Figure pct00093
식 12-12:
Figure pct00094
식 12-1∼12-12 중,
X, L1, L2, S1 및 S2는 각각 상기와 동의이고, n1'∼n12'는 각각 독립적으로 1∼10의 정수이다.
본 발명의 핵산 복합체는, 식 1로 표시되는 핵산 복합체에 있어서, S1 및 S2에 대응하는 식 2에 기재한 구조와 S3에 대응하는 식 11에 기재한 구조를 조합한 핵산 복합체인 것이 바람직하다. 식 2가 식 4-1∼식 4-9라도 좋고, 식 6-1∼식 6-9라도 좋고, 식 7-1∼식 7-9라도 좋으며, 식 2가 식 4-1∼식 4-9, 식 6-1∼식 6-9 혹은 식 7-1∼식 7-9인 경우에, 식 11이 식 12-1∼식 12-12라도 좋다. 본 발명의 핵산 복합체는, 식 1로 표시되는 핵산 복합체에 있어서, S1 및 S2에 대응하는 식 4-1∼식 4-9에 기재한 어느 하나의 구조 및 S3에 대응하는 식 12-1∼식 12-12에 기재한 어느 하나의 구조를 조합한 핵산 복합체, S1 및 S2에 대응하는 식 6-1∼식 6-9에 기재한 어느 하나의 구조 및 S3에 대응하는 식 12-1∼식 12-12에 기재한 어느 하나의 구조를 조합한 핵산 복합체, S1 및 S2에 대응하는 식 7-1∼식 7-9에 기재한 어느 하나의 구조 및 S3에 대응하는 식 12-1∼식 12-12에 기재한 어느 하나의 구조를 조합한 핵산 복합체인 것이 보다 적합하다.
본 발명의 핵산 복합체는 하기 식 7-8-1로 표시되는 것이 바람직하다.
식 7-8-1:
Figure pct00095
(식 7-8-1 중, X는 상기와 동의이다.)
식 1에 있어서의 X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이고, 이 이중 사슬 핵산은, 상기 안티센스 사슬 중의, 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이다. 센스 사슬의 3' 말단 또는 5' 말단이 S3에 결합하기 때문에, 식 1에 있어서, S3과 결합하는 X는 이중 사슬 핵산을 구성하는 센스 사슬이며, 후술하는 표 1-1∼표 1-13 또는 표 M1-1∼표 M1-3 및 표 R-1∼표 R-2 중의 센스 사슬 서열로 표시되는 센스 사슬이다.
본 발명에 있어서, APCS mRNA에 대하여 상보적인 염기 서열을 포함하는 핵산을 안티센스 사슬 핵산이라고 부르고, 안티센스 사슬 핵산의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산을 센스 사슬 핵산이라고도 부른다.
본 발명의 핵산 복합체를 구성하는 이중 사슬 핵산은, 포유동물 세포에 도입된 경우, APCS 유전자의 발현을 저하 또는 정지시키는 능력을 갖는 이중 사슬 핵산이며, 센스 사슬 및 안티센스 사슬을 갖는 이중 사슬 핵산이다. 또한, 상기 센스 사슬과 상기 안티센스 사슬은 적어도 11개의 염기쌍을 가지고, 상기 안티센스 사슬 중의, 적어도 17개의 뉴클레오티드 또한 많더라도 30개의, 즉 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬이, 표 1-1∼표 1-13에 기재된 군에서 선택되는 표적 APCS mRNA 서열과 상보적이다.
본 발명의 핵산 복합체를 구성하는 이중 사슬 핵산은, 뉴클레오티드 또는 이 뉴클레오티드와 동등한 기능을 갖는 분자가 중합된 중합체라면, 어떠한 이중 사슬 핵산이라도 좋다. 그와 같은 중합체로서는, 예컨대 리보뉴클레오티드의 중합체인 RNA, 데옥시리보뉴클레오티드의 중합체인 DNA, RNA와 DNA를 포함하는 키메라 핵산 및 이들 핵산의 적어도 하나의 뉴클레오티드가 이 뉴클레오티드와 동등한 기능을 갖는 분자로 치환된 뉴클레오티드 중합체를 들 수 있다. 또한, 이들 핵산 내에 뉴클레오티드와 동등한 기능을 갖는 분자를 적어도 하나 포함하는 유도체도 본 발명에서 이용되는 약물로서의 이중 사슬 핵산에 포함된다. 또한, 우라실(U)은 티민(T)으로 일의적으로 바꿔 읽을 수 있다.
뉴클레오티드와 동등한 기능을 갖는 분자로서는 예컨대 뉴클레오티드 유도체 등을 들 수 있다. 뉴클레오티드 유도체로서는, 뉴클레오티드에 수식을 행한 분자라면 어떠한 분자라도 좋지만, 예컨대 RNA 또는 DNA와 비교하여, 뉴클레아제 내성의 향상 혹은 안정화를 위해서, 상보 사슬 핵산과의 어피니티를 올리기 위해서, 세포 투과성을 올리기 위해서, 또는 가시화시키기 위해서, 리보뉴클레오티드 또는 데옥시리보뉴클레오티드에 수식을 행한 분자 등이 적합하게 이용된다.
뉴클레오티드에 수식을 행한 분자로서는, 예컨대 당부 수식 뉴클레오티드, 인산디에스테르 결합 수식 뉴클레오티드, 염기 수식 뉴클레오티드, 그리고 당부, 인산디에스테르 결합 및 염기의 적어도 하나가 수식된 뉴클레오티드 등을 들 수 있다.
당부 수식 뉴클레오티드로서는, 뉴클레오티드의 당의 화학 구조의 일부 혹은 전부에 대하여 임의의 치환기로 수식 혹은 치환한 것, 또는 임의의 원자로 치환한 것이라면 어떠한 것이라도 좋지만, 2'- 수식 뉴클레오티드가 바람직하게 이용된다.
2'- 수식 뉴클레오티드로서는, 예컨대 리보오스의 2'-OH기가 H, OR, R, R'OR, SH, SR, NH2, NHR, NR2, N3, CN, F, Cl, Br 및 I로 이루어지는 군(R은 알킬 또는 아릴, 바람직하게는 탄소수 1∼6의 알킬이고, R'은 알킬렌, 바람직하게는 탄소수 1∼6의 알킬렌이다)에서 선택되는 치환기로 치환된 뉴클레오티드이고, 보다 바람직하게는 2'-OH 기가 H, F 또는 메톡시기로 치환된 뉴클레오티드이고, 더욱 바람직하게는 2'-OH기가 F 또는 메톡시기로 치환된 뉴클레오티드이다. 또한, 2'-OH기가 2-(메톡시)에톡시기, 3-아미노프로폭시기, 2-[(N,N-디메틸아미노)옥시]에톡시기, 3-(N,N-디메틸아미노)프로폭시기, 2-[2-(N,N-디메틸아미노)에톡시]에톡시기, 2-(메틸아미노)-2-옥소에톡시기, 2-(N-메틸카르바모일)에톡시기 및 2-시아노에톡시기로 이루어지는 군에서 선택되는 치환기로 치환된 뉴클레오티드 등도 들 수 있다.
이중 사슬 핵산 영역 내의 뉴클레오티드에 대하여, 2'- 수식 뉴클레오티드는 50∼100% 포함되는 것이 바람직하고, 70∼100% 포함되는 것이 보다 바람직하고, 90∼100% 포함되는 것이 더욱 바람직하다. 또한, 센스 사슬의 뉴클레오티드에 대하여, 2'- 수식 뉴클레오티드는 20∼100% 포함되는 것이 바람직하고, 40∼100% 포함되는 것이 보다 바람직하고, 60%∼100% 포함되는 것이 더욱 바람직하다. 또한, 안티센스 사슬의 뉴클레오티드에 대하여, 2'- 수식 뉴클레오티드는 20∼100% 포함되는 것이 바람직하고, 40∼100% 포함되는 것이 보다 바람직하고, 60∼100% 포함되는 것이 더욱 바람직하다.
인산디에스테르 결합 수식 뉴클레오티드로서는, 뉴클레오티드의 인산디에스테르 결합의 화학 구조의 일부 혹은 전부에 대하여, 임의의 치환기로 수식 혹은 치환한 것, 또는 임의의 원자로 치환한 것이라면 어떠한 것이라도 좋으며, 예컨대 인산디에스테르 결합이 포스포로티오에이트 결합으로 치환된 뉴클레오티드, 인산디에스테르 결합이 포스포로디티오에이트 결합으로 치환된 뉴클레오티드, 인산디에스테르 결합이 알킬포스포네이트 결합으로 치환된 뉴클레오티드, 인산디에스테르 결합이 포스포로아미데이트 결합으로 치환된 뉴클레오티드 등을 들 수 있다.
염기 수식 뉴클레오티드로서는, 뉴클레오티드의 염기의 화학 구조의 일부 혹은 전부에 대하여, 임의의 치환기로 수식 혹은 치환한 것, 또는 임의의 원자로 치환한 것이라면 어떠한 것이라도 좋으며, 예컨대 염기 내의 산소 원자가 황 원자로 치환된 것, 수소 원자가 탄소수 1∼6의 알킬기, 할로겐 등으로 치환된 것, 메틸기가 수소, 히드록시메틸, 탄소수 2∼6의 알킬기 등으로 치환된 것, 아미노기가 탄소수 1∼6의 알킬기, 탄소수 1∼6의 알카노일기, 옥소기, 히드록시기 등으로 치환된 것을 들 수 있다.
뉴클레오티드 유도체로서는, 뉴클레오티드 또는 당부, 인산디에스테르 결합 혹은 염기의 적어도 하나가 수식된 뉴클레오티드 유도체에, 펩티드, 단백질, 당, 지질, 인지질, 페나진, 폴레이트, 페난트리딘, 안트라퀴논, 아크리딘, 플루오레세인, 로다민, 쿠마린, 색소 등, 별도의 화학 물질을 직접 또는 링커를 통해 부가한 것도 예로 들 수 있고, 구체적으로는 5'-폴리아민 부가 뉴클레오티드 유도체, 콜레스테롤 부가 뉴클레오티드 유도체, 스테로이드 부가 뉴클레오티드 유도체, 담즙산 부가 뉴클레오티드 유도체, 비타민 부가 뉴클레오티드 유도체, Cy5 부가 뉴클레오티드 유도체, Cy3 부가 뉴클레오티드 유도체, 6-FAM 부가 뉴클레오티드 유도체 및 비오틴 부가 뉴클레오티드 유도체 등을 들 수 있다.
뉴클레오티드 유도체는, 핵산 내의 다른 뉴클레오티드 또는 뉴클레오티드 유도체와 알킬렌 구조, 펩티드 구조, 뉴클레오티드 구조, 에테르 구조, 에스테르 구조 및 이들의 적어도 하나를 조합한 구조 등의 가교 구조를 형성하여도 좋다.
본 명세서에 있어서 「상보」란, 2개의 염기 사이에서 염기 짝짓기를 할 수 있는 관계를 의미하며, 예컨대 아데닌과 티민 또는 우라실과의 관계, 그리고 구아닌과 사이토신과의 관계와 같이 완만한 수소 결합을 통해 이중 사슬 영역 전체적으로 이중 나선 구조를 취하는 것을 말한다.
본 명세서에 있어서 「상보적」이란, 2개의 뉴클레오티드 서열이 완전히 상보하는 경우뿐만 아니라, 상기 뉴클레오티드 서열 사이에서 0∼30%, 0∼20% 또는 0∼10%의 미스매치 염기를 가질 수 있으며, 예컨대 APCS mRNA에 대하여 상보적인 안티센스 사슬은, 상기 mRNA의 부분 염기 서열과 완전히 상보하는 염기 서열에 있어서, 하나 또는 복수의 염기의 치환을 포함하여도 좋다는 것을 의미한다. 구체적으로는, 안티센스 사슬은 표적 유전자의 표적 서열에 대하여 1∼8개, 바람직하게는 1∼6개, 1∼4개, 1∼3개, 특히 2개 또는 1개의 미스매치 염기를 가지고 있어도 좋다. 예컨대 안티센스 사슬이 21 염기 길이인 경우에는, 표적 유전자의 표적 서열에 대하여 6개, 5개, 4개, 3개, 2개 또는 1개의 미스매치 염기를 갖더라도 좋으며, 그 미스매치의 위치는 각각의 서열의 5' 말단 또는 3' 말단이라도 좋다.
또한, 「상보적」이란, 한쪽의 뉴클레오티드 서열이 다른 쪽의 뉴클레오티드 서열과 완전히 상보하는 염기 서열에 있어서, 하나 또는 복수의 염기가 부가 및/또는 결손된 서열인 경우를 포함하는 의미이다. 예컨대 APCS mRNA와 본 발명의 안티센스 사슬 핵산은, 안티센스 사슬에 있어서의 염기의 부가 및/또는 결손에 의해, 안티센스 사슬 및/또는 표적 APCS mRNA 영역에 1개 또는 2개의 벌지 염기를 갖더라도 좋다.
본 발명에서 이용되는 약물로서의 이중 사슬 핵산은, APCS mRNA의 일부의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산 및/또는 이 핵산의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산이라면, 어느 뉴클레오티드 또는 그 유도체로 구성되어 있어도 좋다. 본 발명의 이중 사슬 핵산은, 표적 APCS mRNA 서열에 대하여 상보적인 염기 서열을 포함하는 핵산과 이 핵산의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산이 적어도 11개의 염기쌍의 이중 사슬을 형성할 수 있으면 어느 길이라도 좋지만, 이중 사슬을 형성할 수 있는 서열의 길이는 통상 11∼27 염기이며, 15∼25 염기가 바람직하고, 17∼23 염기가 보다 바람직하고, 19∼23 염기가 더욱 바람직하다.
본 발명의 핵산 복합체의 안티센스 사슬로서는, 표적 APCS mRNA 서열에 대하여 상보적인 염기 서열을 포함하는 핵산이 이용되지만, 상기 핵산 중 1∼3 염기, 바람직하게는 1∼2 염기, 보다 바람직하게는 1 염기가 결손, 치환 또는 부가된 것을 이용하여도 좋다.
APCS의 발현을 억제하는 핵산으로서는, 표적 APCS mRNA 서열에 대하여 상보적인 염기 서열을 포함하는 핵산이며 또한 APCS의 발현을 억제하는 단일 사슬 핵산, 혹은 표적 APCS mRNA 서열에 대하여 상보적인 염기 서열을 포함하는 핵산과 이 핵산의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산을 포함하며 또한 APCS의 발현을 억제하는 이중 사슬 핵산이 적합하게 이용된다.
이중 사슬 핵산을 구성하는 단일 사슬의 안티센스 사슬 핵산 및 센스 사슬 핵산은, 각각 동일하거나 또는 다르며, 통상 11∼30 염기를 포함하지만, 각각 동일하거나 또는 다르며, 17∼27 염기를 포함하는 것이 바람직하고, 17∼25 염기를 포함하는 것이 보다 바람직하고, 19∼25 염기를 포함하는 것이 더욱 바람직하고, 21 또는 23 염기를 포함하는 것이 보다 더욱 바람직하다.
본 발명에서 이용되는 약물로서의 이중 사슬 핵산에 있어서, 이중 사슬 영역에 이어지는 3' 측 또는 5' 측에 이중 사슬을 형성하지 않는 추가 뉴클레오티드 또는 뉴클레오티드 유도체를 갖는 경우에는, 이것을 돌출부(오버행)라고 부른다. 돌출부를 갖는 경우에는, 돌출부를 구성하는 뉴클레오티드는 리보뉴클레오티드, 데옥시리보뉴클레오티드 또는 이들의 유도체라도 좋다.
돌출부를 갖는 이중 사슬 핵산으로서는, 적어도 한쪽 사슬의 3' 말단 또는 5' 말단에 1∼6 염기, 통상은 1∼3 염기를 포함하는 돌출부를 갖는 것이 이용되지만, 2 염기를 포함하는 돌출부를 갖는 것이 바람직하게 이용되며, 예컨대 dTdT(dT는 데옥시티미딘을 나타낸다) 또는 UU(U는 우리딘을 나타낸다)을 포함하는 돌출부를 갖는 것을 예로 들 수 있다. 돌출부는, 안티센스 사슬에만, 센스 사슬에만 및 안티센스 사슬과 센스 사슬 양쪽에 가질 수 있지만, 본 발명에 있어서, 안티센스 사슬에 돌출부를 갖는 이중 사슬 핵산이 바람직하게 이용된다. 또한, 안티센스 사슬은, 이중 사슬 영역과 그것에 이어지는 돌출부를 포함하는, 17개∼30개의 뉴클레오티드를 포함하는 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 군에서 선택되는 표적 APCS mRNA 서열의 어느 하나와 충분히 상보적이다. 더욱이, 본 발명의 이중 사슬 핵산으로서는, 예컨대 Dicer 등의 리보뉴클레아제의 작용에 의해 이중 사슬 핵산을 생성하는 핵산 분자(WO2005/089287)나, 3' 말단이나 5' 말단의 돌출부를 갖지 않고서 평활 말단을 형성하는 이중 사슬 핵산, 센스 사슬만이 돌출된 이중 사슬 핵산(US2012/0040459) 등을 이용할 수도 있다.
본 발명의 핵산 복합체를 구성하는 이중 사슬 핵산으로서는, 표적 유전자의 염기 서열 또는 그 상보 사슬의 염기 서열과 동일한 서열을 포함하는 핵산을 이용하여도 좋지만, 상기 핵산의 적어도 한쪽 사슬의 5' 말단 또는 3' 말단이 1∼4 염기 삭제된 핵산과, 상기 핵산의 염기 서열에 대하여 상보적인 염기 서열을 포함하는 핵산을 포함하는 이중 사슬 핵산을 이용하여도 좋다.
본 발명의 핵산 복합체를 구성하는 이중 사슬 핵산은, RNA끼리 이중 사슬을 형성한 이중 사슬 RNA(dsRNA), DNA끼리 이중 사슬을 형성한 이중 사슬 DNA(dsDNA), 또는 RNA와 DNA가 이중 사슬을 형성한 하이브리드 핵산이라도 좋다. 혹은 이중 사슬 중 한쪽 혹은 양쪽의 사슬이 DNA와 RNA의 키메라 핵산이라도 좋다. 바람직하게는 이중 사슬 RNA(dsRNA)이다.
본 발명의 핵산 복합체의 안티센스 사슬의 5' 말단에서부터 2번째의 뉴클레오티드는, 표적 APCS mRNA 서열의 3' 말단에서부터 2번째의 데옥시리보뉴클레오티드와 상보인 것이 바람직하고, 안티센스 사슬의 5' 말단에서부터 2∼7번째의 뉴클레오티드가 표적 APCS mRNA 서열의 3' 말단에서부터 2∼7번째의 데옥시리보뉴클레오티드와 완전히 상보인 것이 보다 바람직하고, 안티센스 사슬의 5' 말단에서부터 2∼11번째의 뉴클레오티드가 표적 APCS mRNA 서열의 3' 말단에서부터 2∼11번째의 데옥시리보뉴클레오티드와 완전히 상보인 것이 더욱 바람직하다. 또한, 본 발명의 핵산에 있어서의 안티센스 사슬의 5' 말단에서부터 11번째의 뉴클레오티드가 표적 APCS mRNA 서열의 3' 말단에서부터 11번째의 데옥시리보뉴클레오티드와 상보인 것이 바람직하고, 안티센스 사슬의 5' 말단에서부터 9∼13번째의 뉴클레오티드가 표적 APCS mRNA 서열의 3' 말단에서부터 9∼13번째의 데옥시리보뉴클레오티드와 완전히 상보인 것이 보다 바람직하고, 안티센스 사슬의 5' 말단에서부터 7∼15번째의 뉴클레오티드가 표적 APCS mRNA 서열의 3' 말단에서부터 7∼15번째의 데옥시리보뉴클레오티드와 완전히 상보인 것이 더욱 바람직하다.
본 발명의 핵산 복합체의 안티센스 사슬 및 센스 사슬은, 예컨대 Genbank Accession No. NM_001639.3으로서 등록되어 있는 인간 APCS의 완전장(完全長) mRNA의 cDNA(센스 사슬)의 염기 서열(서열 번호 1)에 기초하여 설계할 수 있다.
이중 사슬 핵산은 APCS 유전자 서열 내의 표적 서열과 상호 작용하도록 설계할 수 있다.
이중 사슬 핵산의 하나의 사슬의 서열은 상기한 표적 부위 서열에 대하여 상보적이다. 이중 사슬 핵산은 본 명세서에 기술된 방법을 사용하여 화학적으로 합성할 수 있다.
RNA는 효소적 또는 부분/전체 유기 합성에 의해서 생성하여도 좋고, 또한 수식된 리보뉴클레오티드는 인비트로로 효소적 또는 유기 합성에 의해서 도입할 수 있다. 하나의 양태에 있어서, 각각의 사슬은 화학적으로 조제된다. RNA 분자를 화학적으로 합성하는 방법은 해당 기술 분야에서 공지되어 있다[뉴클레익 애시즈 리서치(Nucleic Acids Research), 1998년, 제32권, p. 936-948 참조]. 일반적으로, 이중 사슬 핵산은 고상(固相) 올리고뉴클레오티드 합성법을 사용함으로써 합성할 수 있다(예컨대 Usman et al., 미국 특허 제5,804,683호 명세서; 미국 특허 제5,831,071호 명세서; 미국 특허 제5,998,203호 명세서; 미국 특허 제6,117,657호 명세서; 미국 특허 제6,353,098호 명세서; 미국 특허 제6,362,323호 명세서; 미국 특허 제6,437,117호 명세서; 미국 특허 제6,469,158호 명세서; Scaringe et al., 미국 특허 제6,111,086호 명세서; 미국 특허 제6,008,400호 명세서; 미국 특허 제6,111,086호 명세서를 참조).
단일 사슬 핵산은 고상 포스포로아미다이트법(뉴클레익 애시즈 리서치(Nucleic Acids Research), 1993년, 제30권, p. 2435-2443 참조)을 사용하여 합성되고, 탈보호되고, 그리고 NAP-5 컬럼(Amersham Pharmacia Biotech, Piscataway, NJ) 상에서 탈염된다. 올리고머는, 15분 공정의 리니어 구배를 사용하는 Amersham Source 15Q 컬럼 -1.0 cm. 높이. 25 cm(Amersham Pharmacia Biotech, Piscataway, NJ)에서의 이온 교환 고성능 액체 크로마토그래피(IE-HPLC)를 사용하여 정제한다. 구배는 90:10의 완충액 A:B에서 52:48의 완충액 A:B로 변화되고, 완충액 A는 100 mmol/L Tris pH 8.5이며, 그리고 완충액 B는 100 mmol/L Tris pH 8.5(1 mol/L의 NaCl)이다. 시료는 260 nm로 모니터되고, 전장(全長) 올리고뉴클레오티드종에 대응하는 피크는 수집되고, 풀되고, NAP-5 컬럼으로 탈염되고, 그리고 동결 건조된다.
각 단일 사슬 핵산의 순도는, Beckman PACE 5000(Beckman Coulter, Inc., Fullerton, Calif)에서의 캐필러리 전기 영동(CE)에 의해서 결정된다. CE 캐필러리 는 100 ㎛의 내경을 가지고, ssDNA 100R Gel(Beckman-Coulter)을 포함한다. 전형적으로는, 약 0.6 nmole의 올리고뉴클레오티드를 캐필러리에 주사하고, 444 V/cm의 전계에 있어서 실행하여, 260 nm에 있어서의 UV 흡광도에 의해서 검출된다. 변성 트리스-붕산-7 mol/L-요소 영동 완충액은 Beckman-Coulter로부터 구입한다. 이하에 기술한 실험에 사용하기 위한, CE에 의해서 평가하는 적어도 90% 순수한 단일 사슬 핵산을 얻을 수 있다. 화합물 동일성은 제조업자의 장려 프로토콜에 따라서 Voyager DE. TM. Biospectometry 워크스테이션(Applied Biosystems, Foster City,, Calif.)에서의 매트릭스 지원 레이저 탈리 이온화-비행시간형(MALDI-TOF) 질량 분광법에 의해서 검증된다. 단일 사슬 핵산의 상대적인 분자 질량은 예상되는 분자 질량의 0.2% 이내로 얻을 수 있다.
단일 사슬 핵산은, 100 mmol/L 아세트산칼륨, 30 mmol/L HEPES, pH 7.5를 포함하는 완충액 중에 100 ㎛ol/L 농도로 재현탁시킨다. 상보적 센스 사슬 및 안티센스 사슬을 동등한 몰량으로 혼합하여, 50 ㎛ol/L 이중 사슬 핵산의 최종 용액을 얻는다. 시료를 95℃까지 5분간 가열하여, 사용 전에 실온으로 냉각시킨다. 이중 사슬 핵산은 -20℃에서 보존한다. 단일 사슬 핵산은 동결 건조시키거나 또는 뉴클레아제 프리 수중에 -80℃에서 저장한다.
본 발명에 있어서의 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하고, 상기 안티센스 사슬 중의, 11개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 후술하는 표 1-1∼표 1-13에 기재된 군에서 선택되는 표적 APCS mRNA 서열과 상보적인 이중 사슬 핵산으로서, 표 M1-1∼표 M1-3 및 표 R-3∼표 R-4, 그리고 표 1-1∼표 1-13에 기재된 안티센스 사슬로 이루어지는 군에서 선택되는 서열을 포함하는 이중 사슬 핵산이나, 후술하는 표 M1-1∼표 M1-3 및 표 R-1∼표 R-2, 그리고 표 1-1∼표 1-13에 기재된 센스 사슬로 이루어지는 군에서 선택되는 서열을 포함하는 이중 사슬 핵산이나, 혹은 표 M1-1∼표 M1-3 및 표 R-1∼표 R-4, 그리고 표 1-1∼표 1-13에 기재한 센스 사슬/안티센스 사슬로 이루어지는 군에서 선택되는 한 쌍의 센스 사슬/안티센스 사슬의 서열을 포함하는 이중 사슬 핵산을 이용하여도 좋다.
즉, 본 발명에서 이용되는 핵산 복합체를 구성하는 이중 사슬 핵산의 구체예는, 표 M1-1∼표 M1-3 및 표 R-1∼표 R-4, 그리고 표 1-1∼표 1-13 중의 센스 사슬 및 안티센스 사슬을 포함하는 이중 사슬 핵산이다. 또한, 표 M1-1∼표 M1-3 및 표 R-1∼표 R-4 중, N(M)은 2'-O-메틸 수식 RNA, N(F)는 2'-불소 수식 RNA, 그리고 ^은 포스포로티오에이트를 나타낸다. 또한, 표 1-1∼표 1-13 및 표 M1-1∼표 M1-3 및 표 R-3∼표 R-4에 기재한 안티센스 사슬 서열의 5' 말단 뉴클레오티드는, 5' 말단에 있어서 인산화되어 있어도 좋고, 인산화되어 있지 않아도 좋지만, 인산화되어 있는 것이 바람직하다.
표 1-1∼표 1-13에 기재한 센스 사슬/안티센스 사슬의 서열을 포함하는 이중 사슬 핵산은, 1 nM 첨가 시의 녹다운 활성의 측정에 있어서, 이중 사슬 핵산을 가하지 않은 조건에 대하여 이중 사슬 핵산을 가했을 때의, APCS의 상대적 발현량이 0.50 이하인 것이 바람직하고, 0.30 이하인 것이 보다 바람직하고, 0.20 이하인 것이 더욱 바람직하고, 0.10 이하인 것이 가장 바람직하다.
본 발명에 있어서의 올리고뉴클레오티드는, 2'- 수식 뉴클레오티드를 포함하는 이중 사슬 핵산이라도 좋으며, 표 M1∼표 M3에 기재한 것이 바람직하고, 1 nM 첨가 시의 녹다운 활성의 측정에 있어서, 이중 사슬 핵산을 가하지 않은 조건에 대하여 이중 사슬 핵산을 가했을 때의 APCS의 상대적 발현량이 0.10 이하인 것이 보다 바람직하다.
상기한 바람직한 이중 사슬 핵산과 공지된 리간드 링커를 조합한 핵산 복합체도 본 발명에 포함된다. 공지된 리간드 링커로서는 예컨대 국제공개 제2009/073809호 및 국제공개 제2013/075035호에 개시되어 있는 것을 들 수 있다.
본 발명의 핵산 복합체는, 표 S1에서 기재되어 있는 핵산 복합체(화합물 1-2∼화합물 43-2)가 바람직하고, 핵산 복합체를 종농도로 3 nM 첨가할 때의 녹다운 활성의 측정에 있어서, 핵산 복합체를 가하지 않은 음성 대조에 대하여 핵산 복합체를 가했을 때의 APCS의 상대적 발현량이 0.50 이하인 핵산 복합체가 보다 바람직하다. 핵산 복합체의 구체예로서는 화합물 1-2, 5-2, 9-2, 10-2, 15-2, 20-2, 33-2, 35-2를 들 수 있다.
본 발명의 핵산 복합체의 제조법에 관해서 설명한다. 또한, 이하에 나타내는 제조법에 있어서, 정의한 기가 상기 제조법의 조건 하에서 변화되거나 또는 상기 제조법을 실시하는 데 부적절한 경우, 유기합성화학에서 상용되는 보호기의 도입 및 제거 방법[예컨대 프로텍티브 그룹스 인 오가닉 신세시스 제3판(Protective Groups in Organic Synthesis, third edition), 그린(T. W. Greene) 저, John Wiley & Sons Inc.(1999년) 등에 기재된 방법] 등을 이용함으로써 목적 화합물을 제조할 수 있다. 또한, 필요에 따라서 치환기 도입 등의 반응 공정의 순서를 바꿀 수도 있다.
식 1로 표시되는 핵산 복합체는 고상 합성에 의해서도 합성할 수 있다.
식 1로 표시되는 핵산 복합체는 핵산 복합체로서 공지된 링커 구조의 합성 방법을 참고하여 합성할 수 있다.
식 1로 표시되는 핵산 복합체에 있어서의, S1을 링커로 한 L1-벤젠환 유닛이나 S2를 링커로 한 L2-벤젠환 유닛의 합성은, 식 2로 표시되는 핵산 복합체를 예로 들어 설명한다.
식 2로 표시되는 핵산 복합체에 있어서의 L1-벤젠환 유닛이나 L2-벤젠환 유닛은 P1, P2, P3, P4, P5 및 P6, 그리고 T1 및 T2에 의해 연결되어 있다.
P1, P2, P3, P4, P5 및 P6, 그리고 T1 및 T2의 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 또는 -CO-NH- 결합은, 예컨대 제4판 실험화학강좌 19 「유기 화합물의 합성 I」 마루젠(1992년), 제4판 실험화학강좌 20 「유기 화합물의 합성 II」, 마루젠(1992년) 등에 기재된 결합 반응의 방법을 참고하여, 식 2로 표시되는 구조를 형성하는 데 적절한 원료를 선택함으로써 적절하게 합성할 수 있다.
또한, 벤젠환에서부터 순차 Q1을 부분 구조로서 갖는 화합물, B1을 부분 구조로서 갖는 화합물을 결합시킴으로써, L1-벤젠환 유닛의 부분 구조를 제조할 수 있다.
L1과 Q2를 부분 구조로서 갖는 화합물을 별도 합성하여, L1과 Q2를 부분 구조로서 갖는 화합물을 벤젠환, Q1 및 B1을 부분 구조로서 갖는 L1-벤젠환 유닛의 부분 구조를 갖는 화합물과 결합시킴으로써, L1-벤젠환 유닛 구조를 제조할 수 있다.
L2-벤젠환 유닛에 관해서도 마찬가지로, 벤젠환에서부터 순차 Q3을 부분 구조로서 갖는 화합물, B2를 부분 구조로서 갖는 화합물을 결합시킴으로써, L2-벤젠환 유닛의 부분 구조를 제조할 수 있다.
L2와 Q4를 부분 구조로서 갖는 화합물을 별도 합성하여, L2와 Q4를 부분 구조로서 갖는 화합물을 벤젠환, Q3 및 B2를 부분 구조로서 갖는 L2-벤젠환 유닛의 부분 구조를 갖는 화합물과 결합시킴으로써, L2-벤젠환 유닛 구조를 제조할 수 있다.
Q1을 부분 구조로서 갖는 화합물, Q3을 부분 구조로서 갖는 화합물로서는, 탄소수 1∼10의 알킬렌 또는 -(CH2CH2O)n-CH2CH2-의 양 말단에 수산기, 카르복실기, 아미노기, 티올기를 갖는 화합물을 들 수 있다.
B1을 부분 구조로서 갖는 화합물, B2를 부분 구조로서 갖는 화합물로서는, 하기 식 2-1로 표시되는 어느 하나의 구조를 가지고, 각 구조에 있어서의 말단의 둥근 흑점에 있어서, 각각 수산기, 카르복실기, 아미노기 또는 티올기를 갖는 화합물을 들 수 있다.
식 2-1:
Figure pct00096
B1을 부분 구조로서 갖는 화합물, B2를 부분 구조로서 갖는 화합물의 구체예로서는, 글리콜, 글루타민산, 아스파라긴산, 리신, Tris, 이미노이아세트산, 2-아미노-1,3-프로판디올 등을 들 수 있고, 글루타민산, 아스파라긴산, 리신, 이미노이아세트산이 바람직하다. 구체적으로는 B1 및 B2는 이하의 구조가 바람직하다.
Figure pct00097
L1, Q2 및 B1을 부분 구조로서 갖는 화합물을 합성하고 나서, Q1과 벤젠환을 갖는 화합물과 결합함으로써, L1-벤젠환 유닛 구조를 제조하여도 좋다.
L2, Q4 및 B2를 부분 구조로서 갖는 화합물을 합성하고 나서, Q3과 벤젠환을 갖는 화합물과 결합함으로써, L2-벤젠환 유닛 구조를 제조하여도 좋다.
본 발명에서는, [L1-T1-(Q2-P3)q2-]p1-B1-(P2-Q1)q1-P1-인 부분 구조와 [L2-T2-(Q3-P6)q4-]p2-B2-(P5-Q3)q3-P2-인 부분 구조는, 동일하더라도 또는 다르더라도 좋지만, 동일한 것이 바람직하다.
당 리간드의 L1-T1-Q2에 상당하는 유닛으로서, 예컨대 L3-T1-Q2-COOH, L3-T1-(Q2-P3)q2-1-Q2-NH2 등을 들 수 있다. 구체적으로는 L3-O-탄소수 1∼12의 알킬렌-COOH나 L3-탄소수 1∼12의 알킬렌-CO-NH-탄소수 2∼12의 알킬렌-NH2 등을 들 수 있다.
L3은 탈보호함으로써 L1이 되는 당 리간드 유도체라면 특별히 한정되지 않는다. 당 리간드의 치환기로서는, 당질 화학 분야에서 범용되는 치환기라면 특별히 한정되지 않지만, Ac기가 바람직하다.
S1을 링커로 한 L1-벤젠환 유닛이나 S2를 링커로 한 L2-벤젠환 유닛의 합성은, 구체적으로는 실시예에 기재한 방법을 참고하여 알킬렌 사슬의 탄소수를 적절히 증감하고, 또한 말단 아미노기나 말단 카르복실기를 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 또는 -CO-NH- 결합을 형성할 수 있는 기로 변환한 화합물을 이용함으로써 합성할 수 있다. 또한, L1의 당 리간드에 관해서도 실시예에서는 만노오스 또는 N-아세틸갈락토사민을 예시하고 있지만, 다른 당 리간드로 변경하여 실시할 수 있다.
식 1로 표시되는 핵산 복합체에 있어서의, S3를 링커로 한 X-벤젠환 유닛의 합성은, 식 12로 표시되는 핵산 복합체를 예로 들어 설명한다.
식 12로 표시되는 핵산 복합체에 있어서의 X-벤젠환 유닛은, 올리고뉴클레오티드의 결합 이외에, P7 및 P8에 의해 표시되는 결합을 갖는다.
P7 및 P8의 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 또는 -CO-NH- 결합은, 예컨대 제4판 실험화학강좌 19 「유기 화합물의 합성 I」 마루젠(1992년), 제4판 실험화학강좌 20 「유기 화합물의 합성 II」, 마루젠(1992년)에 기재된 결합 반응의 방법을 참고하여 식 12로 표시되는 구조를 형성하는 데 적절한 원료를 선택함으로써 적절하게 합성할 수 있다.
또한, 벤젠환에서부터 순차 Q5를 부분 구조로서 갖는 화합물, B3을 부분 구조로서 갖는 화합물을 결합시킴으로써 X-벤젠환 유닛의 부분 구조를 제조할 수 있다.
X와 Q7을 부분 구조로서 갖는 화합물이나 X와 Q6을 부분 구조로서 갖는 화합물을 별도 합성하고, X와 Q7을 부분 구조로서 갖는 화합물이나 X와 Q6을 부분 구조로서 갖는 화합물을 벤젠환 및 Q5를 부분 구조로서 갖는 X-벤젠환 유닛의 부분 구조를 갖는 화합물과 결합시켜, B3 부분을 구축함으로써, X-벤젠환 유닛 구조를 제조할 수 있다.
구체적으로는, 벤젠환 및 Q5를 부분 구조로서 갖는 X-벤젠환 유닛의 부분 구조를 갖는 화합물의 말단에 아지드기를 갖는 경우를 예로 들면, 실시예에 개시하는 것과 같은 말단 결합성 작용기화한 올리고뉴클레오티드를 반응시킴으로써 고리화 부가시키고, 트리아졸환을 형성하게 하여 B3 부분을 구축함으로써 X-벤젠환 유닛 구조를 제조할 수 있다.
Q5를 부분 구조로서 갖는 화합물, Q6을 부분 구조로서 갖는 화합물, Q7을 부분 구조로서 갖는 화합물로서는, 탄소수 1∼10의 알킬렌 또는 -(CH2CH2O)n8-CH2CH2-의 양 말단에 수산기, 카르복실기, 아미노기, 티올기를 갖는 화합물을 들 수 있다.
L1-벤젠환 유닛 구조, L2-벤젠환 유닛 구조와 X-벤젠환 유닛 구조는, 각각 순차 제조해 나갈 수 있지만, L1-벤젠환 유닛 구조 및 L2-벤젠환 유닛 구조를 합성하고 나서 X-벤젠환 유닛 구조를 결합시키는 것이 바람직하다. 특히, 올리고뉴클레오티드 부분을 갖는 X에 관해서는, 당 리간드 복합체 합성의 최종 공정 근처에서 화합물 내에 도입하는 것이 바람직하다.
본 발명에서는, 하기 식 8∼식 10으로 표시되는 화합물을 합성 중간체로서 얻을 수 있다.
식 8:
Figure pct00098
(식 8 중,
R1 및 R2는 각각 독립적으로 수소 원자, t-부톡시카르보닐기(Boc기), 벤질옥시카르보닐기(Z기), 9-플루오레닐메틸옥시카르보닐기(Fmoc기), -CO-R4 또는 -CO-B4-[(P9-Q8)q7-T3-L3]p3이고,
P9 및 T3은 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q8은 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는-(CH2CH2O)n1-CH2CH2-이며, n1은 0∼99의 정수이고,
B4는 각각 독립적으로 결합수이거나 또는 하기 식 8-1로 표시되는 어느 하나의 구조이고, 각 구조에 있어서의 말단의 둥근 흑점은 각각 카르보닐기 또는 P9와의 결합점이며, m7, m8, m9 및 m10은 각각 독립적으로 0∼10의 정수이고,
식 8-1:
Figure pct00099
p3은 1, 2 또는 3의 정수이고,
q7은 0∼10의 정수이고,
L3은 당 리간드이고,
Y는 -O-(CH2)m11-NH- 및 -NH-CO-(CH2)m12-NH이며, m11 및 m12는 각각 독립적으로 1∼10의 정수이고,
R3은 수소 원자, t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기, -CO-R4, -CO-(CH2CH2O)n2-CH2CH2-N3 또는 -CO-Q9-B5-(Q10-P10)q8-X1이며, n2는 0∼99의 정수이고,
P10은 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q9 및 Q10은 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n3-CH2CH2-이며, n3은 0∼99의 정수이고,
B5는 하기 식 8-2로 표시되는 어느 하나의 구조이며, 파선에 있어서 각각 Q9 및 Q10과의 결합수를 의미하고,
식 8-2:
Figure pct00100
식 8-2 중, 트리아졸환을 갖는 기에 있어서의 치환은 상기 트리아졸환의 1 위치 및 3 위치의 질소 원자의 어느 하나이다.
q8은 0∼10의 정수이고,
X1은 수소 원자 또는 고상 담체이고,
R4는 t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기로 치환 혹은 무치환의 아미노기, 카르복시기, 말레이미드기 및 아랄킬옥시카르보닐기로 이루어지는 군에서 선택되는 1 또는 2개의 치환기로 치환된 탄소수 2∼10의 알킬기이다.)
식 9:
Figure pct00101
(식 9 중,
R5 및 R6은 각각 독립적으로 수소 원자, t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기, -CO-R4' 또는 -CO-Q11-(P11-Q11')q9-T4-L4이고,
P11 및 T4는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q11 및 Q11'은 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n4-CH2CH2-이며, n4는 0∼99의 정수이고,
q9는 0∼10의 정수이고,
L4는 당 리간드이고,
Y'는 -O-(CH2)m11'-NH- 및 -NH-CO-(CH2)m12'-NH이며, m11' 및 m12'는 각각 독립적으로 1∼10의 정수이고,
R3'은 수소 원자, t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기, -CO-R4', -CO-(CH2CH2O)n2'-CH2CH2-N3 또는 -CO-Q9'-B5'-(Q10'-P10')q8'-X1'이며, n2'는 0∼99의 정수이고,
P10'은 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q9' 및 Q10'은 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n3'-CH2CH2-이며, n3'은 0∼99의 정수이고,
B5'는 하기 식 9-1로 표시되는 어느 하나의 구조이며, 파선에 있어서 각각 Q9' 및 Q10'과의 결합수를 의미하고,
식 9-1:
Figure pct00102
식 9-1 중, 트리아졸환을 갖는 기에 있어서의 치환은 상기 트리아졸환의 1 위치 및 3 위치의 질소 원자의 어느 하나이다.
q8'은 0∼10의 정수이고,
X1'은 수소 원자 또는 고상 담체이고,
R4'는 t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기로 치환 혹은 무치환의 아미노기, 카르복시기, 말레이미드기 및 아랄킬옥시카르보닐기로 이루어지는 군에서 선택되는 1 또는 2개의 치환기로 치환된 탄소수 2∼10의 알킬기이다.)
식 10:
Figure pct00103
식 10 중,
R7 및 R8은 각각 독립적으로 히드록시기, t-부톡시기, 벤질옥시기, -NH-R10 또는 -NH-Q12-(P12-Q12')q10-T4-L4이고,
P12 및 T4는 각각 독립적으로 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q12 및 Q12'는 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n2-CH2CH2-이며, n2는 0∼99의 정수이고,
L4는 당 리간드이고,
Y2는 -O-(CH2)m9-NH- 및 -NH-CO-(CH2)m10-NH이며, m9, m10은 각각 독립적으로 1∼10의 정수이고,
q10은 0∼10의 정수이고,
R9는 수소 원자, t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기, -CO-R10, -CO-(CH2CH2O)n6-CH2CH2-N3 또는 -CO-Q13-B6-(Q14-P13)q11-X2이며, n6은 0∼99의 정수이고,
P13은 존재하지 않거나 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
Q13 및 Q14는 각각 독립적으로 존재하지 않거나 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n7-CH2CH2-이며, n7은 0∼99의 정수이고,
B6은 하기 식 10-1로 표시되는 어느 하나의 구조이며, 파선에 있어서 각각 Q13 및 Q14와의 결합수를 의미하고,
식 10-1:
Figure pct00104
식 10-1 중, 트리아졸환을 갖는 기에 있어서의 치환은 상기 트리아졸환의 1 위치 및 3 위치의 질소 원자의 어느 하나이다.
q11은 0∼10의 정수이고,
X2는 수소 원자 또는 고상 담체이고,
R10은 t-부톡시카르보닐기, 벤질옥시카르보닐기, 9-플루오레닐메틸옥시카르보닐기로 치환 혹은 무치환의 아미노기, 카르복시기, 말레이미드기 및 아랄킬옥시카르보닐기로 이루어지는 군에서 선택되는 1 또는 2개의 치환기로 치환된 탄소수 2∼10의 알킬기이다.)
이하, 본 발명과 관련하여 제조 방법을 일례로서 나타낸다. 또한, 이하의 제조 방법 1∼제조 방법 17에 관한 기재에 있어서, 본 발명의 핵산 유도체 등에 있어서의 식 1∼식 12로 표시되는 화합물에서, 기를 나타내는 기호로서 동일한 기호가 이용되고 있는 것이 있지만, 양자는 분리하여 이해되는 것이며, 제조 방법 1∼제조 방법 12에 대하여 기재되는 기의 설명에 의해 본 발명이 한정적으로 해석되는 것이 아니다. 또한, 본 발명에 있어서의 핵산 유도체에 관해서, 올리고뉴클레오티드를 나타내는 X를, 제조 방법 1∼제조 방법 17에서는 -O-X로서 기재한다.
제조 방법 1
본 발명에 있어서의 핵산 유도체는, 식 (I')로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00105
(식 중, P1은 Fmoc 등의 염기에 의해 탈보호 가능한 보호기이고, DMTr은 p,p'-디메톡시트리틸기를 나타내고, R은 당 리간드 테더 유닛을 나타내고, R'은 R 중의 당 리간드의 각 수산기가 아세틸기 등의 염기로 탈보호 가능한 보호기로 보호된 기를 나타내고, Polymer는 고상 담체를 나타내고, Q'는 -CO-이다.)
공정 1
화합물 (I-B)는, 화합물 (I-A)와 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, 피리딘, 물 등을 들 수 있으며, 이들은 단독으로 또는 혼합하여 이용된다.
공정 2
화합물 (I-C)는, 화합물 (I-B)를, 무용매로 또는 용매 중, 1∼1000 당량의 2급 아민 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 있으며, 이들은 단독으로 또는 혼합하여 이용된다.
2급 아민으로서는 예컨대 디에틸아민, 피페리딘 등을 들 수 있다.
공정 3
화합물 (1-E)는, 화합물 (I-C)와 화합물 (I-D)를, 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 반응시킴으로써 제조할 수 있다.
용매로서는 공정 2에서 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 있다.
축합제로서는, 예컨대 1,3-디시클로헥산카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드·염산염(EDC), 카르보닐디이미다졸, 벤조트리아졸-1-일옥시트리스(디메틸아미노)포스포늄 헥사플루오로포스파이트, (벤조트리아졸-1-일옥시)트리피롤리디노포스포늄헥사플루오로포스파이트, O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄 헥사플루오로포스파이트(HATU), O-(벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄 헥사플루오로포스파이트(HBTU), 요오드화 2-클로로-1-메틸피리디늄 등을 들 수 있다.
첨가제로서는 예컨대 1-히드록시벤조트리아졸(HOBt), 4-디메틸아미노피리딘(DMAP) 등을 들 수 있다.
화합물 (I-D)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958, (2014)를 참조) 혹은 그것에 준한 방법으로 얻을 수 있다.
공정 4
화합물 (I-F)는, 화합물 (I-E)와 숙신산무수물을, 용매 중, 1∼30 당량의 염기 존재 하에, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 공정 2에서 예시한 것을 들 수 있다.
염기로서는 공정 3에서 예시한 것을 들 수 있다.
공정 5
화합물 (I-G)는, 화합물 (I-F)와 말단이 아미노화된 고상 담체를, 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 용액과, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 공정 2에서 예시한 것을 들 수 있다.
염기, 축합제 및 첨가제로서는 각각 공정 3에서 예시한 것을 들 수 있다.
아미노화된 고상 담체로서는, 예컨대 장쇄 알킬아민 세공성 유리(LCAA-CPG) 등을 들 수 있으며, 이들은 시판 제품으로서 얻을 수 있다.
공정 6
식 (I')로 표시되는 당 리간드 테더 블랜처 유닛을 갖는 핵산 복합체는, 화합물 (I-G)를 이용하여, 공지된 올리고뉴클레오티드 화학 합성법으로 대응하는 뉴클레오티드 사슬을 신장한 후에, 고상으로부터의 탈리, 보호기의 탈보호 및 정제를 행함으로써 제조할 수 있다.
공지된 올리고뉴클레오티드 화학 합성법으로서는, 포스포로아미다이트법, 포스포로티오에이트법, 포스포트리에스테르법, CEM법(Nucleic Acids Research, 35, 3287(2007)를 참조) 등을 들 수 있으며, 예컨대 ABI3900 하이 스루풋 핵산 합성기(어플라이드바이오시스템즈사 제조)에 의해 합성할 수 있다.
고상으로부터의 탈리, 탈보호는, 올리고뉴클레오티드 화학 합성 후, 용매 또는 무용매 중, -80℃에서부터 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 있다.
용매로서는 물, 메탄올, 에탄올, THF 등을 들 수 있다.
올리고뉴클레오티드는, C18 역상 컬럼 혹은 음이온 교환 컬럼, 바람직하게는 상술한 2개의 수법을 조합하여 정제할 수 있다. 정제 후의 핵산 복합체 순도는 90% 이상, 바람직하게는 95% 이상으로 하는 것이 좋다.
또한, 상기 공정 3에 있어서, 필요에 따라 화합물 (I-D)를 2개의 유닛으로 분할하고, 2단계로 나눠 화합물 (I-C)와 축합함으로써 행할 수도 있다. 구체적으로는, 예컨대 R-Q'가 R-NH-CO-Q4'-CO-인 경우(Q4'는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌이다), 공정 3에 있어서 화합물 (I-C)와 CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의)를 공정 3과 같은 방법으로 축합시키고, 얻어진 화합물의 에틸에스테르를 에탄올이나 물 등의 용매 중, 수산화리튬 등의 염기로 가수분해한 후에, 또한 R'-NH2(R'는 상기와 동의)와 축합시킴으로써 목적으로 하는 화합물을 얻을 수 있다. 또한, CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의) 및 R'-NH2(R'은 상기와 동의)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958(2014)을 참조) 혹은 또한 그것에 준한 방법으로 얻을 수 있다. 여기서, Q4'에 있어서, 치환 혹은 무치환의 탄소수 1∼12의 알킬렌에 있어서의 치환기 및 알킬렌 부분은 상기와 마찬가지다.
Q가 -CO-인 경우를 예시하여 나타내고 있지만, Q가 -CO-가 아닌 경우의 화합물에 관해서도, Q의 구조를 적절하게 변경하고, 상기와 같은 방법, 공지된 방법 또는 이들을 조합하여, 적절하게 반응 조건을 변경함으로써 조제할 수 있다.
제조 방법 2
본 발명에 있어서의 핵산 유도체는, 식 (II')로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00106
(식 중, DMTr, R, R', X, Q' 및 Polymer는 상기와 동의. TBDMS는 t-부틸디메틸실릴기, Fmoc는 9-플루오레닐메틸옥시카르보닐기를 나타낸다)
공정 7
화합물 (II-A)는, 화합물 (I-A), t-부틸디메틸실릴클로리드 및 디메틸아미노피리딘을 N,N-디메틸포름아미드(DMF) 등의 용매 중, 바람직하게는 2 등량의 염기의 존재 하에, 0℃∼100℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
염기로서는 제조 방법 1의 공정 3에서 예시한 것을 들 수 있다.
공정 8
화합물 (II-B)는, 화합물 (II-A)를 이용하여, 제조 방법 1의 공정 1과 같은 조건으로 제조할 수 있다.
공정 9
화합물 (II-C)는, 화합물 (II-B)와 불화n-테트라부틸암모늄(TBAF)을, 용매 중, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 공정 2에서 예시한 것을 들 수 있다.
공정 10
화합물 (II-D)는, 화합물 (II-C)를 이용하여, 제조 방법 1의 공정 2와 같은 조건으로 제조할 수 있다.
공정 11
화합물 (II-E)는, 화합물 (II-D) 및 화합물 (I-D)를 이용하여, 제조 방법 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 12∼14
화합물 (II')는, 화합물 (II-E)를 이용하여, 제조 방법 1의 공정 4∼공정 6과 같은 조건으로 제조할 수 있다.
또한, 상기 공정 11에 있어서, 필요에 따라 화합물 (I-D)를 2개의 유닛으로 분할하고, 2단계로 나눠 화합물 (II-C)와 축합함으로써 행할 수도 있다. 구체적으로는, 예컨대 R-Q'가 -NH-CO-Q4'-CO-인 경우(Q4'는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌), 공정 11에 있어서 화합물 (II-C)와 CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의)를 공정 11과 같은 방법으로 축합시키고, 얻어진 화합물의 에틸에스테르를 에탄올이나 물 등의 용매 중, 수산화리튬 등의 염기로 가수분해한 후에, 또한 R'-NH2(R'은 상기와 동의)와 축합시킴으로써 목적으로 하는 화합물을 얻을 수 있다. 또한, CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의) 및 R'-NH2(R'는 상기와 동의)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958(2014)를 참조) 혹은 그것에 준한 방법으로 얻을 수 있다.
Q가 -CO-인 경우를 예시하여 나타내고 있지만, Q가 -CO-가 아닌 경우의 화합물에 관해서도, Q의 구조를 적절하게 변경하고, 상기와 같은 방법, 공지된 방법 또는 이들을 조합하여, 적절하게 반응 조건을 변경함으로써 조제할 수 있다.
제조 방법 3
본 발명에 있어서의 핵산 유도체는, 식 (III')으로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00107
(식 중, DMTr, Fmoc, R, R', Q', X 및 Polymer는 상기와 동의이다.)
화합물 (III')은, 화합물 (III-A)를 이용하여, 제조 방법 1의 공정 1∼공정 6과 같은 조건으로 제조할 수 있다. 또한, 화합물 (III-A)는 시판 제품으로서 얻을 수 있다.
공정 15
화합물 (III-B)는, 화합물 (III-A)를 이용하여, 제조법 1의 공정 1과 같은 조건으로 제조할 수 있다.
화합물 (III-A)는 시판 제품으로서 구입할 수 있다.
공정 16
화합물 (III-C)는, 화합물 (III-B)를 이용하여, 제조법 1의 공정 2와 같은 조건으로 제조할 수 있다.
공정 17
화합물 (III-E)는, 화합물 (III-C)를 이용하여, 제조법 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 18∼20
화합물 (III')은, 화합물 (III-E)를 이용하여, 제조 방법 1의 공정 4∼공정 6과 같은 조건으로 제조할 수 있다.
또한, 상기 공정 17에 있어서, 필요에 따라 화합물 (I-D)를 2개의 유닛으로 분할하고, 2단계로 나눠 화합물 (III-C)와 축합함으로써 행할 수도 있다. 구체적으로는, 예컨대 R-Q'가 -NH-CO-Q4'-CO-인 경우(Q4'는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌), 공정 17에 있어서 화합물 (III-C)와 CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의)를 공정 17과 같은 방법으로 축합시키고, 얻어진 화합물의 에틸에스테르를 에탄올이나 물 등의 용매 중, 수산화리튬 등의 염기로 가수분해한 후에, 또한 R'-NH2(R'은 상기와 동의)와 축합시킴으로써 목적으로 하는 화합물을 얻을 수 있다. 또한, CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의) 및 R'-NH2(R'은 상기와 동의)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958(2014)를 참조) 혹은 그것에 준한 방법으로 얻을 수 있다.
Q가 -CO-인 경우를 예시하여 나타내고 있지만, Q가 -CO-가 아닌 경우의 화합물에 관해서도, Q의 구조를 적절하게 변경하고, 상기와 같은 방법, 공지된 방법 또는 이들을 조합하여, 적절하게 반응 조건을 변경함으로써 조제할 수 있다.
제조 방법 4
본 발명에 있어서의 핵산 유도체는, 식 (IV')로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00108
(식 중, DMTr, Fmoc, R, R', Q', X 및 Polymer는 상기와 동의이다.)
화합물 (IV')는, 화합물 (IV-A)를 이용하여, 제조 방법 1의 공정 1∼공정 6과 같은 조건으로 제조할 수 있다. 또한, 화합물 (IV-A)는 시판 제품으로서 얻을 수 있다.
또한, 상기 공정 23에 있어서, 필요에 따라 화합물 (I-D)를 2개의 유닛으로 분할하고, 2단계로 나눠 화합물 (IV-C)와 축합함으로써 행할 수도 있다. 구체적으로는, 예컨대 R'-Q'가 -NH-CO-Q4'-CO-인 경우(Q4'는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌이다), 공정 23에 있어서 화합물 (IV-C)와 CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의)를 공정 23과 같은 방법으로 축합시키고, 얻어진 화합물의 에틸에스테르를 에탄올이나 물 등의 용매 중, 수산화리튬 등의 염기로 가수분해한 후에, 또한 R'-NH2(R'은 상기와 동의)와 축합시킴으로써 목적으로 하는 화합물을 얻을 수 있다. 또한, CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의) 및 R'-NH2(R'은 상기와 동의)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958(2014)를 참조) 혹은 그것에 준한 방법으로 얻을 수 있다.
Q가 -CO-인 경우를 예시하여 나타내고 있지만, Q가 -CO-가 아닌 경우의 화합물에 관해서도, Q의 구조를 적절하게 변경하고, 상기와 같은 방법, 공지된 방법 또는 이들을 조합하여, 적절하게 반응 조건을 변경함으로써 조제할 수 있다.
제조 방법 5
본 발명에 있어서의 핵산 유도체는, 식 (V')로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00109
(식 중, DMTr, R, R', X, Q', TBDMS, Fmoc 및 Polymer는 상기와 동의.)
화합물 (V')는, 화합물 (IV-A)를 이용하여, 제조 방법 2의 공정 1∼공정 7과 같은 조건으로 제조할 수 있다. 또한, 화합물 (IV-A)는 시판 제품으로서 얻을 수 있다.
또한, 상기 공정 31에 있어서, 필요에 따라 화합물 (I-D)를 2개의 유닛으로 분할하고, 2단계로 나눠 화합물 (V-D)와 축합함으로써 행할 수도 있다. 구체적으로는, 예컨대 R'-Q'가 -NH-CO-Q4'-CO-인 경우(Q4'는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌이다.), 공정 31에 있어서 화합물 (V-D)와 CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의)를 공정 31과 같은 방법으로 축합시키고, 얻어진 화합물의 에틸에스테르를 에탄올이나 물 등의 용매 중, 수산화리튬 등의 염기로 가수분해한 후에, 또한 R'-NH2(R'은 상기와 동의)와 축합시킴으로써 목적으로 하는 화합물을 얻을 수 있다. 또한, CH3CH2-O-CO-Q4'-CO-OH(Q4'는 상기와 동의) 및 R'-NH2(R'는 상기와 동의)는 공지된 방법(예컨대 Journal of American Chemical Society, 136, 16958(2014)를 참조) 혹은 그것에 준한 방법으로 얻을 수 있다.
Q가 -CO-인 경우를 예시하여 나타내고 있지만, Q가 -CO-가 아닌 경우의 화합물에 관해서도, Q-OH의 구조를 적절하게 변경하고, 상기와 같은 방법, 공지된 방법 또는 이들을 조합하여, 적절하게 반응 조건을 변경함으로써 조제할 수 있다.
제조 방법 6
올리고뉴클레오티드의 5' 말단에 당 리간드 테더 블랜처 유닛이 결합한 본 발명의 핵산 복합체의 제조 방법을 이하에 예시한다.
Figure pct00110
(식 중, R, R', Q', DMTr 및 X는 상기와 동의이다.)
공정 35
화합물 (I-H)는, 화합물 (II-E)와 2-시아노에틸-N,N,N',N'-테트라이소프로필포스포디아미다이트를, 무용매로 또는 용매 중, 염기 및 반응촉진제 공존 하에, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 제조 방법 1의 공정 2에서 예시한 것을 들 수 있다.
염기로서는 제조 방법 1의 공정 3에서 예시한 것을 들 수 있다.
반응촉진제로서는, 예컨대 1H-테트라졸, 4,5-디시아노이미다졸, 5-에틸티오테트라졸, 5-벤질티오테트라졸 등을 들 수 있으며, 시판 제품으로서 구입할 수 있다.
공정 36
올리고뉴클레오티드 사슬을 신장하고, 마지막으로 화합물 (I-H)를 이용하여, 올리고뉴클레오티드의 5' 말단을 당 리간드 테더 블랜처 유닛으로 수식한 후, 고상으로부터의 탈리 보호기의 탈보호 및 정제를 행함으로써 화합물 (I'')을 제조할 수 있다. 여기서, 고상으로부터의 탈리, 보호기의 탈보호 및 정제는 각각 제조 방법 1의 공정 7과 같은 식으로 하여 제조할 수 있다.
제조 방법 7
올리고뉴클레오티드의 5' 말단에 당 리간드 테더 블랜처 유닛이 결합한 본 발명의 핵산 복합체의 제조 방법을 이하에 예시한다.
제조 방법 6의 공정 35 및 36과 같은 조건으로 제조할 수 있다.
Figure pct00111
(식 중, R, R', Q', DMTr 및 X는 상기와 동의이다.)
제조 방법 8
올리고뉴클레오티드의 5' 말단에 당 리간드 테더 블랜처 유닛이 결합한 본 발명의 핵산 복합체의 제조 방법을 이하에 예시한다.
제조 방법 6의 공정 35 및 36과 같은 조건으로 제조할 수 있다.
Figure pct00112
(식 중, R, R', Q', DMTr 및 X는 상기와 동의이다.)
제조 방법 9
올리고뉴클레오티드의 5' 말단에 당 리간드 테더 블랜처 유닛이 결합한 본 발명의 핵산 복합체의 제조 방법을 이하에 예시한다.
제조 방법 6의 공정 35 및 36과 같은 조건으로 제조할 수 있다.
Figure pct00113
(식 중, R, R', Q', DMTr 및 X는 상기와 동의이다.)
제조 방법 10
올리고뉴클레오티드의 5' 말단에 당 리간드 테더 블랜처 유닛이 결합한 본 발명의 핵산 복합체의 제조 방법을 이하에 예시한다.
제조 방법 6의 공정 35 및 36과 같은 조건으로 제조할 수 있다.
Figure pct00114
(식 중, R, R', Q', DMTr 및 X는 상기와 동의이다.)
제조 방법 11
이중 사슬 핵산을 구성하는 센스 사슬의 3 말단' 또는 5' 말단에 당 리간드 테더 블랜처 유닛을 갖는 센스 사슬과, 이중 사슬 핵산을 구성하는 안티센스 사슬을, 물 또는 적당한 완충액에 각각 용해하여 혼합함으로써, 이중 사슬 핵산을 갖는 핵산 복합체를 얻을 수 있다.
완충액으로서는, 예컨대 아세트산 완충액, 트리스 완충액, 시트르산 완충액, 인산 완충액, 물 등을 들 수 있으며, 이들을 단독으로 또는 혼합하여 이용된다.
센스 사슬과 안티센스 사슬의 혼합비로서는, 센스 사슬 1 당량에 대하여 안티센스 사슬 0.5∼2 당량이 바람직하고, 0.9∼1.1 당량이 보다 바람직하고, 0.95 당량∼1.05 당량이 더욱 바람직하다.
또한, 상기 센스 사슬과 상기 안티센스 사슬을 혼합한 후, 적절하게 어닐링 처리를 행하여도 좋다. 어닐링 처리는, 센스 사슬과 안티센스 사슬의 혼합물을, 바람직하게는 50∼100℃, 보다 바람직하게는 60∼100℃, 더욱 바람직하게는 80∼100℃로 가열한 후에, 실온까지 서냉함으로써 행할 수 있다.
안티센스 사슬은 상기한 공지된 올리고뉴클레오티드 합성법에 준하여 얻을 수 있다.
제조 방법 12
본 발명에 있어서의 핵산 유도체는, 식 (VI')으로 표시되는 부분 구조를 갖는 화합물의 제조 방법으로서, 그 제조 방법을 예시할 수 있다.
Figure pct00115
(식 중, DMTr, R, R', X, Q', Polymer 및 Fmoc는 상기와 동의이고, TBS는 t-부틸디메틸실릴기를 나타내고, R0 및 Rx는 동일하거나 또는 다르며, 수소 원자, C1∼C10의 알킬렌 또는 C3-C8의 시클로알킬렌을 나타내고, W는 C1∼C10의 알킬렌, C3-C8의 시클로알킬렌이거나, R0와 함께 C4-C8의 함질소 복소환을 형성하여도 좋다.)
공정 45
화합물 (VI-B)는, 화합물 (VI-A)를 이용하여, 제조 방법 1의 공정 1과 같은 조건으로 제조할 수 있다.
화합물 (VI-A)는 시판 제품으로서 또는 공지된 방법(예컨대 바이오 오가닉 앤드 메디시날 케미스트리 레터즈, 제11권, 383-386 페이지) 혹은 그것에 준한 방법으로 얻을 수 있다.
공정 46
화합물 (VI-C)는, 화합물 (VI-B)를 이용하여, 제조 방법 1의 공정 2와 같은 조건으로 제조할 수 있다.
공정 47
화합물 (VI-D)는, 화합물 (VI-C)를 이용하여, 제조 방법 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 48
화합물 (VI-E)는, 화합물 (VI-D)를 이용하여, 제조 방법 1의 공정 2와 같은 조건으로 제조할 수 있다.
공정 49
화합물 (VI-G)는, 화합물 (VI-E)와 화합물 (VI-F)를 이용하여, 제조 방법 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 50
화합물 (VI-H)는, 화합물 (VI-G)를 이용하여, 제조 방법 2의 공정 9와 같은 조건으로 제조할 수 있다.
공정 51∼53
화합물 (VI')은, 화합물 (VI-H), 화합물 (VI-I) 및 화합물 (VI-J)를 이용하여, 제조 방법 1의 공정 4∼6과 같은 조건으로 제조할 수 있다.
공정 45∼53은 공지된 방법(예컨대 국제공개 제2015/105083호에 기재된 방법) 또는 그것에 준한 방법으로도 실시할 수 있다.
화합물 (VI-F)는 공지된 방법(예컨대 저널 오브 아메리칸 케미컬 소사이어티(Journal of American Chemical Society), 136권, 16958 페이지, 2014년에 기재된 방법) 또는 그것에 준한 방법으로 얻을 수 있다.
제조 방법 13
식 2에 있어서 P1 및 P4가 -NH-CO-, -O-CO- 또는 -S-CO-인 당 리간드 테더 유닛은 이하의 방법으로 제조할 수 있다.
Figure pct00116
(식 중, Q1, Q2, Q3, Q4, Q5, P2, P3, P5, P6, P7, T1, T2, L1, L2, q1, q2, q3 및 q4는 각각 상기와 동의이며, q2'는 q2보다 1작은 정수를 나타내고, q4'는 q4보다 1 작은 정수를 나타내고, P1' 및 P4'는 각각 독립적으로 -NH-CO-, -O-CO- 또는 -S-CO-를 나타내고, Z는 H, OH, NH2, SH, 염소 원자, 브롬 원자, 요오드 원자, 메탄술포닐옥시, p-톨루엔술포닐옥시 또는 카르복실산을 나타내고, B1' 및 B2'는 하기 식의 구조체의 어느 하나를 나타내고, PG1, PG2, PG3, PG4, PG5, PG6 및 PG7은 각각 적절한 보호기를 나타낸다.)
식:
Figure pct00117
m1, m2, m3 또는 m4는 각각 독립적으로 0∼10의 정수를 나타낸다.
공정 54
화합물 (VII-C)는, 화합물 (VII-A)와 화합물 (VII-B)를, 테트라히드로푸란 등의 용매 중, 트리페닐포스핀 폴리머 담지체를 가하여, 빙냉 하에 디이소프로필아조디카르복실레이트톨루엔 용액을 반응시킴으로써 제조할 수 있다.
용매로서는 제조 공정 1의 공정 2에서 예시한 것을 들 수 있다.
화합물 (VII-A)는 시판 제품으로서 얻을 수 있다.
공정 55
화합물 (VII-D)는, 화합물 (VII-C)를 이용하여, 메탄올 등의 용매 중, 빙냉 하, 염기의 존재 하에 반응시킴으로써 제조할 수 있다.
용매로서는 제조 공정 1의 공정 2에서 예시한 것을 들 수 있다.
염기로서는 제조 공정 1의 공정 3에서 예시한 것을 들 수 있다.
공정 56
화합물 (VII-F)는, 화합물 (VII-D) 및 화합물 (VII-E)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 57
화합물 (VII-H)는, 화합물 (VII-F) 및 화합물 (VII-G)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 58
화합물 (VII-J)는, 화합물 (VII-H) 및 화합물 (VII-I)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
또한, 하기 공정 DP1과 공정 58을 반복하여 행함으로써, 원하는 q1의 값을 갖는 화합물 (VII-J)를 제조할 수 있다.
공정 59
화합물 (VII-L)은, 화합물 (VII-J) 및 화합물 (VII-K)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 60
화합물 (VII-N)은, 화합물 (VII-L) 및 화합물 (VII-M)을 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 61∼63
화합물 (VII')은, 화합물 (VII-O), 화합물 (VII-P) 및 화합물 (VII-Q)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
또한, 하기 공정 DP1과 공정 61을 반복하여 행함으로써, 원하는 q3의 값을 갖는 화합물 (VII')을 제조할 수 있다.
공정 DP1
유기합성화학에서 상용되는 방법[예컨대 프로텍티브 그룹스 인 오가닉 신세시스 제3판(Protective Groups in Organic Synthesis, third edition), 그린(T. W. Greene) 저, John Wiley & Sons Inc.(1999년) 등에 기재된 방법 등]을 적절히 이용함으로써 원하는 화합물을 제조할 수 있다.
화합물 (VII-B), 화합물 (VII-E), 화합물 (VII-G), 화합물 (VII-I), 화합물 (VII-K), 화합물 (VII-M), 화합물 (VII-O), 화합물 (VII-P) 및 화합물 (VII-Q)는, 시판 제품으로서 또는 「실험화학강좌 제4판 유기합성, p. 258, 마루젠(1992년)」, 「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition」에 기재된 방법을 조합하거나 혹은 그것에 준한 방법으로 얻을 수 있다.
제조 방법 14
식 4에 있어서 P7이 -O-인 유닛은 이하의 방법으로 제조할 수 있다.
Figure pct00118
(식 중, Q5, P7, q5는 각각 상기와 동의이며, q5''는 q5보다 2 작은 정수를 나타내고, q5'는 q5보다 1 작은 정수를 나타내고, Z2는 H, OH, NH2 또는 SH를 나타내고, PG8 및 PG9는 각각 적절한 보호기를 나타내고, LC는 당 리간드 테더 유닛을 나타내고, E는 카르복실산 또는 말레이미드를 나타낸다.)
공정 64
화합물 (VIII-C)는, 화합물 (VIII-A) 및 화합물 (VIII-B)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
또한, 하기 공정 DP2와 공정 64를 반복하여 행함으로써 원하는 q5''의 값을 갖는 화합물 (VIII-C)를 제조할 수 있다. 화합물 (VIII-B)는, 시판 제품으로서 또는 「실험화학강좌 제4판 유기합성, p. 258, 마루젠(1992년)」, 「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition」에 기재된 방법을 조합하거나 혹은 그것에 준한 방법으로 얻을 수 있다.
공정 65
화합물 (VIII')은, 화합물 (VIII-C) 및 화합물 (VIII-D)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
화합물 (VIII-D)는, 시판 제품으로서 또는 「실험화학강좌 제4판 유기합성, p. 258, 마루젠(1992년)」, 「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition」에 기재된 방법을 조합하거나 혹은 그것에 준한 방법으로 얻을 수 있다.
공정 DP2
유기합성화학에서 상용되는 방법[예컨대 프로텍티브 그룹스 인 오가닉 신세시스 제3판(Protective Groups in Organic Synthesis, third edition), 그린(T. W. Greene) 저, John Wiley & Sons Inc.(1999년) 등에 기재된 방법 등]을 적절히 이용함으로써 원하는 화합물을 제조할 수 있다.
제조 방법 15
식 2에 있어서 P1 및 P4가 -O-인 당 리간드 테더 유닛은 이하의 방법으로 제조할 수 있다.
Figure pct00119
(식 중, Q1, Q2, Q3, Q4, P2, P3, P5, P6, T1, T2, L1, L2, q1, q2, q3, q4, q2', q4', Z, B1', B2'는 각각 상기와 동의이며, PG10, PG11, PG12, PG13, PG14 및 PG15는 각각 적절히 보호기를 나타낸다)
식:
Figure pct00120
m1, m2, m3 및 m4는 상기와 동의이다.
공정 66
화합물 (IX-C)는, 화합물 (IX-A)와 화합물 (IX-B)를 N,N'-디메틸포름아미드 등의 용매에 용해하고, 탄산수소칼륨 등의 염기를 가하여, 실온∼200℃에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 제조 공정 1의 공정 2에 예시한 것을 들 수 있다.
염기로서는 제조 공정 1의 공정 3에서 예시한 것을 들 수 있다.
공정 67
화합물 (IX-E)는, 화합물 (IX-C)와 화합물 (IX-D)를, N,N'-디메틸포름아미드 등의 용매에 용해하고, 탄산수소칼륨 등의 염기를 가하여, 실온∼200℃에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 제조 공정 1의 공정 2에서 예시한 것을 들 수 있다.
염기로서는 제조 공정 1의 공정 3에서 예시한 것을 들 수 있다.
화합물 (IX-A)는 시판 제품으로서 얻을 수 있다.
공정 68
화합물 (IX-G)는, 화합물 (IX-E) 및 화합물 (IX-F)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 69
화합물 (IX-I)는, 화합물 (IX-G) 및 화합물 (IX-H)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
또한, 공정 DP와 공정 69를 반복하여 행함으로써, 원하는 q1의 값을 갖는 화합물 (VII-J)를 제조할 수 있다.
공정 70
화합물 (IX-K)는, 화합물 (IX-I) 및 화합물 (IX-J)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 71
화합물 (IX-M)은, 화합물 (IX-K) 및 화합물 (IX-L)을 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
공정 72-74
화합물 (IX')는, 화합물 (IX-M), 화합물 (IX-N), 화합물 (IX-O) 및 화합물 (IX-P)를 이용하여, 제조 공정 1의 공정 3과 같은 조건으로 제조할 수 있다.
또한, 하기 공정 DP3과 공정 72를 반복하여 행함으로써, 원하는 q3의 값을 갖는 화합물 (IX')를 제조할 수 있다.
공정 DP3
유기합성화학에서 상용되는 방법[예컨대 프로텍티브 그룹스 인 오가닉 신세시스 제3판(Protective Groups in Organic Synthesis, third edition), 그린(T. W. Greene) 저, John Wiley & Sons Inc.(1999년) 등에 기재된 방법 등]을 적절히 이용함으로써 원하는 화합물을 제조할 수 있다.
화합물 (IX'-B), 화합물 (IX'-D), 화합물 (IX'-F), 화합물 (IX'-H), 화합물 (IX'-J), 화합물 (IX'-L), 화합물 (IX'-N), 화합물 (IX'-O) 및 화합물 (IX'-P)는, 시판 제품으로서 또는 「실험화학강좌 제4판 유기합성, p. 258, 마루젠(1992년)」, 「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition」에 기재된 방법을 조합하거나 혹은 그것에 준한 방법으로 얻을 수 있다.
제조 방법 16
식 1∼식 8의 핵산 복합체의 제조 방법으로서 이하의 방법도 이용할 수 있다.
Figure pct00121
(식 중, LC, Q5, Q6, Q7, P7, P8, q5', q6 및 X는 상기와 동의이다.)
공정 75
화합물 (X-B)는, 화합물 (XIII'')과 화합물 (X-A)를, 용매 중, 0℃∼100℃에서 10초간∼100시간 반응시킴으로써 제조할 수 있다.
용매로서는 물, 인산 완충액, 아세트산나트륨 완충액, 디메틸술폭시드 등을 들 수 있으며, 이들은 단독으로 또는 혼합하여 이용된다.
화합물 (VIII')은 제조법 14를 이용함으로써 얻을 수 있다.
화합물 (X-A)는 공지된 방법(예컨대 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제21권, 187-202 페이지, 2010년, 또는 커런트 프로토콜즈 인 뉴클레익 애시드 케미스트리(Current Protocols in Nucleic Acid Chemistry), 2010년, 9월; CHAPTER: Unit 4.41) 혹은 그것에 준한 방법으로 얻을 수 있다.
공정 76
화합물 (X')는, 화합물 (X-B)를 이용하여, 탄산나트륨 수용액 또는 암모니아수 중 등 pH 8 이상의 조건 하에, 실온과 200℃ 사이의 온도에서 5분간∼100시간 반응시킴으로써 제조할 수 있다.
제조 방법 17
식 1∼식 8의 핵산 복합체의 제조 방법으로서 이하의 방법도 이용할 수 있다.
Figure pct00122
(식 중, LC, Q5, Q6, Q7, P7, P8, q5', q6 및 X는 상기와 동의이다.)
공정 77
화합물 (XI-A)는, 화합물 (VIII'')을 이용하여, 공지된 방법(예컨대 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제26권, 1451-1455 페이지, 2015년에 기재된 방법) 또는 그것에 준한 방법으로 얻을 수 있다.
화합물 (VIII''')은 제조법 14를 이용함으로써 얻을 수 있다.
공정 78
화합물 (XI')은, 화합물 (XI-A)와 화합물 (XI-B)를 이용하여, 공지된 방법(예컨대 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제26권, 1451-1455 페이지, 2015년에 기재된 방법) 또는 그것에 준한 방법으로 얻을 수 있다.
화합물 (XI-B)는, 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제26권, 1451-1455 페이지, 2015년에 기재된 방법) 또는 그것에 준한 방법으로 얻을 수 있다.
공정 79
또 다른 방법으로서, 화합물 (XI')은, 공지된 방법(예컨대 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제22권, 1723-1728 페이지, 2011년을 참조) 혹은 그것에 준한 방법으로 화합물 (XI-A)로부터 직접 얻을 수 있다.
본 명세서에 있어서의 핵산 복합체는, 예컨대 산 부가염, 금속염, 암모늄염, 유기아민 부가염, 아미노산 부가염 등의 염으로서 얻을 수도 있다.
산 부가염으로서는, 예컨대 염산염, 황산염, 인산염 등의 무기산염, 아세트산염, 말레산염, 푸마르산염, 시트르산염, 메탄술폰산염 등의 유기산염을 들 수 있고, 금속염으로서는, 예컨대 나트륨염, 칼륨염 등의 알칼리 금속염, 마그네슘염, 칼슘염 등의 알칼리 토류 금속염, 알루미늄염, 아연염 등을 들 수 있고, 암모늄염으로서는, 예컨대 암모늄, 테트라메틸암모늄 등의 염을 들 수 있고, 유기아민 부가염으로서는, 예컨대 모르폴린, 피페리딘 등의 부가염을 들 수 있고, 아미노산 부가염으로서는, 예컨대 리신, 글리신, 페닐알라닌 등의 부가염을 들 수 있다.
본 명세서의 핵산 복합체의 염을 조제하고 싶은 경우에는, 상기 복합체를 원하는 염의 형태로 얻어질 때는 그대로 정제하면 되고, 또한 유리(遊離) 형태로 얻어질 때는, 상기 복합체를 적당한 용매에 용해 또는 현탁하고, 대응하는 산 또는 염기를 가하여, 단리·정제하면 된다. 또한, 상기 복합체염을 형성하는 카운터 이온을 다른 카운터 이온으로 변환할 때는, 상기 복합체염을 적당한 용매에 용해 또 는 현탁한 후, 산, 염기 및/또는 염(염화나트륨, 염화암모늄 등의 무기염 등)을 몇 당량∼매우 과잉량 가하여 단리, 정제하면 된다.
본 명세서의 핵산 복합체 중에는, 기하 이성체, 광학 이성체 등의 입체 이성체, 호변 이성체 등이 존재할 수 있는 것도 있는데, 모든 가능한 이성체 및 이들의 혼합물도 본 발명에 포함된다.
또한, 본 명세서의 핵산 복합체는, 물 또는 각종 용매와의 부가물 형태로 존재하는 경우도 있으며, 이들 부가물도 본 발명의 핵산 복합체에 포함된다.
더욱이, 본 발명의 핵산 복합체는, 분자 중의 일부 혹은 모든 원자가 질량수가 다른 원자(동위체)(예컨대 중수소 원자 등)로 치환된 것도 포함된다.
본 발명의 의약 조성물은 식 1로 표시되는 핵산 복합체를 포함한다. 본 발명의 핵산 복합체는, L1 및 L2의 당 리간드를 가짐으로써, 표적 세포에 인식되어, 세포 내에 도입된다.
본 발명의 핵산 복합체는, 포유동물에게 투여하여, 생체 내에 있어서 표적 유전자의 발현을 저하 또는 정지시킴으로써 억제하여, 표적 유전자와 관련된 질환의 치료에 이용할 수 있다.
본 발명의 핵산 복합체를 치료제 또는 예방제로서 사용하는 경우, 투여 경로로서는, 치료 시에 가장 효과적인 투여 경로를 사용하는 것이 바람직하며, 특별히 한정되는 것이 아니지만, 예컨대 정맥내 투여, 피하 투여, 근육내 투여 등을 들 수 있고, 바람직하게는 피하 투여이다.
투여량은, 투여 대상의 병상(病狀)이나 연령, 투여 경로 등에 따라 다르지만, 예컨대 이중 사슬의 올리고뉴클레오티드로 환산한 1일 투여량이 0.1 μg∼1000 mg이 되도록 투여하면 되며, 1일 투여량이 1∼100 mg이 되도록 투여하는 것이 보다 바람직하다.
정맥내 투여 또는 근육내 투여에 적당한 제제로서는, 예컨대 주사제를 들 수 있고, 조제한 액제를 그대로 예컨대 주사제 등의 형태로서 이용하는 것도 가능하지만, 상기 액제로부터 예컨대 여과, 원심분리 등에 의해서 용매를 제거하여 사용할 수도 있고, 상기 액제를 동결 건조하여 사용하고/거나 예컨대 만니톨, 락토오스, 트레할로스, 말토오스 혹은 글리신 등의 부형제를 가한 액제를 동결 건조하여 사용할 수도 있다.
주사제의 경우, 액제 또는 용매를 제거 또는 동결 건조한 조성물에, 예컨대 물, 산, 알칼리, 다양한 완충액, 생리식염수 또는 아미노산 수액 등을 혼합하여 주사제를 조제하는 것이 바람직하다. 또한, 예컨대 시트르산, 아스코르빈산, 시스테인 혹은 EDTA 등의 항산화제, 또는 글리세린, 포도당 혹은 염화나트륨 등의 등장화제 등을 첨가하여 주사제를 조제하는 것도 가능하다. 또한, 예컨대 글리세린 등의 동결보존제를 가하여 동결 보존할 수도 있다.
본 발명의 조성물을 포유동물의 세포에 투여함으로써, 본 발명의 조성물 중의 이중 사슬 핵산을 세포 내에 도입할 수 있다.
인비보에 있어서의 본 발명의 핵산 복합체를 포유동물의 세포에 도입하는 방법은, 인비보에 있어서 행할 수 있는 공지된 트랜스펙션의 수순에 따라서 행하면 된다. 본 발명의 조성물을 사람을 포함하는 포유동물에게 정맥내 투여함으로써 간에 송달되어, 간 또는 간세포 내에 본 발명의 조성물 중의 이중 사슬 핵산을 도입할 수 있다.
간 또는 간세포 내에 본 발명의 조성물 중의 이중 사슬 핵산이 도입되면, 그 간세포 내의 APCS 유전자의 발현을 저하시켜, 아밀로이드 관련 질환을 치료 혹은 예방할 수 있다. 아밀로이드 관련 질환으로서는, APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환을 들 수 있으며, 구체적으로는 아밀로이드 섬유로서 알려져 있는 이상한 불용성 단백질 섬유가 조직에 침착하여 장기(臟器) 장해가 야기되는 질환이다. 아밀로이드 관련 질환으로서 보다 구체적으로는, 전신성 아밀로이드시스인 AL 아밀로이드시스, AA 아밀로이드시스, ATTR 아밀로이드시스, 투석 아밀로이드시스, 아밀로이드 침착을 동반하는 심부전, 아밀로이드 침착을 동반하는 신증, 노년성 아밀로이드시스, 수근관증후군 등, 국한성 아밀로이드시스인 알츠하이머형 인지증, 뇌 아밀로이드 혈관병, II형 당뇨병 등을 들 수 있다. 본 발명의 핵산 복합체의 투여 대상은 포유동물이며, 인간인 것이 바람직하다.
본 발명의 핵산 복합체를 아밀로이드 관련 질환의 치료제 또는 예방제로서 사용하는 경우, 투여 경로로서는, 치료 시에 가장 효과적인 투여 경로를 사용하는 것이 바람직하며, 바람직하게는 정맥내 투여, 피하 투여 또는 근육내 투여를 들 수 있고, 보다 바람직하게는 피하 투여를 들 수 있다.
투여량은, 투여 대상의 병상이나 연령, 투여 경로 등에 따라 다르지만, 예컨대 이중 사슬 핵산으로 환산한 1일 투여량이 0.1 μg∼1000 mg이 되도록 투여하면 되고, 1일 투여량이 1∼100 mg이 되도록 투여하는 것이 바람직하다.
또한, 본 발명은, 질환의 치료에 사용하기 위한 핵산 복합체; 질환의 치료에 사용하기 위한 의약 조성물; 질환을 치료하기 위한 핵산 복합체의 용도; 질환의 치료용 의약의 제조에 있어서의 핵산 복합체의 용도; 질환의 치료용 의약의 제조에 사용하기 위한 핵산 복합체; 유효량의 핵산 복합체를, 그 필요가 있는 대상에게 투여하는 것을 포함하는, 질환의 치료 또는 예방 방법을 제공한다.
실시예
이어서, 참고예, 실시예 및 시험예에 의해 본 발명을 구체적으로 설명한다. 단, 본 발명은 이들 실시예 및 시험예에 한정되는 것은 아니다. 또한, 실시예 및 참고예에 기재된 프로톤 핵자기 공명 스펙트럼(1H NMR)은 270 MHz, 300 MHz 또는 400 MHz에서 측정된 것이며, 화합물 및 측정 조건에 따라서는 교환성 프로톤이 명료하게 관측되지 않는 경우가 있다. 또한, 시그널의 다중도 표기로서는 통상 이용되는 것을 이용하고 있지만, br은 broad를 의미하여, 외관상 폭넓은 시그널임을 나타낸다.
UPLC 분석은 이하의 조건을 이용했다.
이동상 A: 0.1% 포름산 함유 수용액, B: 아세토니트릴 용액
그래디언트: 이동상 B가 10%-90%인 리니어 그래디언트(3분간)
컬럼: Waters사 제조 ACQUITY UPLC BEH C18(1.7 ㎛, 내경 2.1x50 mm)
유속: 0.8 mL/min
PDA 검출 파장: 254 nm(검출 범위 190-800 nm)
표 X-1∼표 X-4에 참고예 화합물을 나타낸다.
Figure pct00123
Figure pct00124
Figure pct00125
Figure pct00126
Figure pct00127
Figure pct00128
Figure pct00129
Figure pct00130
Figure pct00131
Figure pct00132
참고예 1
Figure pct00133
화합물 RE1-2의 합성
참고예 1의 공정 1
저널 오브 아메리칸 케미컬 소사이어티(Journal of American Chemical Society), 제136권, 16958-16961 페이지, 2014년에 기재된 방법으로 합성한 화합물 RE1-1(0.8755 g, 1.9567 mmol)을 테트라히드로푸란(10 mL)에 용해하고, 1,3-디시클로헥산카르보디이미드(DCC, 0.4247 g, 2.0584 mmol)와 N-히드록시숙시미드(0.2412 g, 2.0958 mmol)를 가하여 실온에서 하룻밤 교반했다. 반응 혼합물로부터 석출된 고체를 제외하고, 감압 하에 용매를 유거(留去)했다. 얻어진 혼합물을 N,N'-디메틸포름아미드(DMF)에 용해하고, 2-아미노에틸말레이미드브롬산염(0.6479 g, 2.5491 mmol)과 디이소프로필에틸아민(1.7 mL, 9.7835 mmol)을 가한 후, 실온에서 하룻밤 교반했다. 감압 하에 반응액의 용매를 유거하고, 역상 컬럼 크로마토그래피(물/메탄올=80/20)로 용출시킴으로써, 화합물 RE1-2(0.8502 g, 수율 76%)를 얻었다.
ESI-MS m/z: 570(M+H)+;
1H-NMR(DMSO-D6) δ: 1.45-1.56(4H, m), 1.78(3H, s), 1.90(3H, s), 1.97(2H, t, J=7.0 Hz), 2.00(3H, s), 2.11(3H, s), 3.18-3.19(2H, m), 3.38-3.45(3H, m), 3.64-3.71(1H, m), 3.85-3.89(1H, m), 4.01-4.04(3H, m), 4.48(1H, d, J=8.6 Hz), 4.95-4.98(1H, m), 5.21(1H, d, J=3.5 Hz), 6.99(2H, s), 7.81-7.87(2H, m).
화합물 RE1-4의 합성
참고예 1의 공정 2
화합물 RE1-1(0.9602 g, 2.1460 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, N-Boc-에틸렌디아민(시그마알드리치사 제조, 0.6877 g, 4.292 mmol), 디이소프로필에틸아민(1.90 mL, 10.87 mmol) 및 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸유로늄 헥사플루오로인산염(와코쥰야쿠고교사 제조, 1.6437 g, 4.3229 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액에 물을 가하여, 클로로포름으로 2회 추출한 후, 유기층을 포화식염수로 세정하고, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 화합물 RE1-3의 조정제물(粗精製物)을 얻었다.
ESI-MS m/z: 590(M+H)+
참고예 1의 공정 3
화합물 RE1-4의 합성 공정 1에서 합성한 화합물 RE1-3(1.2654 g, 2.1460 mmol)을 디클로로메탄(15 mL)에 용해하고, 트리플루오로아세트산(4 mL)을 가하여, 실온에서 하룻밤 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 역상 컬럼 크로마토그래피(물/메탄올=80/20)로 용출시킴으로써, 화합물 RE1-4(0.3879 g, 수율 37%)를 얻었다.
ESI-MS m/z: 490(M+H)+;
1H-NMR(DMSO-D6) δ: 1.46-1.52(4H, m), 1.78(3H, s), 1.90(3H, s), 2.00(3H, s), 2.08(2H, t, J=7.4 Hz), 2.11(3H, s), 2.85(2H, t, J=6.3 Hz), 3.27(2H, dd, J=12.3, 6.2 Hz), 3.67-3.69(1H, m), 3.68-3.73(1H, m), 3.86-3.90(1H, m), 4.01-4.04(3H, m), 4.49(1H, d, J=8.4 Hz), 4.97(1H, dd, J=11.3, 3.4 Hz), 5.22(1H, d, J=3.5 Hz), 7.86(1H, d, J=9.1 Hz), 7.95-8.02(1H, m).
참고예 2
Figure pct00134
참고예 2의 공정 1
(9H-플루오렌-9-일)메틸((2R,3R)-1,3-디히드록시부탄-2-일)카르바메이트(화합물 RE2-1, Chem-Impex International, Inc사 제조, 1.50 g, 4.58 mmol)를 피리딘(20 mL)에 용해하고, 빙냉 하에 4,4'-디메톡시트리틸클로라이드(도쿄가세이고교사 제조, 1.71 g, 5.04 mmol)를 가한 후, 실온에서 2시간 교반했다. 반응액을 빙냉하고, 10% 시트르산 수용액을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헥산/아세트산에틸=90/10)로 정제함으로써, 화합물 RE2-2(1.07 g, 수율 37%)를 얻었다.
ESI-MS m/z: 630(M+H)+
참고예 2의 공정 2
참고예 2의 공정 1에서 합성한 화합물 RE2-2(1.07 g, 1.699 mmol)를 N,N-디메틸포름아미드(10 mL)에 용해하고, 실온에서 피페리딘(0.336 mL, 3.40 mmol)을 가하여 3시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 아미노 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제함으로써, 화합물 RE2-3(0.59 g, 수율 85%)을 얻었다.
ESI-MS m/z: 408(M+H)+
참고예 3
Figure pct00135
참고예 3의 공정 1
5-히드록시이소프탈산디메틸(화합물 RE3-1, 와코쥰야쿠고교사 제조, 5.0443 g, 24 mmol)을 테트라히드로푸란(와코쥰야쿠고교사 제조 25 mL)에 용해하고, 2-(tert-부톡시카르보닐아미노)-1-에탄올(도쿄가세이고교사 제조, 4.0343 g, 25.03 mmol) 및 트리페닐포스핀 폴리머 담지체(시그마알드리치사 제조, 6.61 g, 25.2 mmol)를 가한 후, 빙냉 하에 40% 디이소프로필아조디카르복실레이트(DIAD) 톨루엔 용액(도쿄가세이고교사 제조, 13.26 mL, 25.2 mmol)을 가하여, 실온에서 하룻밤 교반했다. 반응액을 여과하고, 감압 하에 여과액을 유거한 후, 잔사를 아미노 실리카겔 컬럼 크로마토그래피(헥산/아세트산에틸=95/5∼80/20)로 정제함으로써, 화합물 RE3-2(5.3071 g, 수율 63%)를 얻었다.
ESI-MS m/z: 254(M+H)+, 탈(脫)Boc체로서 검출
참고예 3의 공정 2
참고예 3의 공정 1에서 합성한 화합물 RE3-2(5.3071 g, 15.02 mmol)를 메탄올 (25 mL)에 용해하고, 빙냉 하에 2 mol/L 수산화나트륨 수용액(와코쥰야쿠고교사 제조, 13 mL)을 가하여, 실온에서 4시간 교반했다. 반응액을 빙냉하고, 10% 시트르산 수용액을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거함으로써, 화합물 RE3-3을 정량적으로 얻었다.
ESI-MS m/z: 324(M-H)-
참고예 3의 공정 3
참고예 3의 공정 2에서 합성한 화합물 RE3-3(1.9296 g, 5.93 mmol)을 N,N'-디메틸포름아미드(70 mL)에 용해하고, N-1-(9H-플루오렌-9-일메톡시카르보닐)-에틸렌디아민염산염(3.3493 g, 11.86 mmol), 디이소프로필에틸아민(5.18 mL, 29.7 mmol) 및 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸유로늄헥사플루오로인산염(4.5168 g, 11.88 mmol)을 가하여, 실온에서 4시간 교반했다. 반응액을 빙냉하고, 10% 시트르산 수용액을 가하여, 클로로포름으로 추출한 후, 유기층을 포화탄산수소나트륨 수용액 및 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하고, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올)로 정제함으로써, 화합물 RE3-4(3.4407 g, 수율 68%)를 얻었다.
ESI-MS m/z: 898(M+HCOO)-
참고예 3의 공정 4
참고예 3의 공정 3에서 합성한 화합물 RE3-4(1.6087 g, 1.884 mmol)를 디클로로메탄(20 mL)에 용해하고, 빙냉 하에 트리플루오로아세트산(5 mL, 64.9 mmol)을 가하여, 실온에서 4시간 교반했다. 반응액을 감압 하에 용매를 유거함으로써, 화합물 RE3-5(2.4079 g)를 정량적으로 얻었다.
ESI-MS m/z: 798(M+HCOO)-
참고예 3의 공정 5
참고예 3의 공정 4에서 합성한 화합물 RE3-5(386 mg, 0.512 mmol)를 테트라히드로푸란(10 mL)에 용해하고, 빙냉 하에 염화벤조일(175 mg, 1.024 mmol)을 가하여, 실온에서 1시간 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올)로 정제함으로써, 화합물 RE3-6(373 mg, 수율 82%)을 얻었다.
ESI-MS m/z: 888(M+H)+
참고예 3의 공정 6
참고예 3의 공정 5에서 합성한 화합물 RE3-6(108 mg, 0.122 mmol)을 디클로로메탄(5 mL)에 용해하고, 실온에서 디에틸아민(0.5 mL, 4.8 mmol)을 가하여 1시간 교반했다. 감압 하에 용매를 유거함으로써, 화합물 RE3-7(54.9 mg)을 정량적으로 얻었다.
ESI-MS m/z: 444(M+H)+
참고예 3의 공정 7
참고예 3의 공정 6에서 합성한 화합물 RE3-7(180 mg, 0.406 mmol), Nα,Nε-비스(tert-부톡시카르보닐)-L-리신(노바바이오켐사 제조, 295 mg, 0.852 mmol), 디이소프로필에틸아민(0.354 mL, 2.029 mmol) 및 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸유로늄헥사플루오로인산염(324 mg, 0.852 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 빙냉하고, 10% 시트르산 수용액을 가하여, 클로로포름으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 아미노 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올)로 정제함으로써, 화합물 RE3-8(450 mg)을 정량적으로 얻었다.
ESI-MS m/z: 1101(M+H)+
참고예 3의 공정 8
참고예 3의 공정 7에서 합성한 화합물 RE3-8(2.1558 g, 1.9593 mmol)을 디클로로메탄(20 mL)에 용해하고, 빙냉 하에 트리플루오로아세트산(5 mL)을 가하여, 실온에서 4시간 교반했다. 반응액을 감압 하에 용매를 유거함으로써, 화합물 RE3-9를 정량적으로 얻었다.
ESI-MS m/z: 700(M+H)+
참고예 4
Figure pct00136
(도면에서, Bn은 벤질기를 나타낸다.)
참고예 4의 공정 1
참고예 3에 기재한 방법으로 합성한 화합물 RE4-1(참고예 3에 있어서의 화합물 RE3-5, 0.5716 g, 0.7582 mmol), 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제22권, 690-699 페이지, 2011년에 기재된 방법으로 합성한 도데칸산모노벤질에스테르(0.4859 g, 1.5164 mmol), 디이소프로필에틸아민(0.662 mL, 3.79 mmol) 및 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸유로늄헥사플루오로인산염(0.5766 g, 1.516 mmol)을 N,N디메틸포름아미드(12 mL)에 용해하여, 실온에서 1시간 교반했다. 반응액을 빙냉하고, 포화시트르산 수용액을 가하여, 클로로포름으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올)로 정제함으로써, 화합물 RE4-2(0.88 g, 수율 84%)를 얻었다.
ESI-MS m/z: 1057(M+H)+
참고예 4의 공정 2
참고예 4의 공정 1에서 합성한 화합물 RE4-2(0.7545 g, 0.714 mmol)를 디클로로메탄과 테트라히드로푸란의 혼합 용매(20 mL)에 용해하고, 실온에서 디에틸아민(5 mL, 47.9 mmol)을 가하여 밤새 교반했다. 감압 하에 용매를 유거함으로써, 화합물 RE4-3을 정량적으로 얻었다.
ESI-MS m/z: 612(M+H)+
참고예 4의 공정 3
참고예 4의 공정 2에서 합성한 화합물 RE4-3(0.437 g, 0.7143 mmol), Nα,Nε-비스(tert-부톡시카르보닐)-L-리신(노바바이오켐사 제조, 0.5483 g, 1.583 mmol), 디이소프로필에틸아민(0.624 mL, 3.57 mmol), 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸유로늄헥사플루오로인산염(0.5703 g, 1.5 mmol)을 가하여, 실온에서 2시간 교반했다. 반응액에 10% 시트르산 수용액을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거함으로써, 화합물 RE4-4의 조생성물(粗生成物)을 얻었다.
ESI-MS m/z: 1269(M+H)+
참고예 4의 공정 4
참고예 4의 공정 3에서 합성한 화합물 RE4-4(0.906 g, 0.7143 mmol)를 디클로로메탄(12 mL)에 용해하고, 빙냉 하에 트리플루오로아세트산(3 mL, 38.9 mmol)을 가하여, 실온에서 4시간 교반했다. 반응액을 감압 하에 용매를 유거함으로써, 화합물 RE4-5의 조생성물을 얻었다.
ESI-MS m/z: 869(M+H)+
참고예 5
Figure pct00137
참고예 5의 공정 1
참고예 3에 기재한 방법으로 합성한 화합물 RE5-1(참고예 3에 있어서의 RE3-8, 100 mg, 0.091 mmol)을 메탄올(3 mL)에 용해하고, 아세트산(2 μL)을 첨가한 후, 팔라듐/탄소에 의한 접촉 수소 환원을 행했다. 얻어진 용액 유분(留分)을 감압 하에 용매를 유거함으로써, 화합물 RE5-2를 정량적으로 얻었다.
ESI-MS m/z: 967(M+H)+
참고예 5의 공정 2
화합물 RE5-2(50 mg, 0.052 mmol) 및 N-(6-말레이미드카프로일옥시)숙시미드(48 mg, 0.155 mmol)를 테트라히드로푸란(2 mL)에 용해하고, 디이소프로필에틸아민(0.045 mL, 0.259 mmol)을 가하여, 실온에서 밤새 교반했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올)로 정제함으로써, 화합물 RE5-3(18 mg, 수율 30%)을 얻었다.
ESI-MS m/z: 1160(M+H)+
참고예 5의 공정 3
참고예 5의 공정 2에서 합성한 화합물 RE5-3(18 mg, 0.016 mmol)을 디클로로메탄(2 mL)에 용해하고, 빙냉 하에 트리플루오로아세트산(0.2 mL, 2.6 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 디에틸에테르로 정석한 후, 화합물 RE5-4(7.5 mg, 수율 64%)를 백색 고체로서 얻었다.
ESI-MS m/z: 759(M+H)+
참고예 6
Figure pct00138
참고예 6의 공정 1
참고예 3에 기재한 방법으로 합성한 화합물 RE6-1(참고예 3에 있어서의 화합물 RE3-2, 0.9372 g, 2.8809 mmol), β-알라닌메틸에스테르염산염(도쿄가세이고교가부시키가이샤 제조, 0.8082 g, 5.7902 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE6-2를 정량적으로 얻었다.
ESI-MS m/z: 495(M+H)+
참고예 6의 공정 2
참고예 6의 공정 1에서 합성한 화합물 RE6-2(0.9622 g, 1.952 mmol)를 이용하여, 참고예 3의 공정 4와 같은 방법으로 화합물 RE6-3을 정량적으로 얻었다.
ESI-MS m/z: 396(M+H)+
참고예 6의 공정 3
참고예 6의 공정 2에서 합성한 화합물 RE6-3(0.1146 g, 0.290 mmol) 및 N-숙신이미딜15-아지드-4,7,10,13-테트라옥사펜타데칸산(N3-PEG4-NHS, 도쿄가세이고교가부시키가이샤 제조, 0.0750 g, 0.1931 mmol)을 이용하여, 참고예 5의 공정 2와 같은 방법으로 화합물 RE6-4를 정량적으로 얻었다.
ESI-MS m/z: 669(M+H)+
참고예 6의 공정 4
참고예 6의 공정 3에서 합성한 화합물 RE6-4(0.1291 g, 0.193 mmol)를 이용하여, 참고예 3의 공정 2와 같은 방법으로 화합물 RE6-5를 정량적으로 얻었다.
ESI-MS m/z: 641(M+H)+
참고예 6의 공정 5
참고예 6의 공정 4에서 합성한 화합물 RE6-5(0.1252 g, 0.193 mmol) 및 L-글루타민산 디-tert-부틸에스테르(와타나베카가쿠가부시키가이샤 제조, 0.1180 g, 0.399 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE6-6(0.0521 g, 수율 24%)을 얻었다.
ESI-MS m/z: 1124(M+H)+
참고예 6의 공정 6
참고예 6의 공정 5에서 합성한 화합물 RE6-6(0.0521 g, 0.0464 mmol)을 이용하여, 참고예 3의 공정 4와 같은 방법으로 화합물 RE6-7(36 mg, 수율 86%)을 얻었다.
ESI-MS m/z: 899(M+H)+
참고예 7
Figure pct00139
참고예 7의 공정 1
참고예 3에 기재한 방법으로 합성한 화합물 RE7-1(참고예 3에 있어서의 RE3-9, 0.2586 g, 0.3695 mmol)과, 저널 오브 아메리칸 케미컬 소사이어티(Journal of American Chemical Society), 제136권, 16958-16961 페이지, 2014년에 기재된 방법으로 합성한 참고예 1에 기재한 화합물 RE-1(0.8559 g, 1.7927 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE7-2(0.5272 g, 수율 61%)를 얻었다.
ESI-MS m/z: 2418(M+H)+
참고예 7의 공정 2
참고예 7의 공정 1에서 합성한 화합물 RE7-2(0.2653 g, 0.1097 mmol)를 이용하여, 참고예 5의 공정 1과 같은 방법으로 화합물 RE7-3(0.1524 g, 수율 61%)을 얻었다.
ESI-MS m/z: 2284(M+H)+
참고예 8: 화합물 A1 및 B1의 합성
Figure pct00140
화합물 A1의 합성
참고예 7에 기재한 방법으로 합성한 화합물 RE8-1(참고예 7에 있어서의 화합물 RE7-3, 0.0152 g, 0.006657 mmol)을 이용하여, 참고예 5의 공정 2와 같은 방법으로 화합물 A1(0.0077 g, 수율 47%)을 얻었다.
ESI-MS m/z: 1239(M+2H)2+
1H-NMR(DMSO-D6) δ: 1.11-1.66(34H, m), 1.77(12H, d, J=1.5 Hz), 1.89(12H, s), 2.01-2.14(10H, m), 2.01(12H, s), 2.10(12H, s), 2.92-2.99(4H, m), 3.16-3.54(14H, m), 3.65-3.74(4H, m), 3.81-3.91(4H, m), 3.98-4.08(14H, m), 4.11-4.24(4H, m), 4.48(4H, dd, J=8.4, 1.8 Hz), 4.93-5.00(4H, m), 5.21(4H, d, J=3.5 Hz), 6.99(2H, s), 7.52(2H, s), 7.66-7.75(2H, m), 7.78-7.87(6H, m), 7.91(1H, br s), 8.01-8.08(3H, br m), 8.54-8.60(2H, br m).
화합물 B1의 합성
화합물 RE8-1(참고예 7에 있어서의 화합물 RE7-3, 0.0150 g, 0.00657 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 B1(0.0062 g, 수율 37%)을 얻었다.
ESI-MS m/z: 1279(M+2H)2+
1H-NMR(DMSO-D6) δ: 1.11-1.66(30H, m), 1.77(12H, s), 1.89(12H, s), 2.01-2.14(8H, m), 2.01(12H, s), 2.10(12H, s), 2.33-2.38(2H, m), 2.92-2.99(4H, m), 3.16-3.54(14H, m), 3.58-3.63(16H, m), 3.65-3.74(4H, m), 3.81-3.91(4H, m), 3.98-4.08(12H, m), 4.11-4.24(4H, m), 4.48(4H, dd, J=8.4, 1.8 Hz), 4.93-5.00(4H, m), 5.21(4H, d, J=3.5 Hz), 7.52(2H, s), 7.66-7.75(2H, m), 7.78-7.87(6H, m), 7.91(1H, br s), 8.01-8.08(3H, br m), 8.54-8.60(2H, br m).
참고예 9: 화합물 B2 및 B3의 합성
Figure pct00141
화합물 B2의 합성
참고예 6에 기재한 방법으로 합성한 화합물 RE9-1(참고예 6에 있어서의 화합물 RE6-5, 0.00436 g, 0.00681 mmol) 및 참고예 1의 화합물 RE1-4(0.010 g, 0.020 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 B2의 조생성물을 얻었다.
ESI-MS m/z: 1584(M+H)+
화합물 B3의 합성
참고예 6에 기재한 방법으로 합성한 화합물 RE9-2(참고예 6에 있어서의 화합물 RE6-7, 0.0100 g, 0.01112 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 B3(0.0223 g, 수율 72%)을 얻었다.
ESI-MS m/z: 1393(M+2H)2+
참고예 10: 화합물 C1 및 D1의 합성
Figure pct00142
참고예 10의 공정 1
참고예 4에 기재한 방법으로 합성한 화합물 RE10-1(참고예 4에 있어서의 화합물 RE4-5, 0.1952 g, 0.225 mmol)과, 저널 오브 아메리칸 케미컬 소사이어티(Journal of American Chemical Society), 제136권, 16958-16961 페이지, 2014년에 기재된 방법으로 합성한 참고예 1의 화합물 RE1-1(0.4162 g, 0.93 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE10-2(334.8 mg, 수율 58%)를 얻었다.
ESI-MS m/z: 1294(M+2H)2+
참고예 10의 공정 2
참고예 10의 공정 1에서 합성한 화합물 RE10-2(0.1459 g, 0.056 mmol)를 이용하여, 참고예 5의 공정 1과 같은 방법으로 화합물 D1(112 mg, 수율 80%)을 얻었다.
ESI-MS m/z: 1249(M+2H)2+
1H-NMR(DMSO-D6) δ: 1.11-1.66(44H, m), 1.77(12H, d, J=1.5 Hz), 1.89(12H, s), 2.01-2.20(12H, m), 2.01(12H, s), 2.10(12H, s), 2.92-2.99(4H, m), 3.16-3.54(10H, m), 3.58-3.64(4H, m), 3.65-3.74(4H, m), 3.81-3.91(4H, m), 3.98-4.08(12H, m), 4.11-4.24(4H, m), 4.48(4H, dd, J=8.4, 1.8 Hz), 4.93-5.00(4H, m), 5.21(4H, d, J=3.5 Hz), 6.99(2H, s), 7.52(2H, s), 7.66-7.75(2H, m), 7.78-7.87(6H, m), 7.91(1H, br s), 8.01-8.08(3H, br m), 8.54-8.60(2H, br m).
참고예 10의 공정 3
참고예 10의 공정 2에서 합성한 화합물 D1(0.1091 g, 0.044 mmol) 및 참고예 2의 화합물 RE2-3(0.0748 g, 0.184 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE10-3을 조생성물로서 얻었다.
ESI-MS m/z: 1292(M+2H)2+, 탈DMTr체로서 검출
참고예 10의 공정 4
참고예 10의 공정 3에서 합성한 화합물 RE10-3(0.161 g, 0.05586 mmol)을 디클로로메탄(5 mL)에 용해하고, 숙신산무수물(도쿄가세이고교사 제조, 0.1182 g, 1.181 mmol), N,N-디메틸아미노피리딘(0.0224 g, 0.183 mmol) 및 트리에틸아민(0.55 mL, 3.95 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 빙냉하고, 물을 가하여, 아세트산에틸로 2회 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거함으로써, 화합물 RE10-4의 조생성물을 얻었다.
ESI-MS m/z: 1342(M+2H)2+, 탈DMTr체로서 검출
참고예 10의 공정 5
참고예 10의 공정 4에서 합성한 화합물 RE10-4(0.0816 g, 0.02734 mmol), O-(벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄 헥사플루오로인산염(0.0221 g, 0.05827 mmol) 및 디이소프로필에틸아민(0.02 mL, 0.1094 mmol)을 N,N-디메틸포름아미드(4 mL)에 용해하고, LCAA-CPG(Chem Gene사 제조, 0.4882 g)를 가하여, 실온에서 밤새 교반했다. 혼합물을 여과 분별하고, 디클로로메탄, 10% 메탄올디클로로메탄 용액 및 디에틸에테르로 순차 세정한 후, 무수아세트산/피리딘 용액과 작용시킴으로써, 화합물 C1(49.5 ㎛ol/g, 수율 89%)을 얻었다. 또한, 수율은 1% 트리플루오로아세트산/디클로로메탄 용액을 고상 담지체에 첨가하여, DMTr기에서 유래하는 흡수로부터 계산할 수 있는 고상 담체에의 도입률로부터 산출했다.
참고예 11
Figure pct00143
화합물 RE11-1(1.200 g, 3.640 mmol)로부터 저널 오브 메디시날 케미스트리(Journal of Medicinal Chemistry), 제59권, 2718-2733 페이지, 2016년에 기재된 방법으로 화합물 RE11-2(1.050 g, 수율 50%)를 합성했다.
ESI-MS m/z: 582(M+H)+
참고예 12
Figure pct00144
화합물 RE12-1(4.000 g, 10.27 mmol)을 디클로로메탄(60 mL)에 용해하고, 벤질-2-(2-히드록시에톡시)에틸카르바메이트(2.700 g, 11.30 mmol) 및 트리플루오로메탄술폰산(0.1360 mL, 1.541 mmol)을 가하여, 환류 조건 하에서 밤새 교반했다. 반응액에 10 wt% 탄산칼륨 수용액을 가하여, 디클로로메탄과 분액한 후, 유기상을 물로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 2-메틸테트라히드로푸란으로 치환 농축했다. 잔사를 헵탄에 적하하여, 얻어진 결정을 여과함으로써, 화합물 RE12-2(5.130 g, 수율 88%)를 얻었다.
ESI-MS m/z: 570(M+H)+
참고예 13
Figure pct00145
화합물 RE13-1(참고예 1에 있어서의 화합물 RE1-1, 898.0 mg, 2.007 mmol)을 디클로로메탄(15 mL)에 용해하고, 1-히드록시벤조트리아졸일수화물(338.0 mg, 2.208 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(343 mg, 2.208 mmol) 및 N-1-Z-1,3-디아미노프로판염산염(0.4910 mL, 2.208 mmol)을 가하여, 실온에서 3시간 교반했다. 반응액에 물을 가하여, 디클로로메탄으로 분액한 후, 유기층을 포화탄산수소나트륨 수용액으로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제함으로써, 화합물 RE13-2(873.0 mg, 수율 68%)를 얻었다.
ESI-MS m/z: 639(M+H)+
참고예 14
Figure pct00146
참고예 14의 공정 1
화합물 RE14-1(참고예 1에 있어서의 화합물 RE1-1, 3.00 g, 6.70 mmol)을 디클로로메탄(60 mL)에 용해하고, 실온에서 L-리신벤질에스테르2p-톨루엔술폰산염(1.75 g, 3.02 mmol), 트리에틸아민(0.935 mL, 6.70 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(1.29 g, 6.70 mmol), 1-히드록시벤조트리아졸일수화물(103 mg, 0.670 mmol)을 가하여 2.5시간 교반했다. 반응액을 물과 포화탄산수소나트륨 수용액으로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제함으로써, 화합물 RE14-2를 정량적으로 얻었다.
ESI-MS m/z: 1096(M+H)+
참고예 14의 공정 2
화합물 RE14-2(2.30 g, 2.10 mmol)를 테트라히드로푸란(46 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 424 mg)을 가하여, 수소 분위기 하에서 밤새 교반했다. 반응액을 여과하여, 감압 하에 용매를 유거함으로써, 화합물 RE14-3을 정량적으로 얻었다.
ESI-MS m/z: 1006(M+H)+
참고예 15
Figure pct00147
참고예 15의 공정 1
이미노이아세트산(도쿄가세이고교사 제조, 1.5 g, 6.43 mmol)을 염화메틸렌(30 mL)에 용해하고, 펜타플루오로트리플루오로아세트산(도쿄가세이고교사 제조, 2.75 mL, 16.08 mmol), 트리에틸아민(4.48 mL, 32.2 mmol)을 가하여 4시간 교반했다. 반응액에 10% 시트르산 수용액을 가하여, 클로로포름으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 거기에, 참고예 11에 기재한 방법으로 합성한 화합물 RE15-1(참고예 11에 있어서의 화합물 RE11-2, 2 g, 3.45 mmol)을 아세트산에틸(10 mL)과 아세토니트릴(10 mL)의 혼합액에 용해하여, 팔라듐/탄소에 의한 접촉 수소 환원을 행했다. 얻어진 용액 부분을 감압 하에 용매를 유거함으로써, 화합물 RE15-2의 조생성물을 얻었다.
ESI-MS m/z: 1091(M+H)+
참고예 15의 공정 2
화합물 RE15-2(1.5 g, 1.37 mmol)를 이용하여, 참고예 1의 공정 3과 같은 방법으로 화합물 RE15-3을 정량적으로 얻었다.
ESI-MS m/z: 990(M+H)+
참고예 16
Figure pct00148
참고예 16의 공정 1
N-(t-부톡시카르보닐)-L-글루타민산(도쿄가세이고교사 제조)을 이용하고, 참고예 11에 기재한 방법으로 합성한 화합물 RE16-1(1.855 g, 3.19 mmol)을 이용하여, 참고예 15의 공정 1과 같은 방법으로 화합물 RE16-2의 조정제물을 얻었다.
ESI-MS m/z: 1105(M+H)+
참고예 16의 공정 2
화합물 RE16-2(1.421 g, 1.2866 mmol)를 이용하여, 참고예 1의 공정 3과 같은 방법으로 화합물 RE16-3을 정량적으로 얻었다.
ESI-MS m/z: 1004(M+H)+
참고예 17
Figure pct00149
저널 오브 오가닉 케미스트리(Journal of Organic Chemistry), 제74권, 6837-6842 페이지, 2009년에 기재된 방법으로 합성한 화합물 RE17-1(90 mg, 0.173 mmol)을 테트라히드로푸란(1 mL)에 용해하고, 트리페닐포스핀, 폴리머 담지(시그마알드리치사 제조, 63 mg, 0.189 mmol)를 가하여, 가열 환류 하에 3시간 교반했다. 반응액을 여과하여, 감압 하에 용매를 유거함으로써, 화합물 RE17-2(70 mg, 수율 82%)를 얻었다.
ESI-MS m/z: 516(M+Na)+
1H-NMR(400 MHz, CDCl3): δ 0.89(3H, s), 1.42-1.48(2H, m), 1.52-1.61(2H, m), 1.85(1H, br s), 2.68(2H, t, J=7.2 Hz), 3.06-3.07(2H, m), 3.39-3.44(3H, m), 3.51-3.55(3H, m), 3.78(6H, s), 6.80-6.85(4H, m), 7.17-7.23(1H, m), 7.27-7.33(6H, m), 7.41-7.43(2H, m).
참고예 18
Figure pct00150
참고예 18의 공정 1
화합물 RE18-1(도쿄가세이고교사 제조, 0.500 g, 3.73 mmoL)을 이용하여, 참고예 2의 공정 1과 같은 방법으로 화합물 RE18-2의 조생성물(1.5 g)을 얻었다.
ESI-MS m/z: 435(M-H)-
참고예 18의 공정 2
화합물 RE18-2의 조생성물(1.5 g)과 1,4-디아미노부탄(도쿄가세이고교사 제조, 3.29 g, 37.3 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE18-3(0.18 g, 2단계 수율 10%)을 얻었다.
ESI-MS m/z: 551(M+HCOO)-
1H-NMR(400 MHz, MeOD): δ 1.09(3H, s), 1.45-1.52(4H, m), 2.80(2H, t, J=7.2 Hz), 2.91(2H, s), 3.05(1H, d, J=8.8 Hz), 3.12-3.16(4H, m), 3.24(1H, s), 3.43(1H, d, J=10.8 Hz), 3.62-3.66(7H, m), 6.71-6.76(4H, m), 7.05-7.11(1H, m), 7.12-7.20(6H, m), 7.28-7.32(2H, m).
참고예 19
Figure pct00151
저널 오브 오가닉 케미스트리(Journal of Organic Chemistry), 제74권, 6837-6842 페이지, 2009년에 기재된 방법으로 합성한 화합물 RE19-1(110 mg, 0.212 mmol)을 테트라히드로푸란(2 mL)에 용해하고, N-(1R,8S,9s)-비시클로[6.1.0]논-4-인-9-일메틸옥시카르보닐-1,8-디아미노-3,6-디옥사옥탄(도쿄가세이고교사 제조, 72 mg, 0.222 mmol)을 가하여, 실온에서 1시간 교반했다. 반응액에 물을 가하여, 클로로포름으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 아미노 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제함으로써, 화합물 RE19-2(160 mg, 수율 90%)를 얻었다.
ESI-MS m/z: 845(M+H)+
1H-NMR(400 MHz, CDCl3): δ 0.88(3H, s), 0.91-1.09(3H, m), 1.20-1.25(1H, m), 1.52-1.59(4H, m), 1.80-1.85(2H, m), 2.19-2.25(4H, m), 2.59-2.68(1H, m), 2.84-2.90(4H, m), 3.02-3.11(3H, m), 3.35-3.44(5H, m), 3.49-3.53(5H, m), 3.54-3.58(2H, m), 3.62(5H, s), 3.78(6H, s), 4.13(2H, d, J=6.4 Hz), 4.21(2H, t, J=7.2 Hz), 6.79-6.84(4H, m), 7.18-7.21(1H, m), 7.24-7.27(2H, m), 7.28-7.32(4H, m), 7.39-7.44(2H, m).
참고예 20
Figure pct00152
참고예 20의 공정 1
화합물 RE20-1(AstaTech사 제조, 100 mg, 1.148 mmol) 및 Fmoc-Ser(tBuMe2Si)-OH(와타나베카가쿠고교사 제조, 532 mg, 1.205 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE20-2(410 mg, 수율 70%)를 얻었다.
ESI-MS m/z: 511(M+H)+
1H-NMR(400 MHz, CDCl3): δ 0.06(6H, s), 0.90(9H, s), 2.76-2.85(1H, m), 3.65-3.86(5H, m), 4.02-4.23(3H, m), 4.32-4.40(4H, m), 5.55(1H, d, J=8.0 Hz), 7.31(2H, t, J=7.6 Hz), 7.40(2H, t, J=7.6 Hz), 7.59(2H, d, J=7.6 Hz), 7.76(2H, d, J=7.6 Hz).
참고예 20의 공정 2
화합물 RE20-2(410 mg, 0.803 mmol)를 이용하여, 참고예 2의 공정 1과 같은 방법으로 화합물 RE20-3의 조생성물(680 mg)을 얻었다.
ESI-MS m/z: 814(M+H)+
참고예 20의 공정 3
화합물 RE20-3의 조생성물(680 mg)을 이용하여, 참고예 2의 공정 5와 같은 방법으로 화합물 RE20-4(330 mg, 2단계 수율 70%)를 얻었다.
ESI-MS m/z: 519(M+H)+
1H-NMR(400 MHz, CDCl3): δ 0.02-0.09(6H, m), 0.89(9H, d, J=28.8 Hz), 2.84-2.94(1H, m), 3.24-3.30(2H, m), 3.46(1H, t, J=7.2 Hz), 3.52-3.68(2H, m), 3.75-3.80(1H, m), 3.82(6H, d, J=2.4 Hz), 3.89-3.96(1H, m), 4.05-4.17(1H, m), 4.27-4.37(1H, m), 6.82-6.89(4H, m), 7.22-7.27(1H, m), 7.29-7.34(6H, m), 7.41-7.45(2H, m)
참고예 21
Figure pct00153
참고예 21의 공정 1
N-(Tert-부톡시카르보닐)-1,3-디아미노프로판(도쿄가세이고교사 제조, 1.788 g, 10.26 mmol)을 디클로로메탄(22.8 mL)에 용해하고, 트리에틸아민(1.907 mL, 13.68 mmol)을 가하여, 실온에서 15분 교반했다. 반응액에, 오가닉 레터(Organic Letter), 제16권, 6318-6321 페이지, 2014년에 기재된 방법으로 합성한 화합물 RE21-1(1.126 g, 6.84 mmol)의 디클로로메탄 용액(5 mL)을 적하하여, 실온에서 2시간 교반했다. 반응액에 물을 가하여, 클로로포름으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산마그네슘으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=35/65)로 정제함으로써, 화합물 RE21-2(1.65 g, 수율 80%)를 얻었다.
ESI-MS m/z: 303(M+H)+
참고예 21의 공정 2
화합물 RE21-2(1.65 g, 5.46 mmol)를 이용하여, 참고예 1의 공정 2와 같은 방법으로 화합물 RE21-3(1.10 g, 수율 100%)을 얻었다.
ESI-MS m/z: 203(M+H)+
1H-NMR(400 MHz, CDCl3): δ 1.74(2H, dt, J=12.0, 6.0 Hz), 2.95(2H, t, J=6.0 Hz), 3.18(1H, s), 3.60(2H, td, J=6.0, 5.2 Hz), 7.54(2H, dt, J=8.4, 1.8 Hz), 7.76(2H, dt, J=8.4, 1.8 Hz), 7.97(1H, br s).
참고예 22
Figure pct00154
참고예 22의 공정 1
화합물 RE22-1(도쿄가세이사 제조, 1.2 g, 4.24 mmol)을 이용하여, 참고예 2의 공정 1과 같은 방법으로 화합물 RE22-2의 조생성물을 얻었다.
ESI-MS m/z: 608(M+Na)+
참고예 22의 공정 2
화합물 RE22-2의 조생성물을 이용하여, 참고예 2의 공정 5와 같은 방법으로 화합물 R22-3(1.34 g, 2단계 수율 52%)을 얻었다.
ESI-MS m/z: 386(M+Na)+
1H-NMR(400 MHz, CDCl3) :δ 3.34(2H, t, J=6.4 Hz), 3.47(2H, t, J=6.4 Hz), 3.79(6H, s), 6.78-6.84(4H, m), 7.17-7.21(1H, m), 7.27-7.35(6H, m), 7.42-7.46(2H, m).
참고예 22의 공정 3
화합물 RE22-3(1.15 g, 3.16 mmol) 및 Fmoc-Ser(tBuMe2Si)-OH(와타나베카가쿠고교사 제조, 1.677 g, 3.8 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 RE22-4(560 mg, 수율 31%)를 얻었다.
1H-NMR(400 MHz, CDCl3) δ: 0.00-0.07(6H, m), 0.83-0.89(9H, m), 3.18-3.26(2H, m), 3.39-3.46(2H, m), 3.61-3.68(1H, m), 3.76(6H, s), 3.89(1H, dd, J=10.0, 4.0 Hz), 4.03(1H, dd, J=10.0, 4.0 Hz), 4.15-4.20(1H, m), 4.22-4.28(1H, m), 4.32-4.40(2H, m), 5.65-5.88(1H, m), 6.76-6.85(4H, m), 7.16-7.23(1H, m), 7.25-7.34(8H, m), 7.36-7.44(4H, m), 7.50-7.64(2H, m), 7.72-7.79(2H, m).
참고예 23
표 Y-1에 기재된 화합물 RE23-1∼RE23-5 및 Fmoc-Ser(tBuMe2Si)-OH를 이용하여, 참고예 22와 같은 방법에 의해, 표 Y-2에 기재된 화합물 RE23-6∼RE23-10을 얻었다.
참고예 22의 화합물 RE22-3과 Fmoc-Thr(tBuMe2Si)-OH를 이용하여, 참고예 22와 같은 방법에 의해 표 Y-2에 기재한 화합물 RE23-11을 얻었다.
표 Y-1에 기재된 화합물 RE23-1과 Fmoc-Thr(tBuMe2Si)-OH를 이용하여, 참고예 22와 같은 방법에 의해 표 Y-2에 기재한 화합물 RE23-12를 얻었다.
본 실시예에 의해 합성한 화합물의 NMR 분석 데이터를 표 Y-3에 나타낸다.
Figure pct00155
Figure pct00156
Figure pct00157
참고예 24
Figure pct00158
참고예 22에 기재한 방법으로 합성한 화합물 RE24-1(참고예 22에 있어서의 화합물 RE22-4, 2.487 g, 3.16 mmol)을 이용하여, 참고예 2의 공정 2와 같은 방법으로 화합물 RE24-2를 얻었다(1.2 g, 수율 67%).
ESI-MS m/z: 587(M+Na)+
1H-NMR(400 MHz, CDCl3): δ-0.01-0.07(6H, m), 0.86-0.90(9H, m), 3.15-3.21(2H, m), 3.41-3.48(3H, m), 3.72(1H, dd, J=10.0, 6.4 Hz), 3.79(6H, s), 3.84(1H, dd, J=10.0, 4.8 Hz), 6.79-6.84(4H, m), 7.18-7.23(1H, m), 7.27-7.33(6H, m), 7.40-7.44(2H, m), 7.72-7.75(1H, br m).
참고예 25
표 Y-2에 기재한 화합물 RE23-6∼RE23-12를 이용하여, 참고예 24와 같은 방법에 의해 표 Z-1에 기재한 화합물 RE25-1∼RE25-7을 얻었다.
본 실시예에 의해 합성한 화합물의 질량 분석 결과를 표 Z-2에 나타낸다.
Figure pct00159
Figure pct00160
참고예 26
Figure pct00161
참고예 26의 공정 1
화합물 RE26-1(2.00 g, 9.47 mmol)을 N,N'-디메틸포름아미드(40 mL)에 용해하고, 실온에서 이미노이아세트산디-tert-부틸에스테르(5.11 g, 20.84 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(4.00 g, 20.84 mmol), 1-히드록시벤조트리아졸일수화물(145 mg, 0.947 mmol)을 가하여 2시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액과 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제했다. 또한, 메탄올로 슬러리 정제함으로써, 화합물 RE26-2(4.07 g, 수율 65%)를 얻었다.
ESI-MS m/z: 664(M-H)-
참고예 26의 공정 2
화합물 RE26-2(2.66 g, 4.00 mmol)를 테트라히드로푸란(53 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 490 mg)을 가하여, 수소 분위기 하에서 3시간 교반했다. 반응액을 여과하여, 감압 하에 용매를 유거함으로써, 화합물 RE26-3(2.86 g, 수율 113%)을 얻었다.
ESI-MS m/z: 634(M-H)-
참고예 26의 공정 3
화합물 RE26-3(871.0 mg, 1.370 mmol)을 N,N'-디메틸포름아미드(17 mL)에 용해하고, O-(7-아자벤조트리아졸-1-인)-N,N,N',N'-테트라메틸유로늄헥사플루오로인산염(625.0 mg, 1.644 mmol), 디이소프로필에틸아민(0.5730 mL, 3.290 mmol) 및 도데칸이산모노벤질에스테르(527.0 mg, 1.644 mmol)를 가하여, 실온에서 밤새 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액 및 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=60/40)로 정제함으로써, 화합물 RE26-4(1.030 g, 수율 80%)를 얻었다.
ESI-MS m/z: 939(M+H)+
참고예 26의 공정 4
화합물 RE26-4(1.030 g, 1.098 mmol)를 디클로로메탄(10 mL)에 용해하고, 트리플루오로아세트산(10.00 mL, 130.0 mmol)을 가하여, 실온에서 1시간 교반했다. 감압 하에 용매를 유거하여, 화합물 RE26-5의 조생성물을 얻었다.
ESI-MS m/z: 713(M-H)-
참고예 27
Figure pct00162
참고예 27의 공정 1
화합물 RE27-1(2.000 g, 12.98 mmol)을 N,N'-디메틸포름아미드(30 mL)에 용해하고, 탄산수소칼륨(1.559 g, 15.57 mmol) 및 염화벤질(2.328 mL, 19.47 mmol)을 가하여, 실온에서 4시간 교반했다. 반응액에 포화염화암모늄 수용액을 가하여, 디클로로메탄으로 추출한 후, 유기층을 물로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제함으로써, 화합물 RE27-2(2.850 g, 수율 90%)를 얻었다.
ESI-MS m/z: 243(M-H)-
참고예 27의 공정 2
화합물 RE27-2(2.500 g, 10.24 mmol)를 N,N'-디메틸포름아미드(30 mL)에 용해하고, 탄산칼륨(5.660 g, 40.90 mmol) 및 tert-부틸브로모아세트산(3.300 mL, 22.52 mmol)을 가하여, 90℃에서 4시간 교반했다. 반응액에 포화염화암모늄 수용액을 가하여, 디클로로메탄으로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=75/25)로 정제함으로써, 화합물 RE27-3(4.300 g, 수율 89%)을 얻었다.
ESI-MS m/z: 472(M-H)-
참고예 27의 공정 3
화합물 RE27-3(1.000 g, 2.116 mmol)을 디클로로메탄(10 mL)에 용해하고, 트리플루오로아세트산(10.00 mL, 130.0 mmol)을 가하여, 실온에서 6시간 교반했다. 감압 하에 용매를 유거하여, 화합물 RE27-4의 조생성물을 얻었다.
ESI-MS m/z: 359(M-H)-
참고예 27의 공정 4
화합물 RE27-4(350.0 mg, 0.9710 mmol)를 N,N'-디메틸포름아미드(7 mL)에 용해하고, 1-히드록시벤조트리아졸일수화물(327.0 mg, 2.137 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(410.0 mg, 2.137 mmol) 및 이미노디아세트산디-tert-부틸에스테르(524.0 mg, 2.137 mmol)를 가하여, 실온에서 5시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액 및 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=60/40)로 정제함으로써, 화합물 RE27-5(617.0 mg, 수율 78%)를 얻었다.
ESI-MS m/z: 814(M-H)-
참고예 27의 공정 5
화합물 RE27-5(610.0 mg, 0.7490 mmol)를 디클로로메탄(6 mL)에 용해하고, 트리플루오로아세트산(6 mL, 78.00 mmol)을 가하여, 실온에서 1시간 교반했다. 감압 하에 용매를 유거하여, 화합물 RE27-6의 조생성물을 얻었다.
ESI-MS m/z: 590(M+H)+
참고예 28
Figure pct00163
참고예 28의 공정 1
참고예 26에 기재한 방법으로 합성한 화합물 RE28-1(참고예 26에 있어서의 화합물 RE26-3, 474 mg, 0.744 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 저널 오브 메디시날 케미스트리(Journal of Medicinal Chemistry), 제54권, 2433-2446 페이지, 2011년에 기재된 방법으로 합성한 trans-시클로헥산-1,4-디카르복실산모노벤질에스테르(0.234 mg, 0.893 mmol), 디이소프로필에틸아민(0.312 mL, 1.79 mmol), O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄헥사플루오로포스파이트(339 mg, 0.893 mmol)를 가하여 6시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액과 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제함으로써, 화합물 RE28-2(448 mg, 수율 68%)를 얻었다.
ESI-MS m/z: 879(M-H)-
참고예 28의 공정 2
화합물 RE28-2(341 mg, 0.387 mmol)를 디클로로메탄(3.4 mL)에 용해하고, 실온에서 트리플루오로아세트산(3.4 mL)을 가하여 밤새 교반했다. 반응액을 감압 농축하고, 아세트산에틸로 공비하여, 헵탄으로 슬러리 정제함으로써, 화합물 RE28-3(254 mg, 수율 100%)을 얻었다.
ESI-MS m/z: 656(M+H)+
참고예 29
Figure pct00164
참고예 29의 공정 1
화합물 RE29-1(500 mg, 2.75 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 이미노디아세트산디-tert-부틸에스테르(1.48 g, 6.04 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(1.16 g, 6.04 mmol), 1-히드록시벤조트리아졸일수화물(42.0 mg, 0.275 mmol)을 가하여 4시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제함으로써, 화합물 RE29-2(329 mg, 수율 19%)를 얻었다.
ESI-MS m/z: 635(M-H)-
참고예 29의 공정 2
화합물 RE29-2(323 mg, 0.507 mmol)를 N,N'-디메틸포름아미드(6.5 mL)에 용해하고, 실온에서 탄산칼륨(84.0 mg, 0.609 mmol), 브로모아세트산벤질(139 mg, 0.609 mmol)을 가하여 3시간 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제함으로써, 화합물 RE29-3(313 mg, 수율 79%)을 얻었다.
ESI-MS m/z: 783(M-H)-
참고예 29의 공정 3
화합물 RE29-3(312 mg, 0.398 mmol)을 디클로로메탄(3.1 mL)에 용해하고, 실온에서 트리플루오로아세트산(3.1 mL)을 가하여 밤새 교반했다. 반응액을 감압 농축하여, 아세트산에틸로 공비함으로써, 화합물 RE29-4(252 mg, 정량적)를 얻었다.
ESI-MS m/z: 561(M+H)+
참고예 30
Figure pct00165
참고예 30의 공정 1
화합물 RE30-1(2.00 g, 9.47 mmol)을 N,N'-디메틸포름아미드(40 mL)에 용해하고, 실온에서 2-아미노-1,3-프로판디올(1.90 g, 20.84 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(4.00 g, 20.84 mmol), 1-히드록시벤조트리아졸일수화물(145 mg, 0.947 mmol)을 가하여 2시간 교반했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(아세트산에틸/메탄올=70/30)로 정제했다. 또한, 아세트산에틸로 슬러리 정제함으로써, 화합물 RE30-2(2.68 g, 수율 79%)를 얻었다.
ESI-MS m/z: 356(M-H)-
참고예 30의 공정 2
화합물 RE30-2(500 mg, 1.40 mmol)를 아세토니트릴(10 mL)에 현탁하고, 실온에서 아크릴산tert-부틸에스테르(3.59 g, 28.0 mmol), 벤질트리메틸암모늄히드록시드(40% 수용액; 1.76 mL, 702 mmol)를 가하여 밤새 교반했다. 감압 하에 용매를 유거하고, 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=50/50)로 정제함으로써, 화합물 RE30-3(300 mg, 수율 24%)을 얻었다.
ESI-MS m/z: 871(M+H)+
참고예 30의 공정 3
화합물 RE30-3(340 mg, 0391 mmol)을 테트라히드로푸란(6.8 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 31.3 mg)을 가하여, 수소 분위기 하에서 6시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=30/70)로 정제함으로써, 화합물 RE30-4(235 mg, 수율 72%)를 얻었다.
ESI-MS m/z: 841(M+H)+
참고예 30의 공정 4
화합물 RE30-4(232 mg, 0.276 mmol)를 N,N'-디메틸포름아미드(4.6 mL)에 용해하고, 실온에서 도데칸산모노벤질에스테르(0.133 mg, 0.414 mmol), 디이소프로필에틸아민(0.145 mL, 0.829 mmol), O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄헥사플루오로포스파이트(158 mg, 0.414 mmol)를 가하여 밤새 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액과 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(헵탄/아세트산에틸=30/70)로 정제함으로써, 화합물 RE30-5(274 mg, 수율 87%)를 얻었다.
ESI-MS m/z: 1141(M-H)-
참고예 30의 공정 5
화합물 RE30-5(273 mg, 0.239 mmol)를 디클로로메탄(2.7 mL)에 용해하고, 실온에서 트리플루오로아세트산(2.7 mL)을 가하여 밤새 교반했다. 반응액을 감압 농축하여, 아세트산에틸로 공비함으로써, 화합물 RE30-6(231 mg, 정량적)을 얻었다.
ESI-MS m/z: 919(M+H)+
참고예 31
Figure pct00166
참고예 31의 공정 1
4-니트로이소프탈산 RE31-1(500 mg, 2.37 mmol) 및 N-Boc-에틸렌디아민(808 mg, 5.21 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 트리에틸아민(0.90 mL, 7.11 mmol), 1-히드록시벤조트리아졸일수화물(703 mg, 5.21 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(1.36 g, 7.11 mmol)을 가하여 16시간 교반했다. 반응액을 후처리하여, 조체(粗體)를 실리카겔 컬럼 크로마토그래피로 정제함으로써, 화합물 RE31-2(650 mg, 수율 55%)를 얻었다.
참고예 31의 공정 2
화합물 RE31-2(500 mg, 1.01 mmol) 및 아연 가루(330 mg, 5.05 mmol)를 메탄올(3.5 mL) 및 테트라히드로푸란(3.5 mL)에 현탁하고, 0℃에서 염화암모늄(378 mg, 7.07 mmol)의 수용액을 적하하여, 실온에서 24시간 교반했다. 반응액을 후처리하여, 조체를 실리카겔 컬럼 크로마토그래피로 정제함으로써, 화합물 RE31-3(160 mg, 수율 34%)을 얻었다.
참고예 31의 공정 3
화합물 RE31-3(200 mg, 0.430 mmol) 및 N-벤질옥시카르보닐-글리신(벤질옥시카르보닐을 Cbz라고도 기재한다.)(90.0 mg, 0.430 mmol)을 N,N'-디메틸포름아미드(2.0 mL)에 용해하고, 실온에서 디이소프로필에틸아민(0.220 mL, 1.29 mmol), O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄헥사플루오로포스파이트(245 mg, 0.645 mmol)를 가하여 16시간 교반했다. 반응액을 후처리하여, 조체를 실리카겔 컬럼 크로마토그래피로 정제함으로써, 화합물 RE31-4(180 mg, 수율 64%)를 얻었다.
ESI-MS m/z: 657(M+H)+
참고예 32
Figure pct00167
참고예 32의 공정 1
3,5-디니트로안식향산 RE32-1(500 mg, 2.36 mmol) 및 N-Cbz-에틸렌디아민(588 mg, 2.83 mmol)을 N,N'-디메틸포름아미드(5.0 mL)에 용해하고, 실온에서 트리에틸아민(0.65 mL, 4.72 mmol), 1-히드록시벤조트리아졸일수화물(380 mg, 2.83 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(675 mg, 3.54 mmol)을 가하여 16시간 교반했다. 반응액을 후처리하여, 조체를 실리카겔 컬럼 크로마토그래피로 정제함으로써, 화합물 RE32-2(445 mg, 수율 48%)를 얻었다.
참고예 32의 공정 2
화합물 RE32-2(200 mg, 0.515 mmol)을 에탄올(5.0 mL)에 용해하고, 실온에서 염화주석(II)(584 mg, 3.09 mmol) 및 농염산(0.2 mL)을 가하여, 80℃에서 16시간 교반했다. 반응액을 후처리하여, 화합물 RE32-3(180 mg, 정량적)을 얻었다.
ESI-MS m/z: 329(M+H)+
참고예 33
Figure pct00168
참고예 33의 공정 1
참고예 3에 기재한 방법으로 합성한 화합물 RE33-1(참고예 3에 있어서의 화합물 RE3-2, 8.17 g, 23.12 mmol)을 이용하여, 참고예 3의 공정 4와 같은 방법으로 화합물 RE33-2(3.7 g, 수율 63%)를 얻었다.
ESI-MS m/z: 254(M+H)+
참고예 33의 공정 2
화합물 RE33-2(3.7 g, 14.63 mmol)를 이용하여, 참고예 3의 공정 5와 같은 방법으로 화합물 RE33-3(3.82 g, 수율 67%)을 얻었다.
ESI-MS m/z: 432(M+HCOO)-
참고예 33의 공정 3
화합물 RE33-3(3.82 g, 9.86 mmol)을 이용하여, 참고예 1의 공정 2와 같은 방법으로 화합물 RE33-4(3.08 g, 수율 87%)를 얻었다.
ESI-MS m/z: 360(M+H)+
참고예 34
Figure pct00169
참고예 34의 공정 1
화합물 RE34-1(2 g, 9.53 mmol)과 tert-부톡시카르보닐아미노)-1-펜탄올(도쿄가세이사 제조, 2 g, 10 mmol)을 이용하여, 참고예 3의 공정 1과 같은 방법으로 화합물 RE34-2(2.40 g, 수율 63%)를 얻었다.
ESI-MS m/z: 296(M+H)+, 탈Boc체로서 검출
참고예 34의 공정 2
화합물 RE34-2를 이용하여, 참고예 3의 공정 2∼4 및 참고예 4의 공정 1∼4와 같은 방법으로 화합물 RE34-3(1.579 g, 수율 21%)을 얻었다.
ESI-MS m/z: 910(M+H)+
참고예 35: 화합물 D2의 합성
Figure pct00170
참고예 35의 공정 1
참고예 11에 기재한 방법으로 합성한 화합물 RE35-1(참고예 11에 있어서의 화합물 RE11-2, 1.015 g, 1.748 mmol)을 N,N'-디메틸포름아미드(12 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 187 mg)을 가하여, 수소 분위기 하에서 6시간 교반했다. 반응액을 여과했다. 여과액에 참고예 26에서 합성한 화합물 RE26-5(250.0 mg, 0.350 mmol), 1-히드록시벤조트리아졸일수화물(26.80 mg, 0.1750 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(402.0 mg, 2.099 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액에 물을 가하여, 아세트산에틸로 추출한 후, 유기층을 포화탄산수소나트륨 수용액 및 포화식염수로 세정하여, 무수황산나트륨으로 건조했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=87/13)로 정제함으로써, 화합물 RE35-2(617.0 mg, 수율 88%)를 얻었다.
ESI-MS m/z: 1215(M+2H)2+
참고예 35의 공정 2
화합물 RE35-2(0.7380 g, 0.3040 mmol)를 테트라히드로푸란(7 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 135.90 mg)을 가하여, 수소 분위기 하에서 밤새 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=87/13)로 정제함으로써, 화합물 D2(581 mg, 수율 82%)를 얻었다.
ESI-MS m/z: 1170(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.12-2.36(106H, m), 2.91-3.19(8H, m), 3.23-3.55(14H, m), 3.60-3.76(4H, m), 3.78-3.94(8H, m), 3.95-4.10(16H, m), 4.47(4H, d, J=8.8 Hz), 4.92-5.01(4H, m), 5.17-5.24(4H, m), 6.98(1H, s), 7.64(2H, s), 7.81-7.95(4H, m), 8.28-8.38(2H, m), 8.44-8.56(2H, m), 10.13(1H, s)
참고예 36: 화합물 D3의 합성
Figure pct00171
참고예 36의 공정 1
참고예 12에 기재한 방법으로 합성한 화합물 RE36-1(참고예 12에 있어서의 화합물 RE12-2, 500 mg, 0.879 mmol)을 N,N'-디메틸포름아미드(6.5 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 94 mg)을 가하여, 수소 분위기 하에서 4시간 교반했다. 반응액을 여과했다. 여과액에 참고예 26에 있어서의 화합물 RE26-5(126.0 mg, 0.176 mmol), 1-히드록시벤조트리아졸일수화물(13.47 mg, 0.088 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(202.0 mg, 1.055 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 역상 컬럼 크로마토그래피(물/아세토니트릴)로 정제함으로써, 화합물 RE36-2(249.7 mg, 수율 60%)를 얻었다.
ESI-MS m/z: 1191(M+2H)2+
참고예 36의 공정 2
화합물 RE36-2(0.242 g, 0.102 mmol)를 테트라히드로푸란(3.6 mL) 및 물(1.2 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 45 mg)을 가하여, 수소 분위기 하에서 4시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D3(216 mg, 수율 93%)을 얻었다.
ESI-MS m/z: 1146(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.15-1.65(20H, m), 1.68-2.15(52H, m), 3.13-3.29(6H, m), 3.40-3.67(16H, m), 3.71-3.96(11H, m), 3.98-4.14(16H, m), 4.55(4H, t, J=8.8 Hz), 4.93-5.06(4H, m), 5.12-5.28(4H, m), 6.56(1H, s), 6.98(1H. s), 7.64(2H, s), 7.77-7.93(4H, m), 8.26-8.49(3H, m), 10.10(1H, s)
참고예 37: 화합물 D4의 합성
Figure pct00172
참고예 37의 공정 1
참고예 13에 기재한 방법으로 합성한 화합물 RE37-1(참고예 13에 있어서의 화합물 RE13-2, 430 mg, 0.674 mmol)을 N,N'-디메틸포름아미드(6 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 79 mg)을 가하여, 수소 분위기 하에서 4시간 교반했다. 반응액을 여과했다. 여과액에 참고예 26에 있어서의 화합물 RE26-5(105.0 mg, 0.148 mmol), 1-히드록시벤조트리아졸일수화물(11.31 mg, 0.074 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(170.0.0 mg, 0.887 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 역상 컬럼 크로마토그래피(물/아세토니트릴)로 정제함으로써, 화합물 RE37-2(218.1 mg, 수율 56%)를 얻었다.
ESI-MS m/z: 1329(M+2H)2+
참고예 37의 공정 2
화합물 RE37-2(0.210 g, 0.079 mmol)를 테트라히드로푸란(3.1 mL) 및 물(1.0 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 39 mg)을 가하여, 수소 분위기 하에서 4시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D4(192.7 mg, 수율 95%)를 얻었다.
ESI-MS m/z: 1284(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.17-1.65(42H, m), 1.69-2.13(61H, m), 2.95-3.17(16H, m), 3.65-3.77(3H, m), 3.79-3.94(6H, m), 3.96-4.10(16H, m), 4.48(4H, d, J=8.4 Hz), 4.96(4H, dd, J=2.4, 11.2 Hz), 5.21(4H, d, J=3.2 Hz), 7.01(1H, s), 7.64-7.92(11H, m), 8.26-8.48(4H, m), 10.14(1H, s)
참고예 38: 화합물 D5의 합성
Figure pct00173
참고예 38의 공정 1
참고예 12에 기재한 방법으로 합성한 화합물 RE38-1(참고예 12에 있어서의 화합물 RE12-2, 450 mg, 0.791 mmol)을 N,N'-디메틸포름아미드(6 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 85 mg)을 가하여, 수소 분위기 하에서 5시간 교반했다. 반응액을 여과했다. 여과액에 참고예 27에 있어서의 화합물 RE27-6(94 mg, 0.158 mmol), 1-히드록시벤조트리아졸일수화물(133.0 mg, 0.871 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(182.0 mg, 0.950 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 역상 컬럼 크로마토그래피(물/아세토니트릴)로 정제함으로써, 화합물 RE38-2(99 mg, 수율 28%)를 얻었다.
ESI-MS m/z: 1129(M+2H)2+
참고예 38의 공정 2
화합물 RE38-2(80 mg, 0.035 mmol)를 테트라히드로푸란(1.7 mL) 및 물(0.85 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 26 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D5(57.5 mg, 수율 75%)를 얻었다.
ESI-MS m/z: 1084(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.69-2.21(46H, m), 3.14-3.65(28H, m), 3.67-4.22(27H, m), 4.43-4.66(4H, m), 4.69-4.88(4H, m), 4.89-5.08(4H, m), 5.12-5.32(4H, m), 6.54-6.68(1H, br), 7.01(2H, s), 7.78-8.09(3H, m), 8.13-8.31(2H, m), 8.58-8.75(2H, m)
참고예 39: 화합물 D6의 합성
Figure pct00174
참고예 39의 공정 1
참고예 13에 기재한 방법으로 합성한 화합물 RE39-1(참고예 13에 있어서의 화합물 RE13-2, 418 mg, 0.655 mmol)을 N,N'-디메틸포름아미드 (6 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 77 mg)을 가하여, 수소 분위기 하에서 5시간 교반했다. 반응액을 여과했다. 여과액에 참고예 27에서 합성한 화합물 RE27-6(85 mg, 0.144 mmol), 1-히드록시벤조트리아졸일수화물(121.0 mg, 0.791 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(165.0 mg, 0.863 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 역상 컬럼 크로마토그래피(물/아세토니트릴)로 정제함으로써, 화합물 RE39-2(99 mg, 수율 28%)를 얻었다.
ESI-MS m/z: 1268(M+2H)2+
참고예 39의 공정 2
화합물 RE39-2(186 mg, 0.073 mmol)를 테트라히드로푸란(2.8 mL) 및 물(0.93 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 40 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D6(156.7 mg, 수율 87%)을 얻었다.
ESI-MS m/z: 1222(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.36-1.62(27H, m), 1.67-2.17(64H, m), 2.92-3.21(15H, m), 3.58-3.77(2H, m), 3.80-3.95(7H, m), 3.97-4.13(15H, m), 4.47(4H, d, J=8.8 Hz), 4.88-5.02(7H, m), 5.10-5.24(3H, m), 6.95-7.00(1H, m), 7.26-7.31(2H, m), 7.72-7.88(8H, m), 8.10-8.20(2H, m), 8.51-8.60(2H, m)
참고예 40
Figure pct00175
참고예 40의 공정 1
참고예 38에 기재한 방법으로 합성한 화합물 D5(171 mg, 0.079 mmol)를 N,N'-디메틸포름아미드(3.4 mL)에 용해하고, 글리신벤질 p-톨루엔술폰산염(32.0 mg, 0.095 mmol), 1-히드록시벤조트리아졸일수화물(12.09 mg, 0.079 mmol) 및 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(18.16 mg, 0.095 mmol)을 가하여, 실온에서 밤새 교반했다. 반응액을 감압 하에 용매를 유거하여, 잔사를 역상 컬럼 크로마토그래피(물/아세토니트릴)로 정제함으로써, 화합물 RE40-2(55.7 mg, 수율 31%)를 얻었다.
ESI-MS m/z: 1158(M+2H)2+
참고예 40의 공정 2
화합물 RE40-2(54 mg, 0.023 mmol)를 테트라히드로푸란(0.83 mL) 및 물(0.28 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 18 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 RE40-3(50.1 mg, 수율 97%)을 얻었다.
ESI-MS m/z: 1112(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 0.96-1.06(3H, m), 1.71-2.20(54H, m), 3.41-3.64(15H, m), 3.68-4.20(32H), 4.55(4H, d, J=8.4 Hz), 4.81(4H, s), 4.94-5.02(4H, m), 5.17-5.25(4H, m), 6.63-6.76(2H, m), 6.93-7.02(2H, m), 7.84-8.00(3H, m), 8.17-8.30(2H, m), 8.58-8.70(2H, m)
참고예 41: 화합물 D7의 합성
Figure pct00176
참고예 41의 공정 1
화합물 RE41-1(500 mg, 0.861 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 92.1 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 아르곤 분위기 하에, 실온에서 참고예 27에서 합성한 화합물 RE27-3(113 mg, 0.172 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(198 mg, 1.03 mmol), 1-히드록시벤조트리아졸일수화물(13.2 mg, 0.086 mmol)을 가하여 밤새 교반했다. 반응액을 셀라이트로 여과하고, 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제하고, 또한 역상 분취 HPLC(아세토니트릴/물)로 정제함으로써, 화합물 RE41-2(195 mg, 수율 48%)를 얻었다.
ESI-MS m/z: 1186(M+2H)2+
참고예 41의 공정 2
화합물 RE41-2(194 mg, 0.082 mmol)를 테트라히드로푸란(2.9 mg) 및 물(1.0 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 35.7 mg)을 가하여, 수소 분위기 하에서 8시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D7(183 mg, 수율 98%)을 얻었다.
ESI-MS m/z: 1141(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.21-1.45(m, 40H), 1.76-2.18(m, 50H), 3.00-3.09(m, 8H), 3.40-4.20(m, 32H), 4.47(d, J=8.5 Hz, 4H), 4.96(dd, J=3.1, 11.2 Hz, 4H), 5.21(d, J=3.1 Hz, 4H), 6.98(s, 1H), 7.65(s,2H), 7.84(d, J=9.0 Hz, 4H), 8.31(brs, 1H), 8.44(brs, 1H), 10.11(s, 1H).
참고예 42: 화합물 D8의 합성
Figure pct00177
참고예 42의 공정 1
참고예 11에 기재한 방법으로 합성한 화합물 RE42-1(참고예 11에 있어서의 화합물 RE11-2, 500 mg, 0.861 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 92.1 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 아르곤 분위기 하에, 실온에서 참고예 29에서 합성한 화합물 RE29-4(97.0 mg, 0.172 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(198 mg, 1.03 mmol), 1-히드록시벤조트리아졸일수화물(13.2 mg, 0.086 mmol)을 가하여 밤새 교반했다. 반응액을 셀라이트로 여과하고, 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=85/15)로 정제하고, 또한 역상 분취 HPLC(아세토니트릴/물)로 정제함으로써, 화합물 RE42-2(179 mg, 수율 46%)를 얻었다.
ESI-MS m/z: 1138(M+2H)2+
참고예 42의 공정 2
화합물 RE42-2(175 mg, 0.077 mmol)를 테트라히드로푸란(2.6 mg) 및 물(0.9 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 32.4 mg)을 가하여, 수소 분위기 하에서 1시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D8(160 mg, 수율 95%)을 얻었다.
ESI-MS m/z: 1093(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.23-1.45(m, 32H), 1.77(s, 12H), 1.89(s, 12H), 1.99(s, 12H), 2.10(s, 12H), 3.01-3.11(m, 8H), 3.69-4.02(m, 34H), 4.47-4.50(m, 4H), 4.94-4.98(m, 4H), 5.21(d, J=3.1 Hz, 4H), 6.92(s, 1H), 6.94(s,2H), 7.87(d, J=9.4 Hz, 2H), 7.92(d, J=8.5 Hz, 2H), 8.33(brs, 2H), 8.50(brs, 2H).
참고예 43: 화합물 D9의 합성
Figure pct00178
참고예 43의 공정 1
참고예 13에 기재한 방법으로 합성한 화합물 RE43-1(참고예 13에 있어서의 화합물 RE13-2, 500 mg, 0.784 mmol)을 N,N'-디메틸포름아미드(10 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 92.1 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 아르곤 분위기 하에, 실온에서 참고예 30에서 합성한 화합물 RE30-6(144 mg, 0.157 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(180 mg, 0.941 mmol), 1-히드록시벤조트리아졸일수화물(12.0 mg, 0.078 mmol)을 가하여 밤새 교반했다. 반응액을 셀라이트로 여과하고, 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=80/20)로 정제하고, 또한 역상 분취 HPLC(아세토니트릴/물)로 정제함으로써, 화합물 RE43-2(191 mg, 수율 43%)를 얻었다.
ESI-MS m/z: 1431(M+2H)2+
참고예 43의 공정 2
화합물 RE43-2(186 mg, 0.065 mmol)를 테트라히드로푸란(2.8 mg) 및 물(0.9 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 34.3 mg)을 가하여, 수소 분위기 하에서 1시간 교반했다. 반응액을 여과하고, 감압 하에 용매를 유거하여, 화합물 D9(174 mg, 수율 97%)를 얻었다.
ESI-MS m/z: 1386(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.25-4.02(m, 164H), 4.18-4.26(m,2H), 4.47(d, J=8.1 Hz, 4H), 4.96(dd, J=3.1, 11.2 Hz, 4H), 5.21(d, J=3.6 Hz, 4H), 7.74-7.91(m, 13H), 8.18(s, 2H), 8.36(d, J=7.2 Hz, 2H), 10.27(brs, 1H).
참고예 44: 화합물 A2의 합성
Figure pct00179
참고예 44의 공정 1
참고예 31에 기재한 방법으로 합성한 화합물 RE44-1(참고예 31에 있어서의 화합물 RE31-4, 150 mg, 0.228 mmol)을 디클로로메탄(1.5 mL)에 용해하고, 실온에서 트리플루오로아세트산(1.5 mL)을 가하여 4시간 교반했다. 반응액을 감압 농축하여, 아세트산에틸로 공비했다. 잔사를 N,N'-디메틸포름아미드(3 mL)에 용해하고, 실온에서 참고예 14의 화합물 RE14-3(574 mg, 0.571 mmol), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드염산염(109 mg, 0.571 mmol), 트리에틸아민(0.159 mL, 1.14 mmol), 1-히드록시벤조트리아졸일수화물(3.50 mg, 0.023 mmol)을 가하여 밤새 교반했다. 반응액을 감압 농축하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제하고, 또한 역상 분취 HPLC(아세토니트릴/물)로 정제함으로써, 화합물 RE44-2(242 mg, 수율 44%)를 얻었다.
ESI-MS m/z: 1216(M+2H)2+
참고예 44의 공정 2
화합물 RE44-2(242 mg, 0.100 mmol)를 테트라히드로푸란/물(4/1; 12 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 44.6 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 아르곤 분위기 하에, 실온에서 6-말레이미드헥산산(23.2 mg, 0.110 mmol), 4-(4,6-디메톡시-1,3,5-트리아진-2-일)-4-메틸모르폴리늄클로리드(55.2 mg, 0.199 mmol)를 가하여 밤새 교반했다. 반응액을 셀라이트로 여과하고, 감압 하에 용매를 유거하여, 잔사를 HP20 레진(아세톤/물)으로 정제함으로써, 화합물 A2(97.4 mg, 수율 39%)를 얻었다.
ESI-MS m/z: 1245(M+2H)2+
1H-NMR(400 MHz, DMSO-d6, δ): 1.14-2.16(100H, m), 2.96-2.98(4H, m), 3.24-3.41(18H, m), 3.69-3.73(4H, m), 3.83-3.91(6H, m), 4.14-4.16(2H, m), 4.47(4H, d, J=8.6 Hz), 4.96(4H, dd, J=3.6, 11.3 Hz), 5.21(4H, d, J=3.2 Hz), 7.01(2H, s), 7.73-7.75(2H, m), 7.83-7.94(7H, m), 8.05-8.08(2H, m), 8.14-8.20(3H, m), 8.55-8.56(2H, m), 10.24(1H, brs).
참고예 45: 화합물 A3의 합성
Figure pct00180
참고예 45의 공정 1
참고예 32에 기재한 방법으로 합성한 화합물 RE45-1(참고예 32에 있어서의 화합물 RE32-3, 75.0 mg, 0.228 mmol)을 N,N'-디메틸포름아미드(3.0 mL)에 용해하고, 실온에서 참고예 14의 화합물 RE14-3(574 mg, 0.571 mmol), 디이소프로필에틸아민(0.199 mL, 1.14 mmol), O-(7-아자벤조트리아졸-1-일)-N,N,N',N'-테트라메틸유로늄헥사플루오로포스파이트(217 mg, 0.571 mmol)를 가하여 밤새 교반했다. 감압 하에 용매를 유거하여, 잔사를 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=90/10)로 정제하고, 또한 역상 분취 HPLC(아세토니트릴/물)로 정제함으로써, 화합물 RE45-2(202 mg, 수율 38%)를 얻었다.
ESI-MS m/z: 1152(M+2H)2+
참고예 45의 공정 2
화합물 RE45-2(196 mg, 0.085 mmol)를 테트라히드로푸란/물(4/1; 10 mL)에 용해하고, 실온에서 10% 팔라듐카본 분말(함수 제품, 54.29%; 36.1 mg)을 가하여, 수소 분위기 하에서 2시간 교반했다. 아르곤 분위기 하에, 실온에서 6-말레이미드헥산산(19.8 mg, 0.094 mmol), 4-(4,6-디메톡시-1,3,5-트리아진-2-일)-4-메틸모르폴리늄클로리드(47.0 mg, 0.170 mmol)를 가하여 밤새 교반했다. 반응액을 셀라이트로 여과하고, 감압 하에 용매를 유거하여, 잔사를 HP20 레진(아세톤/물)으로 정제함으로써, 화합물 A3(42.4 mg, 수율 21%)을 얻었다.
ESI-MS m/z: 1182(M+2H)2+
참고예 46: 화합물 D10
Figure pct00181
참고예 34에 기재한 방법으로 합성한 화합물 RE46-1(참고예 34에 있어서의 화합물 RE34-3)을 이용하여, 참고예 10의 공정 1 및 2와 같은 방법으로 화합물 D10(2.2 g, 수율 58%)을 얻었다.
ESI-MS m/z: 2437(M+H)+
참고예 47: 화합물 A4의 합성
Figure pct00182
참고예 47의 공정 1
참고예 33에 기재한 방법으로 합성한 화합물 RE47-1(참고예 33에 있어서의 화합물 RE33-4, 0.101 g, 0.282 mmol)을 이용하고, 참고예 15의 화합물 RE15-2(0.607 g, 0.613 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법에 의해서 화합물 RE47-2(0.25 g, 수율 39%)를 얻었다.
ESI-MS m/z: 2304(M+H)+
참고예 47의 공정 2
화합물 RE47-2(0.255 g, 0.111 mmol)를 이용하여, 참고예 3의 공정 2와 같은 방법에 의해서 화합물 RE47-3(0.15 g, 수율 63%)을 얻었다.
ESI-MS m/z: 2170(M+H)+
참고예 47의 공정 3
화합물 RE47-3(20.8 mg, 9.59 ㎛ol)을 이용하여, 참고예 5의 공정 2와 같은 방법에 의해서 화합물 A4(5.5 mg, 수율 24%)를 얻었다.
ESI-MS m/z: 1182(M+2H)2+
참고예 48: 화합물 A5의 합성
Figure pct00183
참고예 48의 공정 1
참고예 33에 기재한 방법으로 합성한 화합물 RE48-1(참고예 33에 있어서의 화합물 RE33-4, 0.099 g, 0.277 mmol)을 이용하고, 참고예 16의 공정 2에서 합성한 화합물 RE16-3(0.618 g, 0.615 mmol)을 이용하여, 참고예 3의 공정 3과 같은 방법에 의해서 화합물 RE48-2(0.343 g, 수율 53%)를 얻었다.
ESI-MS m/z: 2333(M+H)+
참고예 48의 공정 2
화합물 RE48-2를 이용하여, 참고예 10의 공정 1 및 2와 같은 방법으로 화합물 A5(6.9 mg, 수율 28%)를 얻었다.
ESI-MS m/z: 2392(M+H)+
참고예 49: 화합물 A6의 합성
Figure pct00184
화합물 RE49-1(0.048 g, 0.021 mmol)과 3-말레이미드프로피온산 N-숙신이미딜(도쿄가세이사 제조, 0.017 g, 0.064 mmol)을 이용하여, 참고예 8의 화합물 A1의 합성과 같은 방법으로 화합물 A6(0.040 g, 수율 78%)을 얻었다.
ESI-MS m/z: 2480(M+HCOO)-
참고예 50: 화합물 A7의 합성
Figure pct00185
공정 131
참고예 10에 기재한 방법으로 합성한 화합물 D1(23.6 mg, 9.46 ㎛ol)과 N-(2-아미노에틸)말레이미드 트리플루오로아세트산염(시그마알드리치사 제조, 7.21 mg, 0.028 ㎛ol)을 이용하여, 참고예 3의 공정 3과 같은 방법으로 화합물 A7(9.1 mg, 수율 36%)을 얻었다.
ESI-MS m/z: 1310(M+2H)2+
참고예 51
Figure pct00186
참고예 51의 공정 1
참고예 7에 기재한 방법으로 합성한 화합물 RE51-1(0.122 g, 0.054 mmol)과 바이오콘쥬게이트 케미스트리(Bioconjugate Chemistry), 제22권, 690-699 페이지, 2011년에 기재된 방법과 같은 방법을 이용하여 합성한 헥산산모노벤질에스테르를 이용하여, 참고예 4의 공정 1과 같은 방법으로 화합물 RE51-2(0.076 g, 수율 56%)를 얻었다.
ESI-MS m/z: 2503(M+H)+
참고예 51의 공정 2
화합물 RE51-2(0.076 g, 0.03 mmol)를 이용하여, 참고예 3의 공정 1과 같은 방법으로 화합물 RE51-3(0.030 g, 수율 40%)을 얻었다.
ESI-MS m/z: 2412(M+H)+
참고예 52
Figure pct00187
참고예 6에 기재한 방법으로 합성한 화합물 RE52-1(참고예 6에 있어서의 화합물 RE6-5, 4.36 mg, 0.006 mmol)과 참고예 1의 화합물 RE1-4(10 mg, 0.02 mmol) 를 이용하여, 참고예 3의 공정 7과 같은 방법으로 화합물 RE52-2(7 mg, 수율 65%)를 얻었다.
ESI-MS m/z: 1581(M-H)-
참고예 53: 화합물 C2의 합성
Figure pct00188
참고예 53의 공정 1
참고예 46에 기재한 방법으로 합성한 화합물 D10(0.2011 g, 0.079 mmol)을 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE53-1(0.129 g, 수율 55%)을 얻었다.
ESI-MS m/z: 2972(M+HCOO)-
참고예 53의 공정 2
화합물 RE53-1(0.129 g, 0.044 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE53-2의 조생생물을 얻었다.
ESI-MS m/z: 1535(M+HCOOH-2H)2-
참고예 53의 공정 3
화합물 RE53-2(0.0467 g, 0.013 mmol)를 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C2(19.4 ㎛ol/g, 수율 35%)를 얻었다.
참고예 54: 화합물 C3의 합성
Figure pct00189
참고예 54의 공정 1
참고예 10에 기재한 방법으로 합성한 화합물 D1(100 mg, 0.040 mmol) 및 참고예 17의 화합물 RE17-2를 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE54-1(90 mg, 수율 76%)을 얻었다.
ESI-MS m/z: 1335(M-DMTr+2H)2+
참고예 54의 공정 2
화합물 RE54-1(90 mg, 0.030 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE54-2의 조생성물을 얻었다.
ESI-MS m/z: 1558(M+HCOOH-2H)2-
참고예 54의 공정 3
화합물 RE54-2의 조생성물을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C3(21.5 ㎛ol/g, 2단계 수율 32%)을 얻었다.
참고예 55: 화합물 C4의 합성
Figure pct00190
참고예 55의 공정 1
참고예 46에 기재한 방법으로 합성한 화합물 D10(100 mg, 0.039 mmol) 및 참고예 17에서 합성한 화합물 RE17-2를 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE55-1(90 mg, 수율 76%)을 얻었다.
ESI-MS m/z: 1356(M+2H)2+ 탈DMTr체로서 검출
참고예 55의 공정 2
화합물 RE55-1(90 mg, 0.030 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE55-2의 조생성물을 얻었다.
ESI-MS m/z: 1579(M+HCOOH-2H)2-
참고예 55의 공정 3
화합물 RE55-2의 조생성물을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C4(17.0 ㎛ol/g, 2단계 수율 26%)를 얻었다.
참고예 56: 화합물 C5의 합성
Figure pct00191
참고예 56의 공정 1
참고예 46에 기재한 방법으로 합성한 화합물 D10(100 mg, 0.039 mmol) 및 참고예 18의 공정 2에서 합성한 화합물 RE18-3을 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE56-1(50 mg, 수율 42%)을 얻었다.
ESI-MS m/z: 1363(M+2H)2+ 탈DMTr체로서 검출
참고예 56의 공정 2
화합물 RE56-1(50 mg, 0.017 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE56-2의 조생성물을 얻었다.
ESI-MS m/z: 1587(M+HCOOH-2H)2-
참고예 56의 공정 3
화합물 RE56-2의 조생성물을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C5(0.5 ㎛ol/g, 2단계 수율 1%)를 얻었다.
참고예 57: 화합물 C6의 합성
Figure pct00192
참고예 57의 공정 1
참고예 46에 기재한 방법으로 합성한 화합물 D10(100 mg, 0.039 mmol) 및 참고예 19의 화합물 RE19-2를 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE57-1(40 mg, 수율 30%)을 얻었다.
ESI-MS m/z: 1532(M+2H)2+ 탈DMTr체로서 검출
참고예 57의 공정 2
화합물 RE57-1(40 mg, 0.012 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE57-2의 조생성물을 얻었다.
ESI-MS m/z: 1582(M+2H)2+ 탈DMTr체로서 검출
참고예 57의 공정 3
화합물 RE57-2의 조생성물을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C6(0.2 ㎛ol/g, 2단계 수율 1%)을 얻었다.
참고예 58: 화합물 C7의 합성
Figure pct00193
참고예 58의 공정 1
참고예 10에 기재한 방법으로 합성한 화합물 D1(70 mg, 0.028 mmol) 및 참고예 21의 화합물 RE21-3을 이용하여, 참고예 10의 공정 3과 같은 방법으로 화합물 RE58-1(58 mg, 수율 77%)을 얻었다.
ESI-MS m/z: 1341(M+2H)2+
참고예 58의 공정 2
화합물 RE58-1(58 mg, 0.022 mmol)을 메탄올(0.15 mL)에 용해하고, 저널 오브 오가닉 케미스트리(Journal of Organic Chemistry), 제74권, 6837-6842 페이지, 2009년에 기재된 방법으로 합성한 참고예 17의 화합물 RE17-1(16.9 mg, 0.032 mmol), 1 mol/L 소듐 L-아스코르베이트 수용액(0.022 mL, 0.022 mmol), 20 mmol/L 황산구리(II) 수용액(0.011 mL, 0.22 ㎛ol) 및 10 mmol/L 트리스(2-벤즈이미다졸릴메틸)아민/DMSO 용액(0.022 mL, 0.22 ㎛ol)을 가하여, 실온에서 3시간 교반했다. 반응액을 실리카겔 컬럼 크로마토그래피(클로로포름/메탄올=80/20)로 정제하여, 화합물 RE58-2(7 mg, 수율 10%)를 얻었다.
ESI-MS m/z: 1450(M+2H)2+ 탈DMTr체로서 검출
참고예 58의 공정 3
화합물 RE58-2(10 mg, 3.13 ㎛ol)를 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE58-3의 조생성물을 얻었다.
ESI-MS m/z: 1500(M+2H)2+ 탈DMTr체로서 검출
참고예 58의 공정 4
화합물 RE58-3의 조생성물을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C7(8.4 ㎛ol/g, 수율 27%)을 얻었다.
참고예 59
Figure pct00194
참고예 59의 공정 1
참고예 46에 기재한 방법으로 합성한 화합물 D10(74.1 mg, 0.029 mmol)과 참고예 22의 화합물 RE22-2(15 mg, 0.027 mmol)를 이용하여, 참고예 3의 공정 3과 같은 방법, 또는 바이오콘쥬게이트 케미스트리, 제26권, 1451-1455 페이지, 2015년에 기재된 방법으로 화합물 RE59-1의 조생성물을 얻었다.
ESI-MS m/z: 1392(M+H)+, 탈DMTr체로서 검출
참고예 59의 공정 2
화합물 RE59-1(0.083 g, 0.027 mmol)을 이용하여, 국제공개공보 2015105083호에 기재된 방법에 의해 화합물 RE59-2의 조생성물을 얻었다.
ESI-MS m/z: 2669(M+H)+, 탈DMTr체로서 검출
참고예 59의 공정 3
화합물 RE59-2(0.08 g, 0.027 mmol)을 이용하여, 참고예 10의 공정 4와 같은 방법으로 화합물 RE59-3의 조생성물을 얻었다.
ESI-MS m/z: 1556(M+HOOH-2H)2-
1H-NMR(400 MHz, MeOD): δ 1.45-1.86(48H, m), 1.93(12H, s), 1.94(12H, s), 2.02(12H, s), 2.13(12H, s), 2.16-2.28(17H, m), 2.48(4H, s), 3.10-3.16(6H, m), 3.36-3.56(19H, m), 3.77(6H, s), 3.80-3.89(6H, m), 3.98-4.35(30H, m), 4.53-4.59(4H, m), 4.66-4.72(1H, m), 5.04-5.10(4H, m), 5.31-5.36(4H, m), 6.81-6.88(4H, m), 7.17-7.23(1H, m), 7.26-7.32(6H, m), 7.38-7.44(2H, m), 7.54(2H, br s), 7.90(1H, br s).
참고예 60
화합물 D1 및 표 Z-1에 기재한 구조 또는 참고예 20의 화합물 RE20-4를 이용하여, 참고예 59의 공정 1 및 공정 2와 같은 방법으로 표 P-1 및 표 P-2에 기재한 화합물을 얻었다.
본 실시예에 의해 합성한 화합물의 질량 분석 결과를 표 P-3에 나타낸다.
Figure pct00195
Figure pct00196
Figure pct00197
Figure pct00198
참고예 61: 화합물 C8의 합성
Figure pct00199
참고예 59에 기재한 화합물 RE59-3을 이용하여, 참고예 10의 공정 5와 같은 방법으로 화합물 C8(10.0 ㎛ol/g)을 얻었다.
참고예 62: C9∼C17의 합성
표 P-1 및 표 P-2에 기재한 화합물을 이용하여, 참고예 61과 같은 방법으로 표 Q-1 및 표 Q-2에 기재한 화합물을 얻었다.
본 실시예에 의해 합성한 화합물의 담지량을 표 Q-3에 나타낸다.
Figure pct00200
Figure pct00201
Figure pct00202
Figure pct00203
실시예 1: 화합물 1-1 및 1-2의 합성
Figure pct00204
공정 1
참고예 화합물 A1과, 몰레큘즈(Molecules), 제17권, 13825-13843 페이지, 2012년에 기재된 방법으로 합성한 말단 티올화된 올리고뉴클레오티드를 가하여, 실온에서 4시간 정치했다. 반응 혼합물에 탄산나트륨을 가하여, 4℃에서 하룻밤 정치했다. 음이온 교환 크로마토그래피(GE Healthcare, MonoQ 5/50GL, 10 ㎛, 5.0 mmx50 mm, A액: 10 mmol/L Tris 완충액/30% 아세토니트릴, B액: 10 mmol/L Tris 완충액/30% 아세토니트릴/1 mol/L NaBr에 의한 그래디언트) 혹은 역상 액체 크로마토그래피(워터즈, X BridgeC18, 5 ㎛, 4.6 mmx250 mm, 0.1 mol/L 아세트산트리에틸암모늄 완충액, B액: 아세토니트릴에 의한 그래디언트)의 어느 하나의 방법으로 정제함으로써 화합물 1-1을 얻었다. 센스 사슬 서열은 표 R-1∼표 R-2에 기재되어 있는 것과 같다.
공정 2
공정 1에서 합성한 화합물 1-1(3'-APCS-ssRNA)을, 혼합 완충액(100 mmol/L 아세트산칼륨, 30 mmol/L 2-[4-(2-히드록시에틸)피페라진-1-일]에탄술폰산, HEPES)-KOH(pH 7.4), 2 mmol/L 아세트산마그네슘)으로 농도 조정(50 ㎛ol/L)했다. 상술한 센스 사슬과 안티센스 사슬(50 ㎛ol/L)을 각각 등량 혼합하여, 80℃에서 10분간 정치했다. 안티센스 사슬 서열은 표 R-3∼표 R-4에 기재되어 있는 것과 같다. 서서히 온도를 내리고, 37℃에서 1시간 정치하여, 이중 사슬의 화합물 1-2를 얻었다.
실시예 2∼10: 화합물 2-1∼10-1 및 화합물 2-2∼10-2의 합성
실시예 1과는 염기 서열이 다른 올리고뉴클레오티드를 이용하여, 실시예 1과 같은 식으로 하여, 화합물 2-1∼10-1 및 화합물 2-2∼10-2를 합성했다.
실시예 11: 화합물 11-1 및 화합물 11-2의 합성
Figure pct00205
공정 1
참고예 화합물 D5를 이용하여, 몰레큘즈(Molecules), 제17권, 13825-13843 페이지, 2012년에 기재된 방법으로 합성한 말단이 아미노기로 수식된 올리고뉴클레오티드를 가하여, 바이오콘쥬게이트 케미스트리, 제22권, 1723-1728 페이지, 2011년 혹은 바이오콘쥬게이트 케미스트리, 제26권, 1451-1455 페이지, 2015년에 기재된 방법으로 반응시켰다. 실시예 1에 기재한 방법으로 정제함으로써 화합물 11-1을 얻었다.
공정 2
실시예 1의 공정 2와 같은 방법으로 화합물 11-2를 얻었다.
실시예 12∼43: 화합물 12-1∼43-1 및 화합물 12-2∼43-2의 합성
실시예 11과는 염기 서열이 다른 올리고뉴클레오티드를 이용하여, 실시예 11과 같은 식으로 화합물 12-1∼43-1 및 화합물 12-2∼43-2를 합성했다.
본 실시예에 의해 합성한 화합물의 리간드 링커 구조를 이하에 나타낸다.
Figure pct00206
본 실시예에 의해 합성한 핵산 복합체의 서열(센스 사슬) 및 질량 분석 결과를 표 R-1∼표 R-2에 나타낸다. 또한, 표 R-1∼표 R-2 중, N(M)은 2'-O-메틸 수식 RNA, N(F)는 2'-불소 수식 RNA, p는 5' 말단에 있어서의 인산화, ^는 포스포로티오에이트, X는 참고예 화합물 A1의 잔기 및 Y는 참고예 화합물 D5의 잔기를 나타낸다. 서열 번호 2069∼∼2111에 나타내는 리보뉴클레오티드를 포함하는 센스 사슬과, 서열 번호 2112∼2154에 나타내는 리보뉴클레오티드를 포함하는 안티센스 사슬의 이중 사슬 핵산으로 구성된다(서열 번호 n(n=2069∼∼2111)에 나타내는 센스 사슬과 서열 번호 [n+43]에 나타내는 안티센스 사슬이 쌍을 이룬다).
Figure pct00207
Figure pct00208
본 실시예에 의해 합성한 핵산 복합체의 서열을 표 R-3∼표 R-4에 나타낸다. 또한, 표 R-3∼표 R-4 중, N(M)은 2'-O-메틸 수식 RNA, N(F)는 2'-불소 수식 RNA, p는 5' 말단에 있어서의 인산화 및 ^은 포스포로티오에이트를 나타낸다.
Figure pct00209
Figure pct00210
참고 시험예 1: siRNA의 인간 세포에 있어서의 APCS mRNA의 녹다운 활성의 측정
이중 사슬 핵산은 표 1-1∼표 1∼13에 기재한 것을 시그마알드리치사에서 합성하여 이용했다. 구체적으로는 서열 번호 2∼644에 나타내는 리보뉴클레오티드를 포함하는 센스 사슬, 서열 번호 645∼1287에 나타내는 리보뉴클레오티드를 포함하는 안티센스 사슬을 어닐링시킨 이중 사슬 핵산으로 구성된다(서열 번호 n(n=2∼644)에 나타내는 센스 사슬과 서열 번호 [n+643]에 나타내는 안티센스 사슬이 쌍을 이룬다). 384 웰의 배양 플레이트에, 이중 사슬 핵산과 RNAiMax 트랜스펙션 시약(Thermo Fisher Scientific사 제조, 카탈로그 번호 13778150)을 Opti-MEM I Reduced Serum Medium 배지(Thermo Fisher Scientific사 제조, 카탈로그 번호31985070)로 희석한 siRNA/RNAiMax 혼합액 20 μL를 첨가했다. 인간 난소암 유래의 세포주인 RMG-I 세포(JCRB 세포뱅크, JCRB0172)를, 10,000 세포/40 μL/웰이 되도록 각각 384 웰의 배양 플레이트에 파종하고, 37℃, 5% CO2 조건 하에서 24시간 배양했다. 배지는, 10% 소 태아 혈청(Thermo Fisher Scientific사 제조, 카탈로그 번호 10091-148)을 포함하는 Ham's F-12 Nutrient Mix 배지(Thermo Fisher Scientific사 제조, 카탈로그 번호 11765-047)를 이용했다. 이중 사슬 핵산의 종농도는 1 nM이 되게 했다. 그 후, 세포를 DPBS, 칼슘 무함유, 마그네슘 무함유(Thermo Fisher Scientific사 제조, 카탈로그 번호 14190-144)으로 세정하고, 각각의 플레이트로부터 TaqMan(등록상표) Fast Cells-to-CT(상표) 키트(Thermo Fisher Scientific사 제조, 카탈로그 번호 4399003)를 이용하여 이하의 방법으로 cDNA를 합성했다. 용해(Lysis)액(키트 내용물)과 DNase I(키트 내용물)을 100:1로 혼합한 용액을 10 μL씩 첨가하여, 5분간 혼합했다. 정지액(키트 내용물)을 1 μL씩 첨가, 2분간 혼합하여, RNA 추출액으로 했다. 5 μL의 2×RT 버퍼(키트 내용물), 0.5 μL의 20×RT Enzyme Mix(키트 내용물), 2.5 μL의 뉴클레아제-프리 워터, 2 μL의 RNA 추출액을 혼합하고, 이것을 37℃, 60분간, 95℃, 5분간으로 반응시켜, cDNA를 합성했다. 이 cDNA 2 μL를 MicroAmp(등록상표) EnduraPlate(상표) 바코드가 부착된 광학 384-웰 클리어 반응 플레이트(Thermo Fisher Scientific사 제조, 카탈로그 번호 4483285)에 가하고, 또한 5 μL의 TaqMan(등록상표) Fast Universal PCR Master Mix(Thermo Fisher Scientific사 제조, 카탈로그 번호 4352042), 2.5 μL의 증류수(초고순도)(Thermo Fisher Scientific사 제조, 카탈로그 번호 10977015), 0.25 μL의 인간 APCS 프로브, 0.25 μL의 인간 ACTB 프로브를 첨가했다. QuantStudio(상표) 7 Flex를 이용하여, 인간 APCS 유전자 및 인간 ACTB(액틴 베타) 유전자의 리얼타임 PCR을 행했다. ACTB는 구성적 발현 유전자이며 내부 대조로서 측정하여, APCS 유전자 발현량을 보정했다. siRNA를 첨가하지 않고서 트랜스펙션 시약만으로 RMG-I 세포를 처리했을 때의 APCS mRNA량을 1.0으로 하여, 각 siRNA를 도입했을 때의 APCS mRNA 상대 발현량의 값을 산출했다. 본 실험을 2회 행하여, APCS mRNA 상대 발현량 값의 최소치를 표 1-1∼표 1-13에 나타냈다.
Figure pct00211
Figure pct00212
Figure pct00213
Figure pct00214
Figure pct00215
Figure pct00216
Figure pct00217
Figure pct00218
Figure pct00219
Figure pct00220
Figure pct00221
Figure pct00222
Figure pct00223
또한, APCS 제2 가닥 cDNA의 전장의 염기 서열을 표 2에 나타낸다.
Figure pct00224
참고 시험예 2: 수식 siRNA의 인간 세포에 있어서의 APCS mRNA의 녹다운 활성의 측정 1
진디자인사에 의뢰하여, 서열 번호 1931∼1974에 나타내는 리보뉴클레오티드를 포함하는 센스 사슬 핵산, 서열 번호 1975∼2018에 나타내는 리보뉴클레오티드를 포함하는 안티센스 사슬 핵산 및 이들을 어닐링시킨 이중 사슬 핵산(서열 번호 n(n=1931∼1974)에 나타내는 센스 사슬과 서열 번호 [n+44]에 나타내는 안티센스 사슬이 쌍을 이룬다)을 합성했다.
합성한 이중 사슬 핵산의 종농도는 1 nM 또는 0.1 nM이 되게 하고, 상기 이중 사슬 핵산을 RMG-1 세포에 도입하여, 24시간 배양한 것 이외에는, 참고 시험예 1과 같은 조작을 행하여, APCS mRNA 상대 발현량을 산출했다. 본 실험을 4회 행하여, APCS mRNA 상대 발현량 값의 중앙치를 표 M1-1∼표 M1-2에 나타냈다. 표 M1-1∼표 M1-2에 있어서, N(M)은 2'-O-메틸-RNA를, N(F)는 2'-F-RNA를 나타낸다.
Figure pct00225
Figure pct00226
참고 시험예 3 수식 siRNA의 인간 세포에 있어서의 APCS mRNA의 녹다운 활성의 측정 2
이중 사슬 핵산은, 표 M1-3에 기재한 것을 진디자인사에서 합성하여 이용했다. 구체적으로는 서열 번호 2019∼2043에 나타내는 리보뉴클레오티드를 포함하는 센스 사슬, 서열 번호 2044∼2068에 나타내는 리보뉴클레오티드를 포함하는 안티센스 사슬을 어닐링시킨 이중 사슬 핵산으로 구성된다(서열 번호 n(n=2019∼2043)에 나타내는 센스 사슬과 서열 번호 [n+25]에 나타내는 안티센스 사슬이 쌍을 이룬다). 96 웰의 배양 플레이트에, 각 이중 사슬 핵산과 RNAiMax 트랜스펙션 시약(Thermo Fisher Scientific사 제조, 카탈로그 번호 13778150)을 Opti-MEM I Reduced Serum Medium 배지(Thermo Fisher Scientific사 제조, 카탈로그 번호 31985070)로 희석한 siRNA/RNAiMax 혼합액 20 μL를 첨가했다. 인간 난소암 유래의 세포주인 RMG-I 세포(JCRB 세포뱅크, JCRB0172)를, 10,000 세포/60 μL/웰이 되도록 각각 96 웰의 배양 플레이트에 파종하고, 37℃, 5% CO2 조건 하에서 24시간 배양했다. 배지는, 10% 소 태아 혈청(Thermo Fisher Scientific사 제조, 카탈로그 번호 10091-148)을 포함하는 Ham's F-12 Nutrient Mix 배지(Thermo Fisher Scientific사 제조, 카탈로그 번호 11765-047)를 이용했다. 이중 사슬 핵산의 종농도는 1 또는 0.1 nM이 되게 했다. 그 후, 세포를 DPBS, 칼슘 무함유, 마그네슘 무함유(Thermo Fisher Scientific사 제조, 카탈로그 번호 14190-144)으로 세정하고, 각각의 플레이트로부터 슈퍼프렙 셀 라이시스 앤드 알티 키트 포 큐피씨알(도요보세키사 제조, 카탈로그 번호 SCQ-101)을 이용하여, 제품에 첨부된 설명서에 기재된 방법에 따라서 전체 RNA를 회수하고, 얻어진 전체 RNA를 주형으로 하는 역전사 반응에 의한 cDNA를 제작했다. 이 cDNA 3 μL를 MicroAmpOptical 384 웰 플레이트(어플라이드바이오시스템즈사 제조, 카탈로그 번호 : 4309849)에 가하고, 또한 10 μL의 TaqMan Gene Expression Master Mix(어플라이드바이오시스템즈사 제조, 카탈로그 번호 4369016), 6 μL의 초고순도 증류수(서모피셔사이엔티픽사 제조, 카탈로그 번호 : 10977-015), 1 μL의 인간 APCS 프로브 혹은 1 μL의 인간 GAPDH(D-글리세르알데히드-3-포스페이트데히드로게나아제) 프로브를 첨가하고, 콴트스튜디오 12케이 플렉스 리얼타임 피씨알 시스템(서모피셔사이엔티픽사 제조)을 이용하여, 인간 APCS 유전자 및 인간 GAPDH 유전자의 리얼타임 PCR을 행했다. GAPDH는 구성적 발현 유전자이며 내부 대조로서 측정하여, APCS 유전자 발현량을 보정했다. siRNA를 첨가하지 않고서 트랜스펙션 시약만으로 RMG-I 세포를 처리했을 때의 APCS mRNA량을 1.0으로 하여, 각 siRNA를 도입했을 때의 APCS mRNA 상대 발현량의 값을 산출했다. 본 실험을 2회 행하여, APCS mRNA 상대 발현량 값의 평균치를 표 M1-3에 나타냈다. 또한, 표 M1-3 중, N(M)은 2'-O-메틸 수식 RNA, N(F)는 2'-불소 수식 RNA를 나타낸다.
Figure pct00227
시험예 1 핵산 복합체의 인간 초대 간세포에 대한 APCS mRNA의 녹다운 시험
실시예 1∼43에서 얻어진 각 핵산 복합체에 관해서, 인간 초대 간세포에 있어서의 인비트로 녹다운 활성을 측정했다. 이 핵산 복합체의 종농도가 300, 30, 3 또는 0.3 nmol/L가 되도록 옵티멤(Opti-MEM)(서모피셔사이엔티픽사 제조, 카탈로그 번호 31985)으로 희석한 각 핵산 복합체를, 96 웰의 콜라겐 I 코트 배양 플레이트 (코닝사 제조, 카탈로그 번호 : 356407)에 20 μL씩 분주한 후, 플레이팅 미디엄(바이오프레딕인터내셔날사 제조, 카탈로그 번호 LV0304-2)에 현탁시킨 인간 초대 간세포(바이오프레딕인터내셔날사 제조, 카탈로그 번호 HEP187)를, 10,000 세포/80 μL/웰이 되도록 파종하고, 37℃, 5% CO2 조건 하에서 6시간 배양한 후에, 배양 상청을 주의 깊게 제거하고, 인큐베이션 미디엄(바이오프레딕인터내셔날사 제조, 카탈로그 번호 LV0304-2)을 첨가하여, 각 핵산 복합체를 인간 초대 간세포에 제공했다. 또한, 음성 대조군으로서 20 μL의 옵티멤을 제공한 인간 초대 간세포를 이용한 각 핵산 복합체를 첨가한 세포를 37℃의 5% CO2 인큐베이터 내에서 18시간 배양하고, 빙냉한 인산 완충화 생리식염수(DPBS)(나카라이테스크사 제조, 카탈로그 번호 14249-95)로 세정하고, 각각의 플레이트로부터 슈퍼프렙 셀 라이시스 앤드 알티 키트 포 큐피씨알(도요보세키 제조, 카탈로그 번호 SCQ-101)을 이용하여, 제품에 첨부된 설명서에 기재된 방법에 따라서 전체 RNA를 회수하고, 얻어진 전체 RNA를 주형으로 하는 역전사 반응에 의한 cDNA를 제작했다. 이 cDNA 3 μL를 MicroAmpOptical 384 웰 플레이트(어플라이드바이오시스템즈사 제조, 카탈로그 번호 : 4309849)에 가하고, 또한 10 μL의 TaqMan Gene Expression Master Mix(어플라이드바이오시스템즈사 제조, 카탈로그 번호 4369016), 6 μL의 초고순도 증류수(서모피셔사이엔티픽사 제조, 카탈로그 번호 : 10977-015), 1 μL의 인간 APCS 프로브(어플라이드바이오시스템즈사 제조) 혹은 1 μL의 인간 GAPDH 프로브(어플라이드바이오시스템즈사 제조)를 첨가하고, 콴트스튜디오 12케이 플렉스 리얼타임 피씨알 시스템(서모피셔사이엔티픽사 제조)를 이용하여, 첨부된 사용설명서에 기재된 방법에 따라서 인간 APCS 유전자 및 인간 GAPDH 유전자의 리얼타임 PCR을 행했다. GAPDH는 구성적 발현 유전자이며 내부 대조로서 측정하여, APCS 발현량을 보정했다. 마찬가지로 측정한 음성 대조에 있어서의 APCS의 mRNA의 준정량치를 1.0으로 하여, 각 핵산 복합체를 도입했을 때의 APCS mRNA 상대 발현량을 산출했다. 본 실험을 2회 행하여, APCS mRNA 상대 발현량의 평균치를 표 S1에 나타냈다.
Figure pct00228
표 S1로부터 분명한 것과 같이, 각 핵산 복합체는 인간 초대 간세포에 첨가한 후, APCS 유전자의 mRNA의 발현을 억제했다.
시험예 2 핵산 복합체의 마우스에 있어서의 인비보 녹다운 시험
실시예 1∼43에서 얻어진 핵산 복합체에 관해서 이하의 방법에 의해 인비보 녹다운 시험을 실시했다. 또한, 각 핵산 복합체는 시험에 맞춰 인산 완충화 생리식염수(DPBS)(나카라이테스크사 제조)로 희석하여 이용했다. 마우스는 인간 간세포가 이식된 PXB 마우스(PXB/human Hepatocyte repopulated cDNA-uPA/SCID Tg, 페닉스바이오사로부터 입수)를 사용하여, 인간 APCS에 대한 핵산 복합체의 효과를 평가했다. PXB 마우스를 순화 사육한 후, 각 핵산 복합체를 마우스에게 피하 투여했다. 투여 용량은 10 mg/kg이고, 투여 용량은 5 mL/kg으로 했다. 컨트롤군으로서는 DPBS만을 마우스에게 피하 투여했다. 투여 6일 전 및 투여 후 1, 2, 3, 6, 10, 13일에 채혈을 하여, 1500×g으로 원심분리함으로써 혈청을 얻었다. 이들 혈청을 인간 SAP ELISA(SAP, 인간, ELISA 키트, HycultBiotech사 제조, #HK331-02)를 이용하여, 혈중 인간 APCS량을 평가했다. ELISA는 부속된 메뉴얼에 따라 실시했다. 각 마우스군의 혈중 인간 APCS 농도 추이를 도 1에 도시했다. DPBS 투여군에 대한 핵산 복합체 투여군에 있어서의 APCS 발현 비율(%)을 표 S2에 나타낸다.
Figure pct00229
표 S2로부터 분명한 것과 같이, 본 발명의 핵산 복합체를, 인간 APCS를 발현하는 마우스에게 투여하여, 마우스 말초혈 중의 APCS 단백질 발현을 저하시킨다는 것이 분명하게 되었다.
본 발명의 핵산 복합체는, 포유동물에게 투여하여, 생체 내에 있어서 아밀로이드 관련 질환을 치료하기 위해서 이용할 수 있다.
SEQUENCE LISTING <110> KYOWA KIRIN CO., LTD. <120> Nucleic acid complexes <130> K1635AKP0009 <150> JP 2018-225829 <151> 2018-11-30 <160> 2154 <170> PatentIn version 3.5 <210> 1 <211> 960 <212> DNA <213> Homo sapiens <400> 1 gggcatgaat atcagacgct agggggacag ccactgtgtt gtctgctacc ctcatcctgg 60 tcactgcttc tgctataaca gccctaggcc aggaatatga acaagccgct gctttggatc 120 tctgtcctca ccagcctcct ggaagccttt gctcacacag acctcagtgg gaaggtgttt 180 gtatttccta gagaatctgt tactgatcat gtaaacttga tcacaccgct ggagaagcct 240 ctacagaact ttaccttgtg ttttcgagcc tatagtgatc tctctcgtgc ctacagcctc 300 ttctcctaca atacccaagg cagggataat gagctactag tttataaaga aagagttgga 360 gagtatagtc tatacattgg aagacacaaa gttacatcca aagttatcga aaagttcccg 420 gctccagtgc acatctgtgt gagctgggag tcctcatcag gtattgctga attttggatc 480 aatgggacac ctttggtgaa aaagggtctg cgacagggtt actttgtaga agctcagccc 540 aagattgtcc tggggcagga acaggattcc tatgggggca agtttgatag gagccagtcc 600 tttgtgggag agattgggga tttgtacatg tgggactctg tgctgccccc agaaaatatc 660 ctgtctgcct atcagggtac ccctctccct gccaatatcc tggactggca ggctctgaac 720 tatgaaatca gaggatatgt catcatcaaa cccttggtgt gggtctgagg tcttgactca 780 acgagagcac ttgaaaatga aatgactgtc taagagatct ggtcaaagca actggatact 840 agatcttaca tctgcagctc tttcttcttt gaatttccta tctgtatgtc tgcctaatta 900 aaaaaatata tattgtatta tgctacctgc aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 960 <210> 2 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 2 gcaugaauau cagacgcuag g 21 <210> 3 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 3 caugaauauc agacgcuagg g 21 <210> 4 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 4 auaucagacg cuagggggac a 21 <210> 5 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 5 cuagggggac agccacugug u 21 <210> 6 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 6 agggggacag ccacuguguu g 21 <210> 7 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 7 ggggacagcc acuguguugu c 21 <210> 8 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 8 gggacagcca cuguguuguc u 21 <210> 9 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 9 ggacagccac uguguugucu g 21 <210> 10 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 10 gacagccacu guguugucug c 21 <210> 11 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 11 gccacugugu ugucugcuac c 21 <210> 12 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 12 ccacuguguu gucugcuacc c 21 <210> 13 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 13 cacuguguug ucugcuaccc u 21 <210> 14 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 14 cuguguuguc ugcuacccuc a 21 <210> 15 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 15 uguguugucu gcuacccuca u 21 <210> 16 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 16 guguugucug cuacccucau c 21 <210> 17 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 17 uguugucugc uacccucauc c 21 <210> 18 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 18 guugucugcu acccucaucc u 21 <210> 19 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 19 gucugcuacc cucauccugg u 21 <210> 20 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 20 cugcuacccu cauccugguc a 21 <210> 21 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 21 gcuacccuca uccuggucac u 21 <210> 22 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 22 cuacccucau ccuggucacu g 21 <210> 23 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 23 uacccucauc cuggucacug c 21 <210> 24 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 24 acccucaucc uggucacugc u 21 <210> 25 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 25 cccucauccu ggucacugcu u 21 <210> 26 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 26 ccucauccug gucacugcuu c 21 <210> 27 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 27 cucauccugg ucacugcuuc u 21 <210> 28 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 28 cauccugguc acugcuucug c 21 <210> 29 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 29 auccugguca cugcuucugc u 21 <210> 30 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 30 uccuggucac ugcuucugcu a 21 <210> 31 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 31 ccuggucacu gcuucugcua u 21 <210> 32 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 32 cuggucacug cuucugcuau a 21 <210> 33 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 33 uggucacugc uucugcuaua a 21 <210> 34 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 34 ggucacugcu ucugcuauaa c 21 <210> 35 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 35 gucacugcuu cugcuauaac a 21 <210> 36 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 36 cacugcuucu gcuauaacag c 21 <210> 37 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 37 acugcuucug cuauaacagc c 21 <210> 38 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 38 cugcuucugc uauaacagcc c 21 <210> 39 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 39 gcuucugcua uaacagcccu a 21 <210> 40 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 40 cuucugcuau aacagcccua g 21 <210> 41 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 41 uucugcuaua acagcccuag g 21 <210> 42 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 42 ucugcuauaa cagcccuagg c 21 <210> 43 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 43 cugcuauaac agcccuaggc c 21 <210> 44 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 44 ugcuauaaca gcccuaggcc a 21 <210> 45 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 45 gcuauaacag cccuaggcca g 21 <210> 46 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 46 cuauaacagc ccuaggccag g 21 <210> 47 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 47 uauaacagcc cuaggccagg a 21 <210> 48 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 48 auaacagccc uaggccagga a 21 <210> 49 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 49 uaacagcccu aggccaggaa u 21 <210> 50 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 50 acagcccuag gccaggaaua u 21 <210> 51 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 51 cagcccuagg ccaggaauau g 21 <210> 52 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 52 agcccuaggc caggaauaug a 21 <210> 53 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 53 gcccuaggcc aggaauauga a 21 <210> 54 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 54 cccuaggcca ggaauaugaa c 21 <210> 55 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 55 ccuaggccag gaauaugaac a 21 <210> 56 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 56 cuaggccagg aauaugaaca a 21 <210> 57 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 57 uaggccagga auaugaacaa g 21 <210> 58 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 58 aggccaggaa uaugaacaag c 21 <210> 59 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 59 ggccaggaau augaacaagc c 21 <210> 60 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 60 gccaggaaua ugaacaagcc g 21 <210> 61 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 61 ccaggaauau gaacaagccg c 21 <210> 62 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 62 caggaauaug aacaagccgc u 21 <210> 63 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 63 aggaauauga acaagccgcu g 21 <210> 64 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 64 ggaauaugaa caagccgcug c 21 <210> 65 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 65 gaauaugaac aagccgcugc u 21 <210> 66 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 66 aauaugaaca agccgcugcu u 21 <210> 67 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 67 auaugaacaa gccgcugcuu u 21 <210> 68 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 68 uaugaacaag ccgcugcuuu g 21 <210> 69 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 69 augaacaagc cgcugcuuug g 21 <210> 70 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 70 ugaacaagcc gcugcuuugg a 21 <210> 71 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 71 gaacaagccg cugcuuugga u 21 <210> 72 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 72 aacaagccgc ugcuuuggau c 21 <210> 73 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 73 acaagccgcu gcuuuggauc u 21 <210> 74 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 74 caagccgcug cuuuggaucu c 21 <210> 75 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 75 aagccgcugc uuuggaucuc u 21 <210> 76 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 76 agccgcugcu uuggaucucu g 21 <210> 77 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 77 gccgcugcuu uggaucucug u 21 <210> 78 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 78 ccgcugcuuu ggaucucugu c 21 <210> 79 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 79 cgcugcuuug gaucucuguc c 21 <210> 80 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 80 gcugcuuugg aucucugucc u 21 <210> 81 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 81 cugcuuugga ucucuguccu c 21 <210> 82 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 82 ugcuuuggau cucuguccuc a 21 <210> 83 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 83 gcuuuggauc ucuguccuca c 21 <210> 84 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 84 cuuuggaucu cuguccucac c 21 <210> 85 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 85 uuuggaucuc uguccucacc a 21 <210> 86 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 86 ggaucucugu ccucaccagc c 21 <210> 87 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 87 gaucucuguc cucaccagcc u 21 <210> 88 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 88 cucuguccuc accagccucc u 21 <210> 89 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 89 cuguccucac cagccuccug g 21 <210> 90 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 90 uguccucacc agccuccugg a 21 <210> 91 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 91 guccucacca gccuccugga a 21 <210> 92 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 92 uccucaccag ccuccuggaa g 21 <210> 93 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 93 cucaccagcc uccuggaagc c 21 <210> 94 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 94 ucaccagccu ccuggaagcc u 21 <210> 95 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 95 accagccucc uggaagccuu u 21 <210> 96 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 96 ccagccuccu ggaagccuuu g 21 <210> 97 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 97 cagccuccug gaagccuuug c 21 <210> 98 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 98 agccuccugg aagccuuugc u 21 <210> 99 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 99 gccuccugga agccuuugcu c 21 <210> 100 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 100 ccuccuggaa gccuuugcuc a 21 <210> 101 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 101 cuccuggaag ccuuugcuca c 21 <210> 102 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 102 uccuggaagc cuuugcucac a 21 <210> 103 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 103 ccuggaagcc uuugcucaca c 21 <210> 104 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 104 cuggaagccu uugcucacac a 21 <210> 105 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 105 ggaagccuuu gcucacacag a 21 <210> 106 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 106 gaagccuuug cucacacaga c 21 <210> 107 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 107 aagccuuugc ucacacagac c 21 <210> 108 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 108 agccuuugcu cacacagacc u 21 <210> 109 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 109 gccuuugcuc acacagaccu c 21 <210> 110 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 110 ccuuugcuca cacagaccuc a 21 <210> 111 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 111 cuuugcucac acagaccuca g 21 <210> 112 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 112 uuugcucaca cagaccucag u 21 <210> 113 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 113 ugcucacaca gaccucagug g 21 <210> 114 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 114 cucacacaga ccucaguggg a 21 <210> 115 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 115 cacacagacc ucagugggaa g 21 <210> 116 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 116 acacagaccu cagugggaag g 21 <210> 117 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 117 cacagaccuc agugggaagg u 21 <210> 118 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 118 agaccucagu gggaaggugu u 21 <210> 119 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 119 gaccucagug ggaagguguu u 21 <210> 120 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 120 accucagugg gaagguguuu g 21 <210> 121 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 121 ccucaguggg aagguguuug u 21 <210> 122 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 122 cucaguggga agguguuugu a 21 <210> 123 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 123 ucagugggaa gguguuugua u 21 <210> 124 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 124 cagugggaag guguuuguau u 21 <210> 125 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 125 agugggaagg uguuuguauu u 21 <210> 126 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 126 gugggaaggu guuuguauuu c 21 <210> 127 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 127 ugggaaggug uuuguauuuc c 21 <210> 128 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 128 gggaaggugu uuguauuucc u 21 <210> 129 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 129 ggaagguguu uguauuuccu a 21 <210> 130 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 130 gaagguguuu guauuuccua g 21 <210> 131 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 131 aagguguuug uauuuccuag a 21 <210> 132 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 132 agguguuugu auuuccuaga g 21 <210> 133 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 133 gguguuugua uuuccuagag a 21 <210> 134 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 134 guguuuguau uuccuagaga a 21 <210> 135 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 135 uguuuguauu uccuagagaa u 21 <210> 136 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 136 guuuguauuu ccuagagaau c 21 <210> 137 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 137 uuuguauuuc cuagagaauc u 21 <210> 138 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 138 uuguauuucc uagagaaucu g 21 <210> 139 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 139 uguauuuccu agagaaucug u 21 <210> 140 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 140 guauuuccua gagaaucugu u 21 <210> 141 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 141 uauuuccuag agaaucuguu a 21 <210> 142 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 142 auuuccuaga gaaucuguua c 21 <210> 143 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 143 uuuccuagag aaucuguuac u 21 <210> 144 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 144 uccuagagaa ucuguuacug a 21 <210> 145 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 145 ccuagagaau cuguuacuga u 21 <210> 146 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 146 cuagagaauc uguuacugau c 21 <210> 147 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 147 uagagaaucu guuacugauc a 21 <210> 148 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 148 agagaaucug uuacugauca u 21 <210> 149 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 149 gagaaucugu uacugaucau g 21 <210> 150 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 150 agaaucuguu acugaucaug u 21 <210> 151 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 151 gaaucuguua cugaucaugu a 21 <210> 152 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 152 aaucuguuac ugaucaugua a 21 <210> 153 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 153 aucuguuacu gaucauguaa a 21 <210> 154 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 154 ucuguuacug aucauguaaa c 21 <210> 155 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 155 cuguuacuga ucauguaaac u 21 <210> 156 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 156 uguuacugau cauguaaacu u 21 <210> 157 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 157 guuacugauc auguaaacuu g 21 <210> 158 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 158 acugaucaug uaaacuugau c 21 <210> 159 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 159 cugaucaugu aaacuugauc a 21 <210> 160 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 160 ugaucaugua aacuugauca c 21 <210> 161 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 161 gaucauguaa acuugaucac a 21 <210> 162 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 162 ucauguaaac uugaucacac c 21 <210> 163 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 163 cauguaaacu ugaucacacc g 21 <210> 164 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 164 uaaacuugau cacaccgcug g 21 <210> 165 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 165 aaacuugauc acaccgcugg a 21 <210> 166 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 166 acuugaucac accgcuggag a 21 <210> 167 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 167 uugaucacac cgcuggagaa g 21 <210> 168 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 168 ugaucacacc gcuggagaag c 21 <210> 169 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 169 gaucacaccg cuggagaagc c 21 <210> 170 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 170 cacaccgcug gagaagccuc u 21 <210> 171 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 171 acaccgcugg agaagccucu a 21 <210> 172 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 172 caccgcugga gaagccucua c 21 <210> 173 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 173 accgcuggag aagccucuac a 21 <210> 174 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 174 ccgcuggaga agccucuaca g 21 <210> 175 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 175 cgcuggagaa gccucuacag a 21 <210> 176 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 176 gcuggagaag ccucuacaga a 21 <210> 177 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 177 cuggagaagc cucuacagaa c 21 <210> 178 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 178 uggagaagcc ucuacagaac u 21 <210> 179 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 179 ggagaagccu cuacagaacu u 21 <210> 180 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 180 gagaagccuc uacagaacuu u 21 <210> 181 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 181 agaagccucu acagaacuuu a 21 <210> 182 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 182 gaagccucua cagaacuuua c 21 <210> 183 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 183 aagccucuac agaacuuuac c 21 <210> 184 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 184 agccucuaca gaacuuuacc u 21 <210> 185 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 185 gccucuacag aacuuuaccu u 21 <210> 186 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 186 ccucuacaga acuuuaccuu g 21 <210> 187 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 187 cucuacagaa cuuuaccuug u 21 <210> 188 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 188 ucuacagaac uuuaccuugu g 21 <210> 189 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 189 cuacagaacu uuaccuugug u 21 <210> 190 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 190 uacagaacuu uaccuugugu u 21 <210> 191 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 191 acagaacuuu accuuguguu u 21 <210> 192 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 192 cagaacuuua ccuuguguuu u 21 <210> 193 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 193 agaacuuuac cuuguguuuu c 21 <210> 194 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 194 gaacuuuacc uuguguuuuc g 21 <210> 195 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 195 aacuuuaccu uguguuuucg a 21 <210> 196 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 196 cuuuaccuug uguuuucgag c 21 <210> 197 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 197 accuuguguu uucgagccua u 21 <210> 198 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 198 ccuuguguuu ucgagccuau a 21 <210> 199 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 199 cuuguguuuu cgagccuaua g 21 <210> 200 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 200 uuguguuuuc gagccuauag u 21 <210> 201 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 201 guguuuucga gccuauagug a 21 <210> 202 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 202 guuuucgagc cuauagugau c 21 <210> 203 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 203 uuuucgagcc uauagugauc u 21 <210> 204 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 204 cgagccuaua gugaucucuc u 21 <210> 205 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 205 gagccuauag ugaucucucu c 21 <210> 206 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 206 agccuauagu gaucucucuc g 21 <210> 207 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 207 gccuauagug aucucucucg u 21 <210> 208 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 208 ccuauaguga ucucucucgu g 21 <210> 209 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 209 cuauagugau cucucucgug c 21 <210> 210 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 210 uauagugauc ucucucgugc c 21 <210> 211 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 211 agugaucucu cucgugccua c 21 <210> 212 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 212 gugaucucuc ucgugccuac a 21 <210> 213 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 213 ugaucucucu cgugccuaca g 21 <210> 214 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 214 gaucucucuc gugccuacag c 21 <210> 215 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 215 cucucgugcc uacagccucu u 21 <210> 216 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 216 ucucgugccu acagccucuu c 21 <210> 217 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 217 cucgugccua cagccucuuc u 21 <210> 218 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 218 cgugccuaca gccucuucuc c 21 <210> 219 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 219 gugccuacag ccucuucucc u 21 <210> 220 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 220 gccuacagcc ucuucuccua c 21 <210> 221 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 221 ccuacagccu cuucuccuac a 21 <210> 222 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 222 cuacagccuc uucuccuaca a 21 <210> 223 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 223 uacagccucu ucuccuacaa u 21 <210> 224 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 224 acagccucuu cuccuacaau a 21 <210> 225 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 225 cagccucuuc uccuacaaua c 21 <210> 226 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 226 agccucuucu ccuacaauac c 21 <210> 227 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 227 gccucuucuc cuacaauacc c 21 <210> 228 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 228 ccucuucucc uacaauaccc a 21 <210> 229 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 229 ucuucuccua caauacccaa g 21 <210> 230 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 230 ucuccuacaa uacccaaggc a 21 <210> 231 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 231 cuccuacaau acccaaggca g 21 <210> 232 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 232 uccuacaaua cccaaggcag g 21 <210> 233 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 233 ccuacaauac ccaaggcagg g 21 <210> 234 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 234 cuacaauacc caaggcaggg a 21 <210> 235 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 235 caauacccaa ggcagggaua a 21 <210> 236 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 236 auacccaagg cagggauaau g 21 <210> 237 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 237 uacccaaggc agggauaaug a 21 <210> 238 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 238 ccaaggcagg gauaaugagc u 21 <210> 239 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 239 aaggcaggga uaaugagcua c 21 <210> 240 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 240 aggcagggau aaugagcuac u 21 <210> 241 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 241 gcagggauaa ugagcuacua g 21 <210> 242 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 242 cagggauaau gagcuacuag u 21 <210> 243 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 243 agggauaaug agcuacuagu u 21 <210> 244 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 244 gggauaauga gcuacuaguu u 21 <210> 245 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 245 ggauaaugag cuacuaguuu a 21 <210> 246 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 246 gauaaugagc uacuaguuua u 21 <210> 247 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 247 auaaugagcu acuaguuuau a 21 <210> 248 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 248 uaaugagcua cuaguuuaua a 21 <210> 249 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 249 augagcuacu aguuuauaaa g 21 <210> 250 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 250 ugagcuacua guuuauaaag a 21 <210> 251 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 251 gagcuacuag uuuauaaaga a 21 <210> 252 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 252 agcuacuagu uuauaaagaa a 21 <210> 253 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 253 gcuacuaguu uauaaagaaa g 21 <210> 254 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 254 cuacuaguuu auaaagaaag a 21 <210> 255 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 255 aguuuauaaa gaaagaguug g 21 <210> 256 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 256 aagaaagagu uggagaguau a 21 <210> 257 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 257 agaaagaguu ggagaguaua g 21 <210> 258 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 258 gaaagaguug gagaguauag u 21 <210> 259 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 259 aagaguugga gaguauaguc u 21 <210> 260 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 260 agaguuggag aguauagucu a 21 <210> 261 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 261 gaguuggaga guauagucua u 21 <210> 262 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 262 aguuggagag uauagucuau a 21 <210> 263 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 263 guuggagagu auagucuaua c 21 <210> 264 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 264 uuggagagua uagucuauac a 21 <210> 265 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 265 uggagaguau agucuauaca u 21 <210> 266 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 266 ggagaguaua gucuauacau u 21 <210> 267 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 267 gagaguauag ucuauacauu g 21 <210> 268 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 268 agaguauagu cuauacauug g 21 <210> 269 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 269 gaguauaguc uauacauugg a 21 <210> 270 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 270 aguauagucu auacauugga a 21 <210> 271 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 271 guauagucua uacauuggaa g 21 <210> 272 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 272 gucuauacau uggaagacac a 21 <210> 273 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 273 cuauacauug gaagacacaa a 21 <210> 274 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 274 uauacauugg aagacacaaa g 21 <210> 275 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 275 auacauugga agacacaaag u 21 <210> 276 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 276 acauuggaag acacaaaguu a 21 <210> 277 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 277 cauuggaaga cacaaaguua c 21 <210> 278 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 278 auuggaagac acaaaguuac a 21 <210> 279 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 279 uggaagacac aaaguuacau c 21 <210> 280 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 280 ggaagacaca aaguuacauc c 21 <210> 281 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 281 gaagacacaa aguuacaucc a 21 <210> 282 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 282 aagacacaaa guuacaucca a 21 <210> 283 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 283 agacacaaag uuacauccaa a 21 <210> 284 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 284 gacacaaagu uacauccaaa g 21 <210> 285 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 285 acacaaaguu acauccaaag u 21 <210> 286 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 286 cacaaaguua cauccaaagu u 21 <210> 287 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 287 caaaguuaca uccaaaguua u 21 <210> 288 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 288 aaaguuacau ccaaaguuau c 21 <210> 289 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 289 aaguuacauc caaaguuauc g 21 <210> 290 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 290 aguuacaucc aaaguuaucg a 21 <210> 291 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 291 guuacaucca aaguuaucga a 21 <210> 292 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 292 uuacauccaa aguuaucgaa a 21 <210> 293 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 293 uacauccaaa guuaucgaaa a 21 <210> 294 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 294 acauccaaag uuaucgaaaa g 21 <210> 295 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 295 cauccaaagu uaucgaaaag u 21 <210> 296 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 296 auccaaaguu aucgaaaagu u 21 <210> 297 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 297 uccaaaguua ucgaaaaguu c 21 <210> 298 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 298 ccaaaguuau cgaaaaguuc c 21 <210> 299 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 299 caaaguuauc gaaaaguucc c 21 <210> 300 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 300 cgaaaaguuc ccggcuccag u 21 <210> 301 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 301 aaaaguuccc ggcuccagug c 21 <210> 302 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 302 cccggcucca gugcacaucu g 21 <210> 303 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 303 cggcuccagu gcacaucugu g 21 <210> 304 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 304 ggcuccagug cacaucugug u 21 <210> 305 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 305 gcuccagugc acaucugugu g 21 <210> 306 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 306 cuccagugca caucugugug a 21 <210> 307 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 307 ccagugcaca ucugugugag c 21 <210> 308 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 308 gugcacaucu gugugagcug g 21 <210> 309 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 309 gcacaucugu gugagcuggg a 21 <210> 310 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 310 acaucugugu gagcugggag u 21 <210> 311 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 311 aucuguguga gcugggaguc c 21 <210> 312 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 312 ugugugagcu gggaguccuc a 21 <210> 313 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 313 gugugagcug ggaguccuca u 21 <210> 314 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 314 agcugggagu ccucaucagg u 21 <210> 315 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 315 gcugggaguc cucaucaggu a 21 <210> 316 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 316 cugggagucc ucaucaggua u 21 <210> 317 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 317 ugggaguccu caucagguau u 21 <210> 318 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 318 gggaguccuc aucagguauu g 21 <210> 319 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 319 ggaguccuca ucagguauug c 21 <210> 320 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 320 gaguccucau cagguauugc u 21 <210> 321 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 321 guccucauca gguauugcug a 21 <210> 322 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 322 uccucaucag guauugcuga a 21 <210> 323 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 323 ccucaucagg uauugcugaa u 21 <210> 324 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 324 cucaucaggu auugcugaau u 21 <210> 325 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 325 ucaucaggua uugcugaauu u 21 <210> 326 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 326 caucagguau ugcugaauuu u 21 <210> 327 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 327 aucagguauu gcugaauuuu g 21 <210> 328 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 328 ucagguauug cugaauuuug g 21 <210> 329 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 329 cagguauugc ugaauuuugg a 21 <210> 330 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 330 agguauugcu gaauuuugga u 21 <210> 331 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 331 gguauugcug aauuuuggau c 21 <210> 332 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 332 guauugcuga auuuuggauc a 21 <210> 333 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 333 auugcugaau uuuggaucaa u 21 <210> 334 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 334 ugcugaauuu uggaucaaug g 21 <210> 335 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 335 gcugaauuuu ggaucaaugg g 21 <210> 336 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 336 cugaauuuug gaucaauggg a 21 <210> 337 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 337 gaauuuugga ucaaugggac a 21 <210> 338 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 338 ggaucaaugg gacaccuuug g 21 <210> 339 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 339 caaugggaca ccuuugguga a 21 <210> 340 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 340 aaugggacac cuuuggugaa a 21 <210> 341 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 341 augggacacc uuuggugaaa a 21 <210> 342 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 342 ugggacaccu uuggugaaaa a 21 <210> 343 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 343 gggacaccuu uggugaaaaa g 21 <210> 344 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 344 ggacaccuuu ggugaaaaag g 21 <210> 345 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 345 accuuuggug aaaaaggguc u 21 <210> 346 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 346 ccuuugguga aaaagggucu g 21 <210> 347 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 347 cuuuggugaa aaagggucug c 21 <210> 348 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 348 ggugaaaaag ggucugcgac a 21 <210> 349 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 349 gugaaaaagg gucugcgaca g 21 <210> 350 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 350 ugaaaaaggg ucugcgacag g 21 <210> 351 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 351 gaaaaagggu cugcgacagg g 21 <210> 352 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 352 aaagggucug cgacaggguu a 21 <210> 353 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 353 aagggucugc gacaggguua c 21 <210> 354 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 354 agggucugcg acaggguuac u 21 <210> 355 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 355 gggucugcga caggguuacu u 21 <210> 356 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 356 ggucugcgac aggguuacuu u 21 <210> 357 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 357 gucugcgaca ggguuacuuu g 21 <210> 358 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 358 ucugcgacag gguuacuuug u 21 <210> 359 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 359 cugcgacagg guuacuuugu a 21 <210> 360 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 360 ugcgacaggg uuacuuugua g 21 <210> 361 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 361 gcgacagggu uacuuuguag a 21 <210> 362 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 362 cgacaggguu acuuuguaga a 21 <210> 363 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 363 gacaggguua cuuuguagaa g 21 <210> 364 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 364 acaggguuac uuuguagaag c 21 <210> 365 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 365 caggguuacu uuguagaagc u 21 <210> 366 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 366 aggguuacuu uguagaagcu c 21 <210> 367 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 367 ggguuacuuu guagaagcuc a 21 <210> 368 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 368 gguuacuuug uagaagcuca g 21 <210> 369 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 369 guuacuuugu agaagcucag c 21 <210> 370 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 370 agaagcucag cccaagauug u 21 <210> 371 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 371 gaagcucagc ccaagauugu c 21 <210> 372 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 372 aagcucagcc caagauuguc c 21 <210> 373 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 373 agcucagccc aagauugucc u 21 <210> 374 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 374 cucagcccaa gauuguccug g 21 <210> 375 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 375 agcccaagau uguccugggg c 21 <210> 376 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 376 ccaagauugu ccuggggcag g 21 <210> 377 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 377 caagauuguc cuggggcagg a 21 <210> 378 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 378 agauuguccu ggggcaggaa c 21 <210> 379 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 379 gauuguccug gggcaggaac a 21 <210> 380 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 380 uuguccuggg gcaggaacag g 21 <210> 381 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 381 uccuggggca ggaacaggau u 21 <210> 382 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 382 cuggggcagg aacaggauuc c 21 <210> 383 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 383 uggggcagga acaggauucc u 21 <210> 384 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 384 ggggcaggaa caggauuccu a 21 <210> 385 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 385 ggcaggaaca ggauuccuau g 21 <210> 386 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 386 gcaggaacag gauuccuaug g 21 <210> 387 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 387 caggaacagg auuccuaugg g 21 <210> 388 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 388 ggaacaggau uccuaugggg g 21 <210> 389 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 389 gaacaggauu ccuauggggg c 21 <210> 390 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 390 acaggauucc uaugggggca a 21 <210> 391 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 391 caggauuccu augggggcaa g 21 <210> 392 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 392 ggauuccuau gggggcaagu u 21 <210> 393 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 393 gauuccuaug ggggcaaguu u 21 <210> 394 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 394 auuccuaugg gggcaaguuu g 21 <210> 395 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 395 uuccuauggg ggcaaguuug a 21 <210> 396 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 396 uccuaugggg gcaaguuuga u 21 <210> 397 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 397 ccuauggggg caaguuugau a 21 <210> 398 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 398 cuaugggggc aaguuugaua g 21 <210> 399 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 399 uaugggggca aguuugauag g 21 <210> 400 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 400 gggggcaagu uugauaggag c 21 <210> 401 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 401 ggggcaaguu ugauaggagc c 21 <210> 402 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 402 gggcaaguuu gauaggagcc a 21 <210> 403 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 403 ggcaaguuug auaggagcca g 21 <210> 404 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 404 gcaaguuuga uaggagccag u 21 <210> 405 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 405 caaguuugau aggagccagu c 21 <210> 406 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 406 aaguuugaua ggagccaguc c 21 <210> 407 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 407 uugauaggag ccaguccuuu g 21 <210> 408 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 408 ugauaggagc caguccuuug u 21 <210> 409 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 409 gauaggagcc aguccuuugu g 21 <210> 410 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 410 auaggagcca guccuuugug g 21 <210> 411 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 411 aggagccagu ccuuuguggg a 21 <210> 412 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 412 ggagccaguc cuuuguggga g 21 <210> 413 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 413 gagccagucc uuugugggag a 21 <210> 414 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 414 agccaguccu uugugggaga g 21 <210> 415 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 415 gccaguccuu ugugggagag a 21 <210> 416 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 416 ccaguccuuu gugggagaga u 21 <210> 417 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 417 caguccuuug ugggagagau u 21 <210> 418 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 418 aguccuuugu gggagagauu g 21 <210> 419 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 419 guccuuugug ggagagauug g 21 <210> 420 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 420 uccuuugugg gagagauugg g 21 <210> 421 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 421 ccuuuguggg agagauuggg g 21 <210> 422 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 422 cuuuguggga gagauugggg a 21 <210> 423 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 423 uugugggaga gauuggggau u 21 <210> 424 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 424 ugugggagag auuggggauu u 21 <210> 425 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 425 gugggagaga uuggggauuu g 21 <210> 426 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 426 ugggagagau uggggauuug u 21 <210> 427 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 427 gggagagauu ggggauuugu a 21 <210> 428 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 428 ggagagauug gggauuugua c 21 <210> 429 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 429 gagagauugg ggauuuguac a 21 <210> 430 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 430 agagauuggg gauuuguaca u 21 <210> 431 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 431 gagauugggg auuuguacau g 21 <210> 432 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 432 agauugggga uuuguacaug u 21 <210> 433 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 433 ggggauuugu acauguggga c 21 <210> 434 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 434 gggauuugua caugugggac u 21 <210> 435 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 435 ggauuuguac augugggacu c 21 <210> 436 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 436 gauuuguaca ugugggacuc u 21 <210> 437 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 437 uguacaugug ggacucugug c 21 <210> 438 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 438 guacaugugg gacucugugc u 21 <210> 439 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 439 acauguggga cucugugcug c 21 <210> 440 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 440 gggacucugu gcugccccca g 21 <210> 441 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 441 ggacucugug cugcccccag a 21 <210> 442 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 442 acucugugcu gcccccagaa a 21 <210> 443 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 443 cucugugcug cccccagaaa a 21 <210> 444 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 444 cugugcugcc cccagaaaau a 21 <210> 445 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 445 ugugcugccc ccagaaaaua u 21 <210> 446 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 446 gugcugcccc cagaaaauau c 21 <210> 447 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 447 gcugccccca gaaaauaucc u 21 <210> 448 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 448 cccccagaaa auauccuguc u 21 <210> 449 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 449 cccagaaaau auccugucug c 21 <210> 450 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 450 ccagaaaaua uccugucugc c 21 <210> 451 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 451 cagaaaauau ccugucugcc u 21 <210> 452 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 452 gaaaauaucc ugucugccua u 21 <210> 453 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 453 aaaauauccu gucugccuau c 21 <210> 454 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 454 aaauauccug ucugccuauc a 21 <210> 455 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 455 ccugucugcc uaucagggua c 21 <210> 456 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 456 cugucugccu aucaggguac c 21 <210> 457 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 457 gucugccuau caggguaccc c 21 <210> 458 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 458 ugccuaucag gguaccccuc u 21 <210> 459 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 459 gccuaucagg guaccccucu c 21 <210> 460 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 460 ccuaucaggg uaccccucuc c 21 <210> 461 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 461 cuaucagggu accccucucc c 21 <210> 462 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 462 caggguaccc cucucccugc c 21 <210> 463 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 463 ggguaccccu cucccugcca a 21 <210> 464 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 464 gguaccccuc ucccugccaa u 21 <210> 465 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 465 guaccccucu cccugccaau a 21 <210> 466 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 466 uaccccucuc ccugccaaua u 21 <210> 467 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 467 ccccucuccc ugccaauauc c 21 <210> 468 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 468 cccucucccu gccaauaucc u 21 <210> 469 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 469 cugccaauau ccuggacugg c 21 <210> 470 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 470 ccaauauccu ggacuggcag g 21 <210> 471 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 471 caauauccug gacuggcagg c 21 <210> 472 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 472 uccuggacug gcaggcucug a 21 <210> 473 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 473 ccuggacugg caggcucuga a 21 <210> 474 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 474 cuggacuggc aggcucugaa c 21 <210> 475 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 475 uggacuggca ggcucugaac u 21 <210> 476 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 476 ggacuggcag gcucugaacu a 21 <210> 477 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 477 gacuggcagg cucugaacua u 21 <210> 478 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 478 acuggcaggc ucugaacuau g 21 <210> 479 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 479 cuggcaggcu cugaacuaug a 21 <210> 480 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 480 uggcaggcuc ugaacuauga a 21 <210> 481 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 481 ggcaggcucu gaacuaugaa a 21 <210> 482 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 482 gcaggcucug aacuaugaaa u 21 <210> 483 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 483 caggcucuga acuaugaaau c 21 <210> 484 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 484 aggcucugaa cuaugaaauc a 21 <210> 485 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 485 ggcucugaac uaugaaauca g 21 <210> 486 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 486 gcucugaacu augaaaucag a 21 <210> 487 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 487 cucugaacua ugaaaucaga g 21 <210> 488 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 488 ucugaacuau gaaaucagag g 21 <210> 489 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 489 gaacuaugaa aucagaggau a 21 <210> 490 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 490 aacuaugaaa ucagaggaua u 21 <210> 491 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 491 acuaugaaau cagaggauau g 21 <210> 492 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 492 cuaugaaauc agaggauaug u 21 <210> 493 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 493 uaugaaauca gaggauaugu c 21 <210> 494 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 494 ugaaaucaga ggauauguca u 21 <210> 495 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 495 gaaaucagag gauaugucau c 21 <210> 496 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 496 aaaucagagg auaugucauc a 21 <210> 497 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 497 aaucagagga uaugucauca u 21 <210> 498 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 498 cagaggauau gucaucauca a 21 <210> 499 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 499 agaggauaug ucaucaucaa a 21 <210> 500 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 500 gaggauaugu caucaucaaa c 21 <210> 501 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 501 aggauauguc aucaucaaac c 21 <210> 502 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 502 ggauauguca ucaucaaacc c 21 <210> 503 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 503 gauaugucau caucaaaccc u 21 <210> 504 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 504 augucaucau caaacccuug g 21 <210> 505 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 505 caucaucaaa cccuuggugu g 21 <210> 506 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 506 ucaucaaacc cuuggugugg g 21 <210> 507 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 507 acccuuggug ugggucugag g 21 <210> 508 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 508 cccuuggugu gggucugagg u 21 <210> 509 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 509 ccuuggugug ggucugaggu c 21 <210> 510 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 510 cuuggugugg gucugagguc u 21 <210> 511 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 511 uggugugggu cugaggucuu g 21 <210> 512 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 512 gguguggguc ugaggucuug a 21 <210> 513 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 513 gugugggucu gaggucuuga c 21 <210> 514 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 514 ugugggucug aggucuugac u 21 <210> 515 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 515 gugggucuga ggucuugacu c 21 <210> 516 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 516 gggucugagg ucuugacuca a 21 <210> 517 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 517 ggucugaggu cuugacucaa c 21 <210> 518 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 518 gucugagguc uugacucaac g 21 <210> 519 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 519 cugaggucuu gacucaacga g 21 <210> 520 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 520 ugaggucuug acucaacgag a 21 <210> 521 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 521 gaggucuuga cucaacgaga g 21 <210> 522 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 522 aggucuugac ucaacgagag c 21 <210> 523 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 523 ggucuugacu caacgagagc a 21 <210> 524 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 524 gucuugacuc aacgagagca c 21 <210> 525 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 525 ucuugacuca acgagagcac u 21 <210> 526 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 526 cuugacucaa cgagagcacu u 21 <210> 527 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 527 uugacucaac gagagcacuu g 21 <210> 528 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 528 ugacucaacg agagcacuug a 21 <210> 529 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 529 gacucaacga gagcacuuga a 21 <210> 530 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 530 acucaacgag agcacuugaa a 21 <210> 531 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 531 cucaacgaga gcacuugaaa a 21 <210> 532 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 532 ucaacgagag cacuugaaaa u 21 <210> 533 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 533 caacgagagc acuugaaaau g 21 <210> 534 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 534 aacgagagca cuugaaaaug a 21 <210> 535 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 535 acgagagcac uugaaaauga a 21 <210> 536 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 536 cgagagcacu ugaaaaugaa a 21 <210> 537 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 537 gagagcacuu gaaaaugaaa u 21 <210> 538 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 538 agagcacuug aaaaugaaau g 21 <210> 539 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 539 gagcacuuga aaaugaaaug a 21 <210> 540 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 540 agcacuugaa aaugaaauga c 21 <210> 541 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 541 gcacuugaaa augaaaugac u 21 <210> 542 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 542 cacuugaaaa ugaaaugacu g 21 <210> 543 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 543 acuugaaaau gaaaugacug u 21 <210> 544 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 544 cuugaaaaug aaaugacugu c 21 <210> 545 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 545 uugaaaauga aaugacuguc u 21 <210> 546 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 546 ugaaaaugaa augacugucu a 21 <210> 547 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 547 gaaaaugaaa ugacugucua a 21 <210> 548 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 548 aaaaugaaau gacugucuaa g 21 <210> 549 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 549 aaaugaaaug acugucuaag a 21 <210> 550 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 550 aaugaaauga cugucuaaga g 21 <210> 551 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 551 augaaaugac ugucuaagag a 21 <210> 552 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 552 ugaaaugacu gucuaagaga u 21 <210> 553 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 553 gaaaugacug ucuaagagau c 21 <210> 554 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 554 aaaugacugu cuaagagauc u 21 <210> 555 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 555 augacugucu aagagaucug g 21 <210> 556 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 556 ugacugucua agagaucugg u 21 <210> 557 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 557 gacugucuaa gagaucuggu c 21 <210> 558 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 558 acugucuaag agaucugguc a 21 <210> 559 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 559 cugucuaaga gaucugguca a 21 <210> 560 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 560 ugucuaagag aucuggucaa a 21 <210> 561 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 561 gucuaagaga ucuggucaaa g 21 <210> 562 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 562 ucuaagagau cuggucaaag c 21 <210> 563 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 563 cuaagagauc uggucaaagc a 21 <210> 564 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 564 uaagagaucu ggucaaagca a 21 <210> 565 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 565 aagagaucug gucaaagcaa c 21 <210> 566 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 566 agagaucugg ucaaagcaac u 21 <210> 567 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 567 gagaucuggu caaagcaacu g 21 <210> 568 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 568 agaucugguc aaagcaacug g 21 <210> 569 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 569 gaucugguca aagcaacugg a 21 <210> 570 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 570 aucuggucaa agcaacugga u 21 <210> 571 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 571 ucuggucaaa gcaacuggau a 21 <210> 572 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 572 cuggucaaag caacuggaua c 21 <210> 573 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 573 uggucaaagc aacuggauac u 21 <210> 574 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 574 ggucaaagca acuggauacu a 21 <210> 575 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 575 gucaaagcaa cuggauacua g 21 <210> 576 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 576 ucaaagcaac uggauacuag a 21 <210> 577 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 577 caaagcaacu ggauacuaga u 21 <210> 578 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 578 aaagcaacug gauacuagau c 21 <210> 579 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 579 aagcaacugg auacuagauc u 21 <210> 580 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 580 agcaacugga uacuagaucu u 21 <210> 581 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 581 gcaacuggau acuagaucuu a 21 <210> 582 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 582 caacuggaua cuagaucuua c 21 <210> 583 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 583 aacuggauac uagaucuuac a 21 <210> 584 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 584 acuggauacu agaucuuaca u 21 <210> 585 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 585 cuggauacua gaucuuacau c 21 <210> 586 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 586 uggauacuag aucuuacauc u 21 <210> 587 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 587 ggauacuaga ucuuacaucu g 21 <210> 588 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 588 gauacuagau cuuacaucug c 21 <210> 589 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 589 auacuagauc uuacaucugc a 21 <210> 590 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 590 acuagaucuu acaucugcag c 21 <210> 591 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 591 cuagaucuua caucugcagc u 21 <210> 592 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 592 agaucuuaca ucugcagcuc u 21 <210> 593 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 593 gaucuuacau cugcagcucu u 21 <210> 594 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 594 aucuuacauc ugcagcucuu u 21 <210> 595 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 595 ucuuacaucu gcagcucuuu c 21 <210> 596 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 596 cuuacaucug cagcucuuuc u 21 <210> 597 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 597 uuacaucugc agcucuuucu u 21 <210> 598 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 598 uacaucugca gcucuuucuu c 21 <210> 599 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 599 acaucugcag cucuuucuuc u 21 <210> 600 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 600 caucugcagc ucuuucuucu u 21 <210> 601 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 601 aucugcagcu cuuucuucuu u 21 <210> 602 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 602 ucugcagcuc uuucuucuuu g 21 <210> 603 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 603 cugcagcucu uucuucuuug a 21 <210> 604 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 604 ugcagcucuu ucuucuuuga a 21 <210> 605 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 605 gcagcucuuu cuucuuugaa u 21 <210> 606 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 606 cagcucuuuc uucuuugaau u 21 <210> 607 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 607 agcucuuucu ucuuugaauu u 21 <210> 608 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 608 gcucuuucuu cuuugaauuu c 21 <210> 609 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 609 cucuuucuuc uuugaauuuc c 21 <210> 610 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 610 ucuuucuucu uugaauuucc u 21 <210> 611 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 611 cuuucuucuu ugaauuuccu a 21 <210> 612 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 612 uuucuucuuu gaauuuccua u 21 <210> 613 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 613 uucuucuuug aauuuccuau c 21 <210> 614 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 614 ucuucuuuga auuuccuauc u 21 <210> 615 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 615 uucuuugaau uuccuaucug u 21 <210> 616 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 616 ucuuugaauu uccuaucugu a 21 <210> 617 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 617 cuuugaauuu ccuaucugua u 21 <210> 618 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 618 uuugaauuuc cuaucuguau g 21 <210> 619 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 619 uugaauuucc uaucuguaug u 21 <210> 620 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 620 ugaauuuccu aucuguaugu c 21 <210> 621 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 621 gaauuuccua ucuguauguc u 21 <210> 622 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 622 auuuccuauc uguaugucug c 21 <210> 623 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 623 uuuccuaucu guaugucugc c 21 <210> 624 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 624 uuccuaucug uaugucugcc u 21 <210> 625 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 625 uccuaucugu augucugccu a 21 <210> 626 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 626 ccuaucugua ugucugccua a 21 <210> 627 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 627 cuaucuguau gucugccuaa u 21 <210> 628 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 628 uaucuguaug ucugccuaau u 21 <210> 629 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 629 aucuguaugu cugccuaauu a 21 <210> 630 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 630 ucuguauguc ugccuaauua a 21 <210> 631 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 631 cuguaugucu gccuaauuaa a 21 <210> 632 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 632 uguaugucug ccuaauuaaa a 21 <210> 633 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 633 guaugucugc cuaauuaaaa a 21 <210> 634 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 634 uaugucugcc uaauuaaaaa a 21 <210> 635 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 635 augucugccu aauuaaaaaa a 21 <210> 636 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 636 ugucugccua auuaaaaaaa u 21 <210> 637 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 637 gucugccuaa uuaaaaaaau a 21 <210> 638 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 638 ucugccuaau uaaaaaaaua u 21 <210> 639 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 639 cugccuaauu aaaaaaauau a 21 <210> 640 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 640 ugccuaauua aaaaaauaua u 21 <210> 641 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 641 gccuaauuaa aaaaauauau a 21 <210> 642 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 642 ccuaauuaaa aaaauauaua u 21 <210> 643 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 643 cuaauuaaaa aaauauauau u 21 <210> 644 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 644 uaaaaaaaua uauauuguau u 21 <210> 645 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 645 uagcgucuga uauucaugcc c 21 <210> 646 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 646 cuagcgucug auauucaugc c 21 <210> 647 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 647 ucccccuagc gucugauauu c 21 <210> 648 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 648 acaguggcug ucccccuagc g 21 <210> 649 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 649 acacaguggc ugucccccua g 21 <210> 650 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 650 caacacagug gcuguccccc u 21 <210> 651 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 651 acaacacagu ggcugucccc c 21 <210> 652 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 652 gacaacacag uggcuguccc c 21 <210> 653 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 653 agacaacaca guggcugucc c 21 <210> 654 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 654 uagcagacaa cacaguggcu g 21 <210> 655 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 655 guagcagaca acacaguggc u 21 <210> 656 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 656 gguagcagac aacacagugg c 21 <210> 657 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 657 aggguagcag acaacacagu g 21 <210> 658 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 658 gaggguagca gacaacacag u 21 <210> 659 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 659 ugaggguagc agacaacaca g 21 <210> 660 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 660 augaggguag cagacaacac a 21 <210> 661 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 661 gaugagggua gcagacaaca c 21 <210> 662 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 662 caggaugagg guagcagaca a 21 <210> 663 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 663 accaggauga ggguagcaga c 21 <210> 664 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 664 ugaccaggau gaggguagca g 21 <210> 665 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 665 gugaccagga ugaggguagc a 21 <210> 666 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 666 agugaccagg augaggguag c 21 <210> 667 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 667 cagugaccag gaugagggua g 21 <210> 668 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 668 gcagugacca ggaugagggu a 21 <210> 669 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 669 agcagugacc aggaugaggg u 21 <210> 670 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 670 aagcagugac caggaugagg g 21 <210> 671 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 671 agaagcagug accaggauga g 21 <210> 672 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 672 cagaagcagu gaccaggaug a 21 <210> 673 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 673 gcagaagcag ugaccaggau g 21 <210> 674 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 674 agcagaagca gugaccagga u 21 <210> 675 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 675 uagcagaagc agugaccagg a 21 <210> 676 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 676 auagcagaag cagugaccag g 21 <210> 677 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 677 uauagcagaa gcagugacca g 21 <210> 678 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 678 uuauagcaga agcagugacc a 21 <210> 679 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 679 uguuauagca gaagcaguga c 21 <210> 680 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 680 cuguuauagc agaagcagug a 21 <210> 681 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 681 gcuguuauag cagaagcagu g 21 <210> 682 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 682 gggcuguuau agcagaagca g 21 <210> 683 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 683 agggcuguua uagcagaagc a 21 <210> 684 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 684 uagggcuguu auagcagaag c 21 <210> 685 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 685 cuagggcugu uauagcagaa g 21 <210> 686 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 686 ccuagggcug uuauagcaga a 21 <210> 687 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 687 gccuagggcu guuauagcag a 21 <210> 688 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 688 ggccuagggc uguuauagca g 21 <210> 689 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 689 uggccuaggg cuguuauagc a 21 <210> 690 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 690 cuggccuagg gcuguuauag c 21 <210> 691 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 691 ccuggccuag ggcuguuaua g 21 <210> 692 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 692 uccuggccua gggcuguuau a 21 <210> 693 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 693 auuccuggcc uagggcuguu a 21 <210> 694 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 694 uauuccuggc cuagggcugu u 21 <210> 695 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 695 auauuccugg ccuagggcug u 21 <210> 696 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 696 cauauuccug gccuagggcu g 21 <210> 697 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 697 ucauauuccu ggccuagggc u 21 <210> 698 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 698 uucauauucc uggccuaggg c 21 <210> 699 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 699 guucauauuc cuggccuagg g 21 <210> 700 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 700 uguucauauu ccuggccuag g 21 <210> 701 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 701 uuguucauau uccuggccua g 21 <210> 702 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 702 cuuguucaua uuccuggccu a 21 <210> 703 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 703 gcuuguucau auuccuggcc u 21 <210> 704 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 704 ggcuuguuca uauuccuggc c 21 <210> 705 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 705 cggcuuguuc auauuccugg c 21 <210> 706 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 706 gcggcuuguu cauauuccug g 21 <210> 707 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 707 agcggcuugu ucauauuccu g 21 <210> 708 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 708 cagcggcuug uucauauucc u 21 <210> 709 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 709 gcagcggcuu guucauauuc c 21 <210> 710 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 710 agcagcggcu uguucauauu c 21 <210> 711 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 711 aagcagcggc uuguucauau u 21 <210> 712 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 712 aaagcagcgg cuuguucaua u 21 <210> 713 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 713 caaagcagcg gcuuguucau a 21 <210> 714 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 714 ccaaagcagc ggcuuguuca u 21 <210> 715 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 715 uccaaagcag cggcuuguuc a 21 <210> 716 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 716 auccaaagca gcggcuuguu c 21 <210> 717 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 717 gauccaaagc agcggcuugu u 21 <210> 718 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 718 agauccaaag cagcggcuug u 21 <210> 719 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 719 gagauccaaa gcagcggcuu g 21 <210> 720 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 720 agagauccaa agcagcggcu u 21 <210> 721 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 721 cagagaucca aagcagcggc u 21 <210> 722 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 722 acagagaucc aaagcagcgg c 21 <210> 723 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 723 gacagagauc caaagcagcg g 21 <210> 724 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 724 ggacagagau ccaaagcagc g 21 <210> 725 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 725 aggacagaga uccaaagcag c 21 <210> 726 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 726 gaggacagag auccaaagca g 21 <210> 727 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 727 ugaggacaga gauccaaagc a 21 <210> 728 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 728 gugaggacag agauccaaag c 21 <210> 729 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 729 cuggugagga cagagaucca a 21 <210> 730 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 730 gcuggugagg acagagaucc a 21 <210> 731 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 731 gaggcuggug aggacagaga u 21 <210> 732 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 732 aggaggcugg ugaggacaga g 21 <210> 733 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 733 caggaggcug gugaggacag a 21 <210> 734 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 734 ccaggaggcu ggugaggaca g 21 <210> 735 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 735 uccaggaggc uggugaggac a 21 <210> 736 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 736 cuuccaggag gcuggugagg a 21 <210> 737 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 737 gcuuccagga ggcuggugag g 21 <210> 738 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 738 aggcuuccag gaggcuggug a 21 <210> 739 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 739 aaggcuucca ggaggcuggu g 21 <210> 740 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 740 aaaggcuucc aggaggcugg u 21 <210> 741 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 741 caaaggcuuc caggaggcug g 21 <210> 742 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 742 gcaaaggcuu ccaggaggcu g 21 <210> 743 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 743 agcaaaggcu uccaggaggc u 21 <210> 744 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 744 gagcaaaggc uuccaggagg c 21 <210> 745 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 745 ugagcaaagg cuuccaggag g 21 <210> 746 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 746 gugagcaaag gcuuccagga g 21 <210> 747 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 747 ugugagcaaa ggcuuccagg a 21 <210> 748 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 748 ugugugagca aaggcuucca g 21 <210> 749 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 749 cugugugagc aaaggcuucc a 21 <210> 750 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 750 ucugugugag caaaggcuuc c 21 <210> 751 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 751 gucuguguga gcaaaggcuu c 21 <210> 752 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 752 ggucugugug agcaaaggcu u 21 <210> 753 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 753 aggucugugu gagcaaaggc u 21 <210> 754 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 754 gaggucugug ugagcaaagg c 21 <210> 755 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 755 ugaggucugu gugagcaaag g 21 <210> 756 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 756 acugaggucu gugugagcaa a 21 <210> 757 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 757 ccacugaggu cugugugagc a 21 <210> 758 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 758 ucccacugag gucuguguga g 21 <210> 759 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 759 uucccacuga ggucugugug a 21 <210> 760 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 760 cuucccacug aggucugugu g 21 <210> 761 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 761 caccuuccca cugaggucug u 21 <210> 762 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 762 acaccuuccc acugaggucu g 21 <210> 763 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 763 aacaccuucc cacugagguc u 21 <210> 764 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 764 aaacaccuuc ccacugaggu c 21 <210> 765 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 765 caaacaccuu cccacugagg u 21 <210> 766 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 766 acaaacaccu ucccacugag g 21 <210> 767 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 767 uacaaacacc uucccacuga g 21 <210> 768 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 768 auacaaacac cuucccacug a 21 <210> 769 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 769 aauacaaaca ccuucccacu g 21 <210> 770 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 770 aaauacaaac accuucccac u 21 <210> 771 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 771 gaaauacaaa caccuuccca c 21 <210> 772 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 772 ggaaauacaa acaccuuccc a 21 <210> 773 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 773 aggaaauaca aacaccuucc c 21 <210> 774 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 774 uaggaaauac aaacaccuuc c 21 <210> 775 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 775 cuaggaaaua caaacaccuu c 21 <210> 776 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 776 ucuaggaaau acaaacaccu u 21 <210> 777 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 777 cucuaggaaa uacaaacacc u 21 <210> 778 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 778 ucucuaggaa auacaaacac c 21 <210> 779 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 779 uucucuagga aauacaaaca c 21 <210> 780 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 780 auucucuagg aaauacaaac a 21 <210> 781 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 781 gauucucuag gaaauacaaa c 21 <210> 782 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 782 agauucucua ggaaauacaa a 21 <210> 783 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 783 cagauucucu aggaaauaca a 21 <210> 784 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 784 acagauucuc uaggaaauac a 21 <210> 785 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 785 aacagauucu cuaggaaaua c 21 <210> 786 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 786 uaacagauuc ucuaggaaau a 21 <210> 787 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 787 aguaacagau ucucuaggaa a 21 <210> 788 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 788 caguaacaga uucucuagga a 21 <210> 789 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 789 ucaguaacag auucucuagg a 21 <210> 790 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 790 aucaguaaca gauucucuag g 21 <210> 791 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 791 gaucaguaac agauucucua g 21 <210> 792 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 792 ugaucaguaa cagauucucu a 21 <210> 793 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 793 augaucagua acagauucuc u 21 <210> 794 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 794 caugaucagu aacagauucu c 21 <210> 795 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 795 acaugaucag uaacagauuc u 21 <210> 796 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 796 uacaugauca guaacagauu c 21 <210> 797 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 797 uuacaugauc aguaacagau u 21 <210> 798 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 798 uuuacaugau caguaacaga u 21 <210> 799 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 799 guuuacauga ucaguaacag a 21 <210> 800 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 800 aguuuacaug aucaguaaca g 21 <210> 801 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 801 ucaaguuuac augaucagua a 21 <210> 802 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 802 aucaaguuua caugaucagu a 21 <210> 803 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 803 gaucaaguuu acaugaucag u 21 <210> 804 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 804 ugaucaaguu uacaugauca g 21 <210> 805 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 805 ugugaucaag uuuacaugau c 21 <210> 806 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 806 gugugaucaa guuuacauga u 21 <210> 807 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 807 agcgguguga ucaaguuuac a 21 <210> 808 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 808 cagcggugug aucaaguuua c 21 <210> 809 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 809 uccagcggug ugaucaaguu u 21 <210> 810 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 810 ucuccagcgg ugugaucaag u 21 <210> 811 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 811 uucuccagcg gugugaucaa g 21 <210> 812 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 812 cuucuccagc ggugugauca a 21 <210> 813 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 813 aggcuucucc agcgguguga u 21 <210> 814 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 814 gaggcuucuc cagcggugug a 21 <210> 815 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 815 agaggcuucu ccagcggugu g 21 <210> 816 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 816 uagaggcuuc uccagcggug u 21 <210> 817 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 817 guagaggcuu cuccagcggu g 21 <210> 818 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 818 uguagaggcu ucuccagcgg u 21 <210> 819 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 819 cuguagaggc uucuccagcg g 21 <210> 820 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 820 ucuguagagg cuucuccagc g 21 <210> 821 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 821 uucuguagag gcuucuccag c 21 <210> 822 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 822 guucuguaga ggcuucucca g 21 <210> 823 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 823 aguucuguag aggcuucucc a 21 <210> 824 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 824 aaguucugua gaggcuucuc c 21 <210> 825 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 825 aaaguucugu agaggcuucu c 21 <210> 826 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 826 uaaaguucug uagaggcuuc u 21 <210> 827 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 827 guaaaguucu guagaggcuu c 21 <210> 828 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 828 gguaaaguuc uguagaggcu u 21 <210> 829 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 829 agguaaaguu cuguagaggc u 21 <210> 830 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 830 aagguaaagu ucuguagagg c 21 <210> 831 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 831 caagguaaag uucuguagag g 21 <210> 832 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 832 acaagguaaa guucuguaga g 21 <210> 833 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 833 cacaagguaa aguucuguag a 21 <210> 834 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 834 acacaaggua aaguucugua g 21 <210> 835 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 835 aacacaaggu aaaguucugu a 21 <210> 836 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 836 aaacacaagg uaaaguucug u 21 <210> 837 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 837 aaaacacaag guaaaguucu g 21 <210> 838 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 838 gaaaacacaa gguaaaguuc u 21 <210> 839 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 839 ucgaaaacac aagguaaagu u 21 <210> 840 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 840 aggcucgaaa acacaaggua a 21 <210> 841 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 841 uaggcucgaa aacacaaggu a 21 <210> 842 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 842 auaggcucga aaacacaagg u 21 <210> 843 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 843 uauaggcucg aaaacacaag g 21 <210> 844 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 844 acuauaggcu cgaaaacaca a 21 <210> 845 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 845 ucacuauagg cucgaaaaca c 21 <210> 846 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 846 aucacuauag gcucgaaaac a 21 <210> 847 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 847 agagaucacu auaggcucga a 21 <210> 848 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 848 gagagaucac uauaggcucg a 21 <210> 849 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 849 agagagauca cuauaggcuc g 21 <210> 850 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 850 gagagagauc acuauaggcu c 21 <210> 851 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 851 cgagagagau cacuauaggc u 21 <210> 852 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 852 acgagagaga ucacuauagg c 21 <210> 853 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 853 cacgagagag aucacuauag g 21 <210> 854 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 854 aggcacgaga gagaucacua u 21 <210> 855 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 855 uaggcacgag agagaucacu a 21 <210> 856 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 856 guaggcacga gagagaucac u 21 <210> 857 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 857 uguaggcacg agagagauca c 21 <210> 858 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 858 gaggcuguag gcacgagaga g 21 <210> 859 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 859 agaggcugua ggcacgagag a 21 <210> 860 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 860 aagaggcugu aggcacgaga g 21 <210> 861 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 861 agaagaggcu guaggcacga g 21 <210> 862 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 862 gagaagaggc uguaggcacg a 21 <210> 863 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 863 aggagaagag gcuguaggca c 21 <210> 864 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 864 uaggagaaga ggcuguaggc a 21 <210> 865 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 865 guaggagaag aggcuguagg c 21 <210> 866 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 866 uguaggagaa gaggcuguag g 21 <210> 867 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 867 uuguaggaga agaggcugua g 21 <210> 868 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 868 auuguaggag aagaggcugu a 21 <210> 869 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 869 uauuguagga gaagaggcug u 21 <210> 870 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 870 guauuguagg agaagaggcu g 21 <210> 871 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 871 gguauuguag gagaagaggc u 21 <210> 872 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 872 uggguauugu aggagaagag g 21 <210> 873 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 873 ccuuggguau uguaggagaa g 21 <210> 874 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 874 gccuugggua uuguaggaga a 21 <210> 875 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 875 ugccuugggu auuguaggag a 21 <210> 876 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 876 cugccuuggg uauuguagga g 21 <210> 877 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 877 ccugccuugg guauuguagg a 21 <210> 878 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 878 aucccugccu uggguauugu a 21 <210> 879 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 879 uuaucccugc cuuggguauu g 21 <210> 880 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 880 auuaucccug ccuuggguau u 21 <210> 881 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 881 cucauuaucc cugccuuggg u 21 <210> 882 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 882 agcucauuau cccugccuug g 21 <210> 883 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 883 uagcucauua ucccugccuu g 21 <210> 884 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 884 aguagcucau uaucccugcc u 21 <210> 885 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 885 uaguagcuca uuaucccugc c 21 <210> 886 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 886 cuaguagcuc auuaucccug c 21 <210> 887 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 887 acuaguagcu cauuaucccu g 21 <210> 888 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 888 aacuaguagc ucauuauccc u 21 <210> 889 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 889 aaacuaguag cucauuaucc c 21 <210> 890 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 890 uaaacuagua gcucauuauc c 21 <210> 891 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 891 auaaacuagu agcucauuau c 21 <210> 892 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 892 uuauaaacua guagcucauu a 21 <210> 893 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 893 uuuauaaacu aguagcucau u 21 <210> 894 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 894 cuuuauaaac uaguagcuca u 21 <210> 895 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 895 ucuuuauaaa cuaguagcuc a 21 <210> 896 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 896 uucuuuauaa acuaguagcu c 21 <210> 897 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 897 uuucuuuaua aacuaguagc u 21 <210> 898 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 898 aacucuuucu uuauaaacua g 21 <210> 899 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 899 uacucuccaa cucuuucuuu a 21 <210> 900 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 900 auacucucca acucuuucuu u 21 <210> 901 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 901 uauacucucc aacucuuucu u 21 <210> 902 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 902 acuauacucu ccaacucuuu c 21 <210> 903 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 903 gacuauacuc uccaacucuu u 21 <210> 904 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 904 agacuauacu cuccaacucu u 21 <210> 905 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 905 uagacuauac ucuccaacuc u 21 <210> 906 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 906 auagacuaua cucuccaacu c 21 <210> 907 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 907 uauagacuau acucuccaac u 21 <210> 908 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 908 guauagacua uacucuccaa c 21 <210> 909 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 909 uguauagacu auacucucca a 21 <210> 910 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 910 auguauagac uauacucucc a 21 <210> 911 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 911 aauguauaga cuauacucuc c 21 <210> 912 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 912 caauguauag acuauacucu c 21 <210> 913 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 913 ccaauguaua gacuauacuc u 21 <210> 914 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 914 uccaauguau agacuauacu c 21 <210> 915 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 915 ugucuuccaa uguauagacu a 21 <210> 916 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 916 ugugucuucc aauguauaga c 21 <210> 917 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 917 uugugucuuc caauguauag a 21 <210> 918 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 918 uuugugucuu ccaauguaua g 21 <210> 919 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 919 acuuuguguc uuccaaugua u 21 <210> 920 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 920 aacuuugugu cuuccaaugu a 21 <210> 921 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 921 uaacuuugug ucuuccaaug u 21 <210> 922 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 922 uguaacuuug ugucuuccaa u 21 <210> 923 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 923 auguaacuuu gugucuucca a 21 <210> 924 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 924 gauguaacuu ugugucuucc a 21 <210> 925 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 925 ggauguaacu uugugucuuc c 21 <210> 926 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 926 uggauguaac uuugugucuu c 21 <210> 927 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 927 uuggauguaa cuuugugucu u 21 <210> 928 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 928 uuuggaugua acuuuguguc u 21 <210> 929 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 929 cuuuggaugu aacuuugugu c 21 <210> 930 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 930 aacuuuggau guaacuuugu g 21 <210> 931 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 931 uaacuuugga uguaacuuug u 21 <210> 932 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 932 auaacuuugg auguaacuuu g 21 <210> 933 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 933 gauaacuuug gauguaacuu u 21 <210> 934 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 934 cgauaacuuu ggauguaacu u 21 <210> 935 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 935 ucgauaacuu uggauguaac u 21 <210> 936 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 936 uucgauaacu uuggauguaa c 21 <210> 937 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 937 uuucgauaac uuuggaugua a 21 <210> 938 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 938 uuuucgauaa cuuuggaugu a 21 <210> 939 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 939 cuuuucgaua acuuuggaug u 21 <210> 940 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 940 acuuuucgau aacuuuggau g 21 <210> 941 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 941 aacuuuucga uaacuuugga u 21 <210> 942 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 942 gaacuuuucg auaacuuugg a 21 <210> 943 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 943 uggagccggg aacuuuucga u 21 <210> 944 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 944 acuggagccg ggaacuuuuc g 21 <210> 945 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 945 gaugugcacu ggagccggga a 21 <210> 946 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 946 cagaugugca cuggagccgg g 21 <210> 947 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 947 acagaugugc acuggagccg g 21 <210> 948 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 948 cacagaugug cacuggagcc g 21 <210> 949 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 949 acacagaugu gcacuggagc c 21 <210> 950 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 950 ucacacagau gugcacugga g 21 <210> 951 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 951 agcucacaca gaugugcacu g 21 <210> 952 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 952 ccagcucaca cagaugugca c 21 <210> 953 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 953 ucccagcuca cacagaugug c 21 <210> 954 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 954 acucccagcu cacacagaug u 21 <210> 955 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 955 aggacuccca gcucacacag a 21 <210> 956 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 956 gaggacuccc agcucacaca g 21 <210> 957 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 957 cugaugagga cucccagcuc a 21 <210> 958 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 958 ccugaugagg acucccagcu c 21 <210> 959 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 959 accugaugag gacucccagc u 21 <210> 960 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 960 uaccugauga ggacucccag c 21 <210> 961 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 961 auaccugaug aggacuccca g 21 <210> 962 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 962 aauaccugau gaggacuccc a 21 <210> 963 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 963 caauaccuga ugaggacucc c 21 <210> 964 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 964 agcaauaccu gaugaggacu c 21 <210> 965 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 965 cagcaauacc ugaugaggac u 21 <210> 966 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 966 ucagcaauac cugaugagga c 21 <210> 967 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 967 uucagcaaua ccugaugagg a 21 <210> 968 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 968 auucagcaau accugaugag g 21 <210> 969 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 969 aauucagcaa uaccugauga g 21 <210> 970 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 970 aaauucagca auaccugaug a 21 <210> 971 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 971 aaaauucagc aauaccugau g 21 <210> 972 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 972 caaaauucag caauaccuga u 21 <210> 973 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 973 ccaaaauuca gcaauaccug a 21 <210> 974 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 974 uccaaaauuc agcaauaccu g 21 <210> 975 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 975 auccaaaauu cagcaauacc u 21 <210> 976 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 976 ugauccaaaa uucagcaaua c 21 <210> 977 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 977 auugauccaa aauucagcaa u 21 <210> 978 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 978 cauugaucca aaauucagca a 21 <210> 979 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 979 ccauugaucc aaaauucagc a 21 <210> 980 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 980 ucccauugau ccaaaauuca g 21 <210> 981 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 981 aaaggugucc cauugaucca a 21 <210> 982 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 982 caccaaaggu gucccauuga u 21 <210> 983 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 983 ucaccaaagg ugucccauug a 21 <210> 984 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 984 uucaccaaag gugucccauu g 21 <210> 985 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 985 uuucaccaaa ggugucccau u 21 <210> 986 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 986 uuuucaccaa agguguccca u 21 <210> 987 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 987 uuuuucacca aagguguccc a 21 <210> 988 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 988 acccuuuuuc accaaaggug u 21 <210> 989 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 989 gacccuuuuu caccaaaggu g 21 <210> 990 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 990 agacccuuuu ucaccaaagg u 21 <210> 991 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 991 ucgcagaccc uuuuucacca a 21 <210> 992 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 992 gucgcagacc cuuuuucacc a 21 <210> 993 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 993 ugucgcagac ccuuuuucac c 21 <210> 994 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 994 cugucgcaga cccuuuuuca c 21 <210> 995 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 995 acccugucgc agacccuuuu u 21 <210> 996 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 996 aacccugucg cagacccuuu u 21 <210> 997 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 997 uaacccuguc gcagacccuu u 21 <210> 998 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 998 guaacccugu cgcagacccu u 21 <210> 999 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 999 aguaacccug ucgcagaccc u 21 <210> 1000 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1000 aaguaacccu gucgcagacc c 21 <210> 1001 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1001 aaaguaaccc ugucgcagac c 21 <210> 1002 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1002 caaaguaacc cugucgcaga c 21 <210> 1003 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1003 acaaaguaac ccugucgcag a 21 <210> 1004 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1004 uacaaaguaa cccugucgca g 21 <210> 1005 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1005 cuacaaagua acccugucgc a 21 <210> 1006 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1006 ucuacaaagu aacccugucg c 21 <210> 1007 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1007 uucuacaaag uaacccuguc g 21 <210> 1008 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1008 cuucuacaaa guaacccugu c 21 <210> 1009 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1009 gcuucuacaa aguaacccug u 21 <210> 1010 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1010 agcuucuaca aaguaacccu g 21 <210> 1011 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1011 gagcuucuac aaaguaaccc u 21 <210> 1012 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1012 ugagcuucua caaaguaacc c 21 <210> 1013 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1013 aaucuugggc ugagcuucua c 21 <210> 1014 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1014 caaucuuggg cugagcuucu a 21 <210> 1015 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1015 acaaucuugg gcugagcuuc u 21 <210> 1016 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1016 gacaaucuug ggcugagcuu c 21 <210> 1017 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1017 aggacaaucu ugggcugagc u 21 <210> 1018 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1018 cccaggacaa ucuugggcug a 21 <210> 1019 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1019 ugccccagga caaucuuggg c 21 <210> 1020 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1020 cugccccagg acaaucuugg g 21 <210> 1021 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1021 uccugcccca ggacaaucuu g 21 <210> 1022 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1022 uuccugcccc aggacaaucu u 21 <210> 1023 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1023 uguuccugcc ccaggacaau c 21 <210> 1024 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1024 uccuguuccu gccccaggac a 21 <210> 1025 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1025 aauccuguuc cugccccagg a 21 <210> 1026 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1026 gaauccuguu ccugccccag g 21 <210> 1027 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1027 ggaauccugu uccugcccca g 21 <210> 1028 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1028 uaggaauccu guuccugccc c 21 <210> 1029 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1029 auaggaaucc uguuccugcc c 21 <210> 1030 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1030 cauaggaauc cuguuccugc c 21 <210> 1031 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1031 cccauaggaa uccuguuccu g 21 <210> 1032 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1032 ccccauagga auccuguucc u 21 <210> 1033 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1033 gcccccauag gaauccuguu c 21 <210> 1034 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1034 ugcccccaua ggaauccugu u 21 <210> 1035 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1035 cuugccccca uaggaauccu g 21 <210> 1036 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1036 acuugccccc auaggaaucc u 21 <210> 1037 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1037 aacuugcccc cauaggaauc c 21 <210> 1038 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1038 aaacuugccc ccauaggaau c 21 <210> 1039 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1039 caaacuugcc cccauaggaa u 21 <210> 1040 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1040 ucaaacuugc ccccauagga a 21 <210> 1041 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1041 aucaaacuug cccccauagg a 21 <210> 1042 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1042 uaucaaacuu gcccccauag g 21 <210> 1043 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1043 uccuaucaaa cuugccccca u 21 <210> 1044 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1044 cuccuaucaa acuugccccc a 21 <210> 1045 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1045 gcuccuauca aacuugcccc c 21 <210> 1046 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1046 ggcuccuauc aaacuugccc c 21 <210> 1047 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1047 uggcuccuau caaacuugcc c 21 <210> 1048 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1048 cuggcuccua ucaaacuugc c 21 <210> 1049 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1049 acuggcuccu aucaaacuug c 21 <210> 1050 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1050 aaggacuggc uccuaucaaa c 21 <210> 1051 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1051 aaaggacugg cuccuaucaa a 21 <210> 1052 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1052 caaaggacug gcuccuauca a 21 <210> 1053 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1053 acaaaggacu ggcuccuauc a 21 <210> 1054 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1054 ccacaaagga cuggcuccua u 21 <210> 1055 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1055 cccacaaagg acuggcuccu a 21 <210> 1056 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1056 ucccacaaag gacuggcucc u 21 <210> 1057 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1057 cucccacaaa ggacuggcuc c 21 <210> 1058 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1058 ucucccacaa aggacuggcu c 21 <210> 1059 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1059 cucucccaca aaggacuggc u 21 <210> 1060 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1060 ucucucccac aaaggacugg c 21 <210> 1061 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1061 aucucuccca caaaggacug g 21 <210> 1062 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1062 aaucucuccc acaaaggacu g 21 <210> 1063 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1063 caaucucucc cacaaaggac u 21 <210> 1064 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1064 ccaaucucuc ccacaaagga c 21 <210> 1065 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1065 cccaaucucu cccacaaagg a 21 <210> 1066 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1066 uccccaaucu cucccacaaa g 21 <210> 1067 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1067 auccccaauc ucucccacaa a 21 <210> 1068 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1068 aauccccaau cucucccaca a 21 <210> 1069 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1069 aaauccccaa ucucucccac a 21 <210> 1070 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1070 caaaucccca aucucuccca c 21 <210> 1071 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1071 acaaaucccc aaucucuccc a 21 <210> 1072 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1072 uacaaauccc caaucucucc c 21 <210> 1073 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1073 guacaaaucc ccaaucucuc c 21 <210> 1074 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1074 uguacaaauc cccaaucucu c 21 <210> 1075 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1075 auguacaaau ccccaaucuc u 21 <210> 1076 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1076 cccacaugua caaaucccca a 21 <210> 1077 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1077 ucccacaugu acaaaucccc a 21 <210> 1078 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1078 gucccacaug uacaaauccc c 21 <210> 1079 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1079 agucccacau guacaaaucc c 21 <210> 1080 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1080 acagaguccc acauguacaa a 21 <210> 1081 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1081 cacagagucc cacauguaca a 21 <210> 1082 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1082 agcacagagu cccacaugua c 21 <210> 1083 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1083 gggggcagca cagaguccca c 21 <210> 1084 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1084 ugggggcagc acagaguccc a 21 <210> 1085 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1085 ucugggggca gcacagaguc c 21 <210> 1086 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1086 uucugggggc agcacagagu c 21 <210> 1087 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1087 uuuucugggg gcagcacaga g 21 <210> 1088 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1088 auuuucuggg ggcagcacag a 21 <210> 1089 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1089 uauuuucugg gggcagcaca g 21 <210> 1090 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1090 gauauuuucu gggggcagca c 21 <210> 1091 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1091 acaggauauu uucugggggc a 21 <210> 1092 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1092 agacaggaua uuuucugggg g 21 <210> 1093 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1093 cagacaggau auuuucuggg g 21 <210> 1094 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1094 gcagacagga uauuuucugg g 21 <210> 1095 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1095 aggcagacag gauauuuucu g 21 <210> 1096 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1096 uaggcagaca ggauauuuuc u 21 <210> 1097 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1097 auaggcagac aggauauuuu c 21 <210> 1098 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1098 acccugauag gcagacagga u 21 <210> 1099 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1099 uacccugaua ggcagacagg a 21 <210> 1100 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1100 gguacccuga uaggcagaca g 21 <210> 1101 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1101 agggguaccc ugauaggcag a 21 <210> 1102 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1102 gagggguacc cugauaggca g 21 <210> 1103 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1103 agagggguac ccugauaggc a 21 <210> 1104 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1104 gagaggggua cccugauagg c 21 <210> 1105 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1105 cagggagagg gguacccuga u 21 <210> 1106 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1106 ggcagggaga gggguacccu g 21 <210> 1107 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1107 uggcagggag agggguaccc u 21 <210> 1108 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1108 uuggcaggga gagggguacc c 21 <210> 1109 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1109 auuggcaggg agagggguac c 21 <210> 1110 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1110 auauuggcag ggagaggggu a 21 <210> 1111 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1111 gauauuggca gggagagggg u 21 <210> 1112 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1112 caguccagga uauuggcagg g 21 <210> 1113 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1113 ugccagucca ggauauuggc a 21 <210> 1114 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1114 cugccagucc aggauauugg c 21 <210> 1115 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1115 agagccugcc aguccaggau a 21 <210> 1116 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1116 cagagccugc caguccagga u 21 <210> 1117 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1117 ucagagccug ccaguccagg a 21 <210> 1118 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1118 uucagagccu gccaguccag g 21 <210> 1119 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1119 guucagagcc ugccagucca g 21 <210> 1120 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1120 aguucagagc cugccagucc a 21 <210> 1121 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1121 uaguucagag ccugccaguc c 21 <210> 1122 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1122 auaguucaga gccugccagu c 21 <210> 1123 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1123 cauaguucag agccugccag u 21 <210> 1124 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1124 ucauaguuca gagccugcca g 21 <210> 1125 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1125 uucauaguuc agagccugcc a 21 <210> 1126 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1126 uuucauaguu cagagccugc c 21 <210> 1127 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1127 auuucauagu ucagagccug c 21 <210> 1128 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1128 gauuucauag uucagagccu g 21 <210> 1129 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1129 ugauuucaua guucagagcc u 21 <210> 1130 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1130 cugauuucau aguucagagc c 21 <210> 1131 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1131 ucugauuuca uaguucagag c 21 <210> 1132 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1132 uccucugauu ucauaguuca g 21 <210> 1133 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1133 auccucugau uucauaguuc a 21 <210> 1134 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1134 uauccucuga uuucauaguu c 21 <210> 1135 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1135 auauccucug auuucauagu u 21 <210> 1136 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1136 cauauccucu gauuucauag u 21 <210> 1137 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1137 gacauauccu cugauuucau a 21 <210> 1138 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1138 ugacauaucc ucugauuuca u 21 <210> 1139 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1139 augacauauc cucugauuuc a 21 <210> 1140 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1140 gaugacauau ccucugauuu c 21 <210> 1141 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1141 gaugaugaca uauccucuga u 21 <210> 1142 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1142 ugaugaugac auauccucug a 21 <210> 1143 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1143 uugaugauga cauauccucu g 21 <210> 1144 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1144 uuugaugaug acauauccuc u 21 <210> 1145 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1145 guuugaugau gacauauccu c 21 <210> 1146 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1146 gguuugauga ugacauaucc u 21 <210> 1147 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1147 aaggguuuga ugaugacaua u 21 <210> 1148 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1148 caccaagggu uugaugauga c 21 <210> 1149 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1149 cacaccaagg guuugaugau g 21 <210> 1150 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1150 ucagacccac accaaggguu u 21 <210> 1151 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1151 cucagaccca caccaagggu u 21 <210> 1152 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1152 ccucagaccc acaccaaggg u 21 <210> 1153 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1153 accucagacc cacaccaagg g 21 <210> 1154 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1154 agaccucaga cccacaccaa g 21 <210> 1155 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1155 aagaccucag acccacacca a 21 <210> 1156 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1156 caagaccuca gacccacacc a 21 <210> 1157 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1157 ucaagaccuc agacccacac c 21 <210> 1158 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1158 gucaagaccu cagacccaca c 21 <210> 1159 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1159 gagucaagac cucagaccca c 21 <210> 1160 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1160 ugagucaaga ccucagaccc a 21 <210> 1161 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1161 uugagucaag accucagacc c 21 <210> 1162 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1162 cguugaguca agaccucaga c 21 <210> 1163 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1163 ucguugaguc aagaccucag a 21 <210> 1164 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1164 cucguugagu caagaccuca g 21 <210> 1165 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1165 ucucguugag ucaagaccuc a 21 <210> 1166 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1166 cucucguuga gucaagaccu c 21 <210> 1167 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1167 gcucucguug agucaagacc u 21 <210> 1168 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1168 ugcucucguu gagucaagac c 21 <210> 1169 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1169 gugcucucgu ugagucaaga c 21 <210> 1170 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1170 agugcucucg uugagucaag a 21 <210> 1171 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1171 aagugcucuc guugagucaa g 21 <210> 1172 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1172 caagugcucu cguugaguca a 21 <210> 1173 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1173 ucaagugcuc ucguugaguc a 21 <210> 1174 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1174 uucaagugcu cucguugagu c 21 <210> 1175 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1175 uuucaagugc ucucguugag u 21 <210> 1176 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1176 uuuucaagug cucucguuga g 21 <210> 1177 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1177 auuuucaagu gcucucguug a 21 <210> 1178 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1178 cauuuucaag ugcucucguu g 21 <210> 1179 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1179 ucauuuucaa gugcucucgu u 21 <210> 1180 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1180 uucauuuuca agugcucucg u 21 <210> 1181 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1181 uuucauuuuc aagugcucuc g 21 <210> 1182 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1182 auuucauuuu caagugcucu c 21 <210> 1183 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1183 cauuucauuu ucaagugcuc u 21 <210> 1184 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1184 ucauuucauu uucaagugcu c 21 <210> 1185 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1185 gucauuucau uuucaagugc u 21 <210> 1186 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1186 agucauuuca uuuucaagug c 21 <210> 1187 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1187 cagucauuuc auuuucaagu g 21 <210> 1188 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1188 acagucauuu cauuuucaag u 21 <210> 1189 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1189 gacagucauu ucauuuucaa g 21 <210> 1190 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1190 agacagucau uucauuuuca a 21 <210> 1191 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1191 uagacaguca uuucauuuuc a 21 <210> 1192 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1192 uuagacaguc auuucauuuu c 21 <210> 1193 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1193 cuuagacagu cauuucauuu u 21 <210> 1194 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1194 ucuuagacag ucauuucauu u 21 <210> 1195 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1195 cucuuagaca gucauuucau u 21 <210> 1196 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1196 ucucuuagac agucauuuca u 21 <210> 1197 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1197 aucucuuaga cagucauuuc a 21 <210> 1198 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1198 agaucucuua gacagucauu u 21 <210> 1199 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1199 cagaucucuu agacagucau u 21 <210> 1200 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1200 ccagaucucu uagacaguca u 21 <210> 1201 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1201 accagaucuc uuagacaguc a 21 <210> 1202 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1202 gaccagaucu cuuagacagu c 21 <210> 1203 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1203 ugaccagauc ucuuagacag u 21 <210> 1204 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1204 uugaccagau cucuuagaca g 21 <210> 1205 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1205 uuugaccaga ucucuuagac a 21 <210> 1206 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1206 cuuugaccag aucucuuaga c 21 <210> 1207 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1207 gcuuugacca gaucucuuag a 21 <210> 1208 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1208 ugcuuugacc agaucucuua g 21 <210> 1209 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1209 uugcuuugac cagaucucuu a 21 <210> 1210 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1210 guugcuuuga ccagaucucu u 21 <210> 1211 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1211 aguugcuuug accagaucuc u 21 <210> 1212 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1212 caguugcuuu gaccagaucu c 21 <210> 1213 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1213 ccaguugcuu ugaccagauc u 21 <210> 1214 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1214 uccaguugcu uugaccagau c 21 <210> 1215 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1215 auccaguugc uuugaccaga u 21 <210> 1216 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1216 uauccaguug cuuugaccag a 21 <210> 1217 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1217 guauccaguu gcuuugacca g 21 <210> 1218 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1218 aguauccagu ugcuuugacc a 21 <210> 1219 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1219 uaguauccag uugcuuugac c 21 <210> 1220 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1220 cuaguaucca guugcuuuga c 21 <210> 1221 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1221 ucuaguaucc aguugcuuug a 21 <210> 1222 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1222 aucuaguauc caguugcuuu g 21 <210> 1223 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1223 gaucuaguau ccaguugcuu u 21 <210> 1224 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1224 agaucuagua uccaguugcu u 21 <210> 1225 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1225 aagaucuagu auccaguugc u 21 <210> 1226 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1226 uaagaucuag uauccaguug c 21 <210> 1227 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1227 guaagaucua guauccaguu g 21 <210> 1228 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1228 uguaagaucu aguauccagu u 21 <210> 1229 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1229 auguaagauc uaguauccag u 21 <210> 1230 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1230 gauguaagau cuaguaucca g 21 <210> 1231 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1231 agauguaaga ucuaguaucc a 21 <210> 1232 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1232 cagauguaag aucuaguauc c 21 <210> 1233 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1233 ugcagaugua agaucuagua u 21 <210> 1234 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1234 cugcagaugu aagaucuagu a 21 <210> 1235 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1235 agcugcagau guaagaucua g 21 <210> 1236 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1236 gagcugcaga uguaagaucu a 21 <210> 1237 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1237 agagcugcag auguaagauc u 21 <210> 1238 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1238 aagagcugca gauguaagau c 21 <210> 1239 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1239 aaagagcugc agauguaaga u 21 <210> 1240 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1240 gaaagagcug cagauguaag a 21 <210> 1241 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1241 agaaagagcu gcagauguaa g 21 <210> 1242 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1242 aagaaagagc ugcagaugua a 21 <210> 1243 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1243 gaagaaagag cugcagaugu a 21 <210> 1244 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1244 agaagaaaga gcugcagaug u 21 <210> 1245 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1245 aagaagaaag agcugcagau g 21 <210> 1246 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1246 aaagaagaaa gagcugcaga u 21 <210> 1247 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1247 caaagaagaa agagcugcag a 21 <210> 1248 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1248 ucaaagaaga aagagcugca g 21 <210> 1249 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1249 uucaaagaag aaagagcugc a 21 <210> 1250 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1250 auucaaagaa gaaagagcug c 21 <210> 1251 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1251 aauucaaaga agaaagagcu g 21 <210> 1252 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1252 aaauucaaag aagaaagagc u 21 <210> 1253 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1253 gaaauucaaa gaagaaagag c 21 <210> 1254 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1254 ggaaauucaa agaagaaaga g 21 <210> 1255 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1255 aggaaauuca aagaagaaag a 21 <210> 1256 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1256 uaggaaauuc aaagaagaaa g 21 <210> 1257 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1257 auaggaaauu caaagaagaa a 21 <210> 1258 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1258 agauaggaaa uucaaagaag a 21 <210> 1259 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1259 cagauaggaa auucaaagaa g 21 <210> 1260 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1260 acagauagga aauucaaaga a 21 <210> 1261 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1261 uacagauagg aaauucaaag a 21 <210> 1262 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1262 auacagauag gaaauucaaa g 21 <210> 1263 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1263 cauacagaua ggaaauucaa a 21 <210> 1264 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1264 acauacagau aggaaauuca a 21 <210> 1265 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1265 agacauacag auaggaaauu c 21 <210> 1266 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1266 cagacauaca gauaggaaau u 21 <210> 1267 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1267 gcagacauac agauaggaaa u 21 <210> 1268 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1268 ggcagacaua cagauaggaa a 21 <210> 1269 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1269 aggcagacau acagauagga a 21 <210> 1270 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1270 uaggcagaca uacagauagg a 21 <210> 1271 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1271 uuaggcagac auacagauag g 21 <210> 1272 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1272 auuaggcaga cauacagaua g 21 <210> 1273 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1273 aauuaggcag acauacagau a 21 <210> 1274 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1274 uaauuaggca gacauacaga u 21 <210> 1275 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1275 uuaauuaggc agacauacag a 21 <210> 1276 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1276 uuuaauuagg cagacauaca g 21 <210> 1277 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1277 uuuuaauuag gcagacauac a 21 <210> 1278 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1278 uuuuuaauua ggcagacaua c 21 <210> 1279 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1279 uuuuuuaauu aggcagacau a 21 <210> 1280 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1280 uuuuuuuaau uaggcagaca u 21 <210> 1281 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1281 auuuuuuuaa uuaggcagac a 21 <210> 1282 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1282 uauuuuuuua auuaggcaga c 21 <210> 1283 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1283 auauuuuuuu aauuaggcag a 21 <210> 1284 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1284 uauauuuuuu uaauuaggca g 21 <210> 1285 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1285 auauauuuuu uuaauuaggc a 21 <210> 1286 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1286 uauauauuuu uuuaauuagg c 21 <210> 1287 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 1287 uacaauauau auuuuuuuaa u 21 <210> 1288 <211> 19 <212> RNA <213> Homo sapiens <400> 1288 gcaugaauau cagacgcua 19 <210> 1289 <211> 19 <212> RNA <213> Homo sapiens <400> 1289 caugaauauc agacgcuag 19 <210> 1290 <211> 19 <212> RNA <213> Homo sapiens <400> 1290 auaucagacg cuaggggga 19 <210> 1291 <211> 19 <212> RNA <213> Homo sapiens <400> 1291 cuagggggac agccacugu 19 <210> 1292 <211> 19 <212> RNA <213> Homo sapiens <400> 1292 agggggacag ccacugugu 19 <210> 1293 <211> 19 <212> RNA <213> Homo sapiens <400> 1293 ggggacagcc acuguguug 19 <210> 1294 <211> 19 <212> RNA <213> Homo sapiens <400> 1294 gggacagcca cuguguugu 19 <210> 1295 <211> 19 <212> RNA <213> Homo sapiens <400> 1295 ggacagccac uguguuguc 19 <210> 1296 <211> 19 <212> RNA <213> Homo sapiens <400> 1296 gacagccacu guguugucu 19 <210> 1297 <211> 19 <212> RNA <213> Homo sapiens <400> 1297 gccacugugu ugucugcua 19 <210> 1298 <211> 19 <212> RNA <213> Homo sapiens <400> 1298 ccacuguguu gucugcuac 19 <210> 1299 <211> 19 <212> RNA <213> Homo sapiens <400> 1299 cacuguguug ucugcuacc 19 <210> 1300 <211> 19 <212> RNA <213> Homo sapiens <400> 1300 cuguguuguc ugcuacccu 19 <210> 1301 <211> 19 <212> RNA <213> Homo sapiens <400> 1301 uguguugucu gcuacccuc 19 <210> 1302 <211> 19 <212> RNA <213> Homo sapiens <400> 1302 guguugucug cuacccuca 19 <210> 1303 <211> 19 <212> RNA <213> Homo sapiens <400> 1303 uguugucugc uacccucau 19 <210> 1304 <211> 19 <212> RNA <213> Homo sapiens <400> 1304 guugucugcu acccucauc 19 <210> 1305 <211> 19 <212> RNA <213> Homo sapiens <400> 1305 gucugcuacc cucauccug 19 <210> 1306 <211> 19 <212> RNA <213> Homo sapiens <400> 1306 cugcuacccu cauccuggu 19 <210> 1307 <211> 19 <212> RNA <213> Homo sapiens <400> 1307 gcuacccuca uccugguca 19 <210> 1308 <211> 19 <212> RNA <213> Homo sapiens <400> 1308 cuacccucau ccuggucac 19 <210> 1309 <211> 19 <212> RNA <213> Homo sapiens <400> 1309 uacccucauc cuggucacu 19 <210> 1310 <211> 19 <212> RNA <213> Homo sapiens <400> 1310 acccucaucc uggucacug 19 <210> 1311 <211> 19 <212> RNA <213> Homo sapiens <400> 1311 cccucauccu ggucacugc 19 <210> 1312 <211> 19 <212> RNA <213> Homo sapiens <400> 1312 ccucauccug gucacugcu 19 <210> 1313 <211> 19 <212> RNA <213> Homo sapiens <400> 1313 cucauccugg ucacugcuu 19 <210> 1314 <211> 19 <212> RNA <213> Homo sapiens <400> 1314 cauccugguc acugcuucu 19 <210> 1315 <211> 19 <212> RNA <213> Homo sapiens <400> 1315 auccugguca cugcuucug 19 <210> 1316 <211> 19 <212> RNA <213> Homo sapiens <400> 1316 uccuggucac ugcuucugc 19 <210> 1317 <211> 19 <212> RNA <213> Homo sapiens <400> 1317 ccuggucacu gcuucugcu 19 <210> 1318 <211> 19 <212> RNA <213> Homo sapiens <400> 1318 cuggucacug cuucugcua 19 <210> 1319 <211> 19 <212> RNA <213> Homo sapiens <400> 1319 uggucacugc uucugcuau 19 <210> 1320 <211> 19 <212> RNA <213> Homo sapiens <400> 1320 ggucacugcu ucugcuaua 19 <210> 1321 <211> 19 <212> RNA <213> Homo sapiens <400> 1321 gucacugcuu cugcuauaa 19 <210> 1322 <211> 19 <212> RNA <213> Homo sapiens <400> 1322 cacugcuucu gcuauaaca 19 <210> 1323 <211> 19 <212> RNA <213> Homo sapiens <400> 1323 acugcuucug cuauaacag 19 <210> 1324 <211> 19 <212> RNA <213> Homo sapiens <400> 1324 cugcuucugc uauaacagc 19 <210> 1325 <211> 19 <212> RNA <213> Homo sapiens <400> 1325 gcuucugcua uaacagccc 19 <210> 1326 <211> 19 <212> RNA <213> Homo sapiens <400> 1326 cuucugcuau aacagcccu 19 <210> 1327 <211> 19 <212> RNA <213> Homo sapiens <400> 1327 uucugcuaua acagcccua 19 <210> 1328 <211> 19 <212> RNA <213> Homo sapiens <400> 1328 ucugcuauaa cagcccuag 19 <210> 1329 <211> 19 <212> RNA <213> Homo sapiens <400> 1329 cugcuauaac agcccuagg 19 <210> 1330 <211> 19 <212> RNA <213> Homo sapiens <400> 1330 ugcuauaaca gcccuaggc 19 <210> 1331 <211> 19 <212> RNA <213> Homo sapiens <400> 1331 gcuauaacag cccuaggcc 19 <210> 1332 <211> 19 <212> RNA <213> Homo sapiens <400> 1332 cuauaacagc ccuaggcca 19 <210> 1333 <211> 19 <212> RNA <213> Homo sapiens <400> 1333 uauaacagcc cuaggccag 19 <210> 1334 <211> 19 <212> RNA <213> Homo sapiens <400> 1334 auaacagccc uaggccagg 19 <210> 1335 <211> 19 <212> RNA <213> Homo sapiens <400> 1335 uaacagcccu aggccagga 19 <210> 1336 <211> 19 <212> RNA <213> Homo sapiens <400> 1336 acagcccuag gccaggaau 19 <210> 1337 <211> 19 <212> RNA <213> Homo sapiens <400> 1337 cagcccuagg ccaggaaua 19 <210> 1338 <211> 19 <212> RNA <213> Homo sapiens <400> 1338 agcccuaggc caggaauau 19 <210> 1339 <211> 19 <212> RNA <213> Homo sapiens <400> 1339 gcccuaggcc aggaauaug 19 <210> 1340 <211> 19 <212> RNA <213> Homo sapiens <400> 1340 cccuaggcca ggaauauga 19 <210> 1341 <211> 19 <212> RNA <213> Homo sapiens <400> 1341 ccuaggccag gaauaugaa 19 <210> 1342 <211> 19 <212> RNA <213> Homo sapiens <400> 1342 cuaggccagg aauaugaac 19 <210> 1343 <211> 19 <212> RNA <213> Homo sapiens <400> 1343 uaggccagga auaugaaca 19 <210> 1344 <211> 19 <212> RNA <213> Homo sapiens <400> 1344 aggccaggaa uaugaacaa 19 <210> 1345 <211> 19 <212> RNA <213> Homo sapiens <400> 1345 ggccaggaau augaacaag 19 <210> 1346 <211> 19 <212> RNA <213> Homo sapiens <400> 1346 gccaggaaua ugaacaagc 19 <210> 1347 <211> 19 <212> RNA <213> Homo sapiens <400> 1347 ccaggaauau gaacaagcc 19 <210> 1348 <211> 19 <212> RNA <213> Homo sapiens <400> 1348 caggaauaug aacaagccg 19 <210> 1349 <211> 19 <212> RNA <213> Homo sapiens <400> 1349 aggaauauga acaagccgc 19 <210> 1350 <211> 19 <212> RNA <213> Homo sapiens <400> 1350 ggaauaugaa caagccgcu 19 <210> 1351 <211> 19 <212> RNA <213> Homo sapiens <400> 1351 gaauaugaac aagccgcug 19 <210> 1352 <211> 19 <212> RNA <213> Homo sapiens <400> 1352 aauaugaaca agccgcugc 19 <210> 1353 <211> 19 <212> RNA <213> Homo sapiens <400> 1353 auaugaacaa gccgcugcu 19 <210> 1354 <211> 19 <212> RNA <213> Homo sapiens <400> 1354 uaugaacaag ccgcugcuu 19 <210> 1355 <211> 19 <212> RNA <213> Homo sapiens <400> 1355 augaacaagc cgcugcuuu 19 <210> 1356 <211> 19 <212> RNA <213> Homo sapiens <400> 1356 ugaacaagcc gcugcuuug 19 <210> 1357 <211> 19 <212> RNA <213> Homo sapiens <400> 1357 gaacaagccg cugcuuugg 19 <210> 1358 <211> 19 <212> RNA <213> Homo sapiens <400> 1358 aacaagccgc ugcuuugga 19 <210> 1359 <211> 19 <212> RNA <213> Homo sapiens <400> 1359 acaagccgcu gcuuuggau 19 <210> 1360 <211> 19 <212> RNA <213> Homo sapiens <400> 1360 caagccgcug cuuuggauc 19 <210> 1361 <211> 19 <212> RNA <213> Homo sapiens <400> 1361 aagccgcugc uuuggaucu 19 <210> 1362 <211> 19 <212> RNA <213> Homo sapiens <400> 1362 agccgcugcu uuggaucuc 19 <210> 1363 <211> 19 <212> RNA <213> Homo sapiens <400> 1363 gccgcugcuu uggaucucu 19 <210> 1364 <211> 19 <212> RNA <213> Homo sapiens <400> 1364 ccgcugcuuu ggaucucug 19 <210> 1365 <211> 19 <212> RNA <213> Homo sapiens <400> 1365 cgcugcuuug gaucucugu 19 <210> 1366 <211> 19 <212> RNA <213> Homo sapiens <400> 1366 gcugcuuugg aucucuguc 19 <210> 1367 <211> 19 <212> RNA <213> Homo sapiens <400> 1367 cugcuuugga ucucugucc 19 <210> 1368 <211> 19 <212> RNA <213> Homo sapiens <400> 1368 ugcuuuggau cucuguccu 19 <210> 1369 <211> 19 <212> RNA <213> Homo sapiens <400> 1369 gcuuuggauc ucuguccuc 19 <210> 1370 <211> 19 <212> RNA <213> Homo sapiens <400> 1370 cuuuggaucu cuguccuca 19 <210> 1371 <211> 19 <212> RNA <213> Homo sapiens <400> 1371 uuuggaucuc uguccucac 19 <210> 1372 <211> 19 <212> RNA <213> Homo sapiens <400> 1372 ggaucucugu ccucaccag 19 <210> 1373 <211> 19 <212> RNA <213> Homo sapiens <400> 1373 gaucucuguc cucaccagc 19 <210> 1374 <211> 19 <212> RNA <213> Homo sapiens <400> 1374 cucuguccuc accagccuc 19 <210> 1375 <211> 19 <212> RNA <213> Homo sapiens <400> 1375 cuguccucac cagccuccu 19 <210> 1376 <211> 19 <212> RNA <213> Homo sapiens <400> 1376 uguccucacc agccuccug 19 <210> 1377 <211> 19 <212> RNA <213> Homo sapiens <400> 1377 guccucacca gccuccugg 19 <210> 1378 <211> 19 <212> RNA <213> Homo sapiens <400> 1378 uccucaccag ccuccugga 19 <210> 1379 <211> 19 <212> RNA <213> Homo sapiens <400> 1379 cucaccagcc uccuggaag 19 <210> 1380 <211> 19 <212> RNA <213> Homo sapiens <400> 1380 ucaccagccu ccuggaagc 19 <210> 1381 <211> 19 <212> RNA <213> Homo sapiens <400> 1381 accagccucc uggaagccu 19 <210> 1382 <211> 19 <212> RNA <213> Homo sapiens <400> 1382 ccagccuccu ggaagccuu 19 <210> 1383 <211> 19 <212> RNA <213> Homo sapiens <400> 1383 cagccuccug gaagccuuu 19 <210> 1384 <211> 19 <212> RNA <213> Homo sapiens <400> 1384 agccuccugg aagccuuug 19 <210> 1385 <211> 19 <212> RNA <213> Homo sapiens <400> 1385 gccuccugga agccuuugc 19 <210> 1386 <211> 19 <212> RNA <213> Homo sapiens <400> 1386 ccuccuggaa gccuuugcu 19 <210> 1387 <211> 19 <212> RNA <213> Homo sapiens <400> 1387 cuccuggaag ccuuugcuc 19 <210> 1388 <211> 19 <212> RNA <213> Homo sapiens <400> 1388 uccuggaagc cuuugcuca 19 <210> 1389 <211> 19 <212> RNA <213> Homo sapiens <400> 1389 ccuggaagcc uuugcucac 19 <210> 1390 <211> 19 <212> RNA <213> Homo sapiens <400> 1390 cuggaagccu uugcucaca 19 <210> 1391 <211> 19 <212> RNA <213> Homo sapiens <400> 1391 ggaagccuuu gcucacaca 19 <210> 1392 <211> 19 <212> RNA <213> Homo sapiens <400> 1392 gaagccuuug cucacacag 19 <210> 1393 <211> 19 <212> RNA <213> Homo sapiens <400> 1393 aagccuuugc ucacacaga 19 <210> 1394 <211> 19 <212> RNA <213> Homo sapiens <400> 1394 agccuuugcu cacacagac 19 <210> 1395 <211> 19 <212> RNA <213> Homo sapiens <400> 1395 gccuuugcuc acacagacc 19 <210> 1396 <211> 19 <212> RNA <213> Homo sapiens <400> 1396 ccuuugcuca cacagaccu 19 <210> 1397 <211> 19 <212> RNA <213> Homo sapiens <400> 1397 cuuugcucac acagaccuc 19 <210> 1398 <211> 19 <212> RNA <213> Homo sapiens <400> 1398 uuugcucaca cagaccuca 19 <210> 1399 <211> 19 <212> RNA <213> Homo sapiens <400> 1399 ugcucacaca gaccucagu 19 <210> 1400 <211> 19 <212> RNA <213> Homo sapiens <400> 1400 cucacacaga ccucagugg 19 <210> 1401 <211> 19 <212> RNA <213> Homo sapiens <400> 1401 cacacagacc ucaguggga 19 <210> 1402 <211> 19 <212> RNA <213> Homo sapiens <400> 1402 acacagaccu cagugggaa 19 <210> 1403 <211> 19 <212> RNA <213> Homo sapiens <400> 1403 cacagaccuc agugggaag 19 <210> 1404 <211> 19 <212> RNA <213> Homo sapiens <400> 1404 agaccucagu gggaaggug 19 <210> 1405 <211> 19 <212> RNA <213> Homo sapiens <400> 1405 gaccucagug ggaaggugu 19 <210> 1406 <211> 19 <212> RNA <213> Homo sapiens <400> 1406 accucagugg gaagguguu 19 <210> 1407 <211> 19 <212> RNA <213> Homo sapiens <400> 1407 ccucaguggg aagguguuu 19 <210> 1408 <211> 19 <212> RNA <213> Homo sapiens <400> 1408 cucaguggga agguguuug 19 <210> 1409 <211> 19 <212> RNA <213> Homo sapiens <400> 1409 ucagugggaa gguguuugu 19 <210> 1410 <211> 19 <212> RNA <213> Homo sapiens <400> 1410 cagugggaag guguuugua 19 <210> 1411 <211> 19 <212> RNA <213> Homo sapiens <400> 1411 agugggaagg uguuuguau 19 <210> 1412 <211> 19 <212> RNA <213> Homo sapiens <400> 1412 gugggaaggu guuuguauu 19 <210> 1413 <211> 19 <212> RNA <213> Homo sapiens <400> 1413 ugggaaggug uuuguauuu 19 <210> 1414 <211> 19 <212> RNA <213> Homo sapiens <400> 1414 gggaaggugu uuguauuuc 19 <210> 1415 <211> 19 <212> RNA <213> Homo sapiens <400> 1415 ggaagguguu uguauuucc 19 <210> 1416 <211> 19 <212> RNA <213> Homo sapiens <400> 1416 gaagguguuu guauuuccu 19 <210> 1417 <211> 19 <212> RNA <213> Homo sapiens <400> 1417 aagguguuug uauuuccua 19 <210> 1418 <211> 19 <212> RNA <213> Homo sapiens <400> 1418 agguguuugu auuuccuag 19 <210> 1419 <211> 19 <212> RNA <213> Homo sapiens <400> 1419 gguguuugua uuuccuaga 19 <210> 1420 <211> 19 <212> RNA <213> Homo sapiens <400> 1420 guguuuguau uuccuagag 19 <210> 1421 <211> 19 <212> RNA <213> Homo sapiens <400> 1421 uguuuguauu uccuagaga 19 <210> 1422 <211> 19 <212> RNA <213> Homo sapiens <400> 1422 guuuguauuu ccuagagaa 19 <210> 1423 <211> 19 <212> RNA <213> Homo sapiens <400> 1423 uuuguauuuc cuagagaau 19 <210> 1424 <211> 19 <212> RNA <213> Homo sapiens <400> 1424 uuguauuucc uagagaauc 19 <210> 1425 <211> 19 <212> RNA <213> Homo sapiens <400> 1425 uguauuuccu agagaaucu 19 <210> 1426 <211> 19 <212> RNA <213> Homo sapiens <400> 1426 guauuuccua gagaaucug 19 <210> 1427 <211> 19 <212> RNA <213> Homo sapiens <400> 1427 uauuuccuag agaaucugu 19 <210> 1428 <211> 19 <212> RNA <213> Homo sapiens <400> 1428 auuuccuaga gaaucuguu 19 <210> 1429 <211> 19 <212> RNA <213> Homo sapiens <400> 1429 uuuccuagag aaucuguua 19 <210> 1430 <211> 19 <212> RNA <213> Homo sapiens <400> 1430 uccuagagaa ucuguuacu 19 <210> 1431 <211> 19 <212> RNA <213> Homo sapiens <400> 1431 ccuagagaau cuguuacug 19 <210> 1432 <211> 19 <212> RNA <213> Homo sapiens <400> 1432 cuagagaauc uguuacuga 19 <210> 1433 <211> 19 <212> RNA <213> Homo sapiens <400> 1433 uagagaaucu guuacugau 19 <210> 1434 <211> 19 <212> RNA <213> Homo sapiens <400> 1434 agagaaucug uuacugauc 19 <210> 1435 <211> 19 <212> RNA <213> Homo sapiens <400> 1435 gagaaucugu uacugauca 19 <210> 1436 <211> 19 <212> RNA <213> Homo sapiens <400> 1436 agaaucuguu acugaucau 19 <210> 1437 <211> 19 <212> RNA <213> Homo sapiens <400> 1437 gaaucuguua cugaucaug 19 <210> 1438 <211> 19 <212> RNA <213> Homo sapiens <400> 1438 aaucuguuac ugaucaugu 19 <210> 1439 <211> 19 <212> RNA <213> Homo sapiens <400> 1439 aucuguuacu gaucaugua 19 <210> 1440 <211> 19 <212> RNA <213> Homo sapiens <400> 1440 ucuguuacug aucauguaa 19 <210> 1441 <211> 19 <212> RNA <213> Homo sapiens <400> 1441 cuguuacuga ucauguaaa 19 <210> 1442 <211> 19 <212> RNA <213> Homo sapiens <400> 1442 uguuacugau cauguaaac 19 <210> 1443 <211> 19 <212> RNA <213> Homo sapiens <400> 1443 guuacugauc auguaaacu 19 <210> 1444 <211> 19 <212> RNA <213> Homo sapiens <400> 1444 acugaucaug uaaacuuga 19 <210> 1445 <211> 19 <212> RNA <213> Homo sapiens <400> 1445 cugaucaugu aaacuugau 19 <210> 1446 <211> 19 <212> RNA <213> Homo sapiens <400> 1446 ugaucaugua aacuugauc 19 <210> 1447 <211> 19 <212> RNA <213> Homo sapiens <400> 1447 gaucauguaa acuugauca 19 <210> 1448 <211> 19 <212> RNA <213> Homo sapiens <400> 1448 ucauguaaac uugaucaca 19 <210> 1449 <211> 19 <212> RNA <213> Homo sapiens <400> 1449 cauguaaacu ugaucacac 19 <210> 1450 <211> 19 <212> RNA <213> Homo sapiens <400> 1450 uaaacuugau cacaccgcu 19 <210> 1451 <211> 19 <212> RNA <213> Homo sapiens <400> 1451 aaacuugauc acaccgcug 19 <210> 1452 <211> 19 <212> RNA <213> Homo sapiens <400> 1452 acuugaucac accgcugga 19 <210> 1453 <211> 19 <212> RNA <213> Homo sapiens <400> 1453 uugaucacac cgcuggaga 19 <210> 1454 <211> 19 <212> RNA <213> Homo sapiens <400> 1454 ugaucacacc gcuggagaa 19 <210> 1455 <211> 19 <212> RNA <213> Homo sapiens <400> 1455 gaucacaccg cuggagaag 19 <210> 1456 <211> 19 <212> RNA <213> Homo sapiens <400> 1456 cacaccgcug gagaagccu 19 <210> 1457 <211> 19 <212> RNA <213> Homo sapiens <400> 1457 acaccgcugg agaagccuc 19 <210> 1458 <211> 19 <212> RNA <213> Homo sapiens <400> 1458 caccgcugga gaagccucu 19 <210> 1459 <211> 19 <212> RNA <213> Homo sapiens <400> 1459 accgcuggag aagccucua 19 <210> 1460 <211> 19 <212> RNA <213> Homo sapiens <400> 1460 ccgcuggaga agccucuac 19 <210> 1461 <211> 19 <212> RNA <213> Homo sapiens <400> 1461 cgcuggagaa gccucuaca 19 <210> 1462 <211> 19 <212> RNA <213> Homo sapiens <400> 1462 gcuggagaag ccucuacag 19 <210> 1463 <211> 19 <212> RNA <213> Homo sapiens <400> 1463 cuggagaagc cucuacaga 19 <210> 1464 <211> 19 <212> RNA <213> Homo sapiens <400> 1464 uggagaagcc ucuacagaa 19 <210> 1465 <211> 19 <212> RNA <213> Homo sapiens <400> 1465 ggagaagccu cuacagaac 19 <210> 1466 <211> 19 <212> RNA <213> Homo sapiens <400> 1466 gagaagccuc uacagaacu 19 <210> 1467 <211> 19 <212> RNA <213> Homo sapiens <400> 1467 agaagccucu acagaacuu 19 <210> 1468 <211> 19 <212> RNA <213> Homo sapiens <400> 1468 gaagccucua cagaacuuu 19 <210> 1469 <211> 19 <212> RNA <213> Homo sapiens <400> 1469 aagccucuac agaacuuua 19 <210> 1470 <211> 19 <212> RNA <213> Homo sapiens <400> 1470 agccucuaca gaacuuuac 19 <210> 1471 <211> 19 <212> RNA <213> Homo sapiens <400> 1471 gccucuacag aacuuuacc 19 <210> 1472 <211> 19 <212> RNA <213> Homo sapiens <400> 1472 ccucuacaga acuuuaccu 19 <210> 1473 <211> 19 <212> RNA <213> Homo sapiens <400> 1473 cucuacagaa cuuuaccuu 19 <210> 1474 <211> 19 <212> RNA <213> Homo sapiens <400> 1474 ucuacagaac uuuaccuug 19 <210> 1475 <211> 19 <212> RNA <213> Homo sapiens <400> 1475 cuacagaacu uuaccuugu 19 <210> 1476 <211> 19 <212> RNA <213> Homo sapiens <400> 1476 uacagaacuu uaccuugug 19 <210> 1477 <211> 19 <212> RNA <213> Homo sapiens <400> 1477 acagaacuuu accuugugu 19 <210> 1478 <211> 19 <212> RNA <213> Homo sapiens <400> 1478 cagaacuuua ccuuguguu 19 <210> 1479 <211> 19 <212> RNA <213> Homo sapiens <400> 1479 agaacuuuac cuuguguuu 19 <210> 1480 <211> 19 <212> RNA <213> Homo sapiens <400> 1480 gaacuuuacc uuguguuuu 19 <210> 1481 <211> 19 <212> RNA <213> Homo sapiens <400> 1481 aacuuuaccu uguguuuuc 19 <210> 1482 <211> 19 <212> RNA <213> Homo sapiens <400> 1482 cuuuaccuug uguuuucga 19 <210> 1483 <211> 19 <212> RNA <213> Homo sapiens <400> 1483 accuuguguu uucgagccu 19 <210> 1484 <211> 19 <212> RNA <213> Homo sapiens <400> 1484 ccuuguguuu ucgagccua 19 <210> 1485 <211> 19 <212> RNA <213> Homo sapiens <400> 1485 cuuguguuuu cgagccuau 19 <210> 1486 <211> 19 <212> RNA <213> Homo sapiens <400> 1486 uuguguuuuc gagccuaua 19 <210> 1487 <211> 19 <212> RNA <213> Homo sapiens <400> 1487 guguuuucga gccuauagu 19 <210> 1488 <211> 19 <212> RNA <213> Homo sapiens <400> 1488 guuuucgagc cuauaguga 19 <210> 1489 <211> 19 <212> RNA <213> Homo sapiens <400> 1489 uuuucgagcc uauagugau 19 <210> 1490 <211> 19 <212> RNA <213> Homo sapiens <400> 1490 cgagccuaua gugaucucu 19 <210> 1491 <211> 19 <212> RNA <213> Homo sapiens <400> 1491 gagccuauag ugaucucuc 19 <210> 1492 <211> 19 <212> RNA <213> Homo sapiens <400> 1492 agccuauagu gaucucucu 19 <210> 1493 <211> 19 <212> RNA <213> Homo sapiens <400> 1493 gccuauagug aucucucuc 19 <210> 1494 <211> 19 <212> RNA <213> Homo sapiens <400> 1494 ccuauaguga ucucucucg 19 <210> 1495 <211> 19 <212> RNA <213> Homo sapiens <400> 1495 cuauagugau cucucucgu 19 <210> 1496 <211> 19 <212> RNA <213> Homo sapiens <400> 1496 uauagugauc ucucucgug 19 <210> 1497 <211> 19 <212> RNA <213> Homo sapiens <400> 1497 agugaucucu cucgugccu 19 <210> 1498 <211> 19 <212> RNA <213> Homo sapiens <400> 1498 gugaucucuc ucgugccua 19 <210> 1499 <211> 19 <212> RNA <213> Homo sapiens <400> 1499 ugaucucucu cgugccuac 19 <210> 1500 <211> 19 <212> RNA <213> Homo sapiens <400> 1500 gaucucucuc gugccuaca 19 <210> 1501 <211> 19 <212> RNA <213> Homo sapiens <400> 1501 cucucgugcc uacagccuc 19 <210> 1502 <211> 19 <212> RNA <213> Homo sapiens <400> 1502 ucucgugccu acagccucu 19 <210> 1503 <211> 19 <212> RNA <213> Homo sapiens <400> 1503 cucgugccua cagccucuu 19 <210> 1504 <211> 19 <212> RNA <213> Homo sapiens <400> 1504 cgugccuaca gccucuucu 19 <210> 1505 <211> 19 <212> RNA <213> Homo sapiens <400> 1505 gugccuacag ccucuucuc 19 <210> 1506 <211> 19 <212> RNA <213> Homo sapiens <400> 1506 gccuacagcc ucuucuccu 19 <210> 1507 <211> 19 <212> RNA <213> Homo sapiens <400> 1507 ccuacagccu cuucuccua 19 <210> 1508 <211> 19 <212> RNA <213> Homo sapiens <400> 1508 cuacagccuc uucuccuac 19 <210> 1509 <211> 19 <212> RNA <213> Homo sapiens <400> 1509 uacagccucu ucuccuaca 19 <210> 1510 <211> 19 <212> RNA <213> Homo sapiens <400> 1510 acagccucuu cuccuacaa 19 <210> 1511 <211> 19 <212> RNA <213> Homo sapiens <400> 1511 cagccucuuc uccuacaau 19 <210> 1512 <211> 19 <212> RNA <213> Homo sapiens <400> 1512 agccucuucu ccuacaaua 19 <210> 1513 <211> 19 <212> RNA <213> Homo sapiens <400> 1513 gccucuucuc cuacaauac 19 <210> 1514 <211> 19 <212> RNA <213> Homo sapiens <400> 1514 ccucuucucc uacaauacc 19 <210> 1515 <211> 19 <212> RNA <213> Homo sapiens <400> 1515 ucuucuccua caauaccca 19 <210> 1516 <211> 19 <212> RNA <213> Homo sapiens <400> 1516 ucuccuacaa uacccaagg 19 <210> 1517 <211> 19 <212> RNA <213> Homo sapiens <400> 1517 cuccuacaau acccaaggc 19 <210> 1518 <211> 19 <212> RNA <213> Homo sapiens <400> 1518 uccuacaaua cccaaggca 19 <210> 1519 <211> 19 <212> RNA <213> Homo sapiens <400> 1519 ccuacaauac ccaaggcag 19 <210> 1520 <211> 19 <212> RNA <213> Homo sapiens <400> 1520 cuacaauacc caaggcagg 19 <210> 1521 <211> 19 <212> RNA <213> Homo sapiens <400> 1521 caauacccaa ggcagggau 19 <210> 1522 <211> 19 <212> RNA <213> Homo sapiens <400> 1522 auacccaagg cagggauaa 19 <210> 1523 <211> 19 <212> RNA <213> Homo sapiens <400> 1523 uacccaaggc agggauaau 19 <210> 1524 <211> 19 <212> RNA <213> Homo sapiens <400> 1524 ccaaggcagg gauaaugag 19 <210> 1525 <211> 19 <212> RNA <213> Homo sapiens <400> 1525 aaggcaggga uaaugagcu 19 <210> 1526 <211> 19 <212> RNA <213> Homo sapiens <400> 1526 aggcagggau aaugagcua 19 <210> 1527 <211> 19 <212> RNA <213> Homo sapiens <400> 1527 gcagggauaa ugagcuacu 19 <210> 1528 <211> 19 <212> RNA <213> Homo sapiens <400> 1528 cagggauaau gagcuacua 19 <210> 1529 <211> 19 <212> RNA <213> Homo sapiens <400> 1529 agggauaaug agcuacuag 19 <210> 1530 <211> 19 <212> RNA <213> Homo sapiens <400> 1530 gggauaauga gcuacuagu 19 <210> 1531 <211> 19 <212> RNA <213> Homo sapiens <400> 1531 ggauaaugag cuacuaguu 19 <210> 1532 <211> 19 <212> RNA <213> Homo sapiens <400> 1532 gauaaugagc uacuaguuu 19 <210> 1533 <211> 19 <212> RNA <213> Homo sapiens <400> 1533 auaaugagcu acuaguuua 19 <210> 1534 <211> 19 <212> RNA <213> Homo sapiens <400> 1534 uaaugagcua cuaguuuau 19 <210> 1535 <211> 19 <212> RNA <213> Homo sapiens <400> 1535 augagcuacu aguuuauaa 19 <210> 1536 <211> 19 <212> RNA <213> Homo sapiens <400> 1536 ugagcuacua guuuauaaa 19 <210> 1537 <211> 19 <212> RNA <213> Homo sapiens <400> 1537 gagcuacuag uuuauaaag 19 <210> 1538 <211> 19 <212> RNA <213> Homo sapiens <400> 1538 agcuacuagu uuauaaaga 19 <210> 1539 <211> 19 <212> RNA <213> Homo sapiens <400> 1539 gcuacuaguu uauaaagaa 19 <210> 1540 <211> 19 <212> RNA <213> Homo sapiens <400> 1540 cuacuaguuu auaaagaaa 19 <210> 1541 <211> 19 <212> RNA <213> Homo sapiens <400> 1541 aguuuauaaa gaaagaguu 19 <210> 1542 <211> 19 <212> RNA <213> Homo sapiens <400> 1542 aagaaagagu uggagagua 19 <210> 1543 <211> 19 <212> RNA <213> Homo sapiens <400> 1543 agaaagaguu ggagaguau 19 <210> 1544 <211> 19 <212> RNA <213> Homo sapiens <400> 1544 gaaagaguug gagaguaua 19 <210> 1545 <211> 19 <212> RNA <213> Homo sapiens <400> 1545 aagaguugga gaguauagu 19 <210> 1546 <211> 19 <212> RNA <213> Homo sapiens <400> 1546 agaguuggag aguauaguc 19 <210> 1547 <211> 19 <212> RNA <213> Homo sapiens <400> 1547 gaguuggaga guauagucu 19 <210> 1548 <211> 19 <212> RNA <213> Homo sapiens <400> 1548 aguuggagag uauagucua 19 <210> 1549 <211> 19 <212> RNA <213> Homo sapiens <400> 1549 guuggagagu auagucuau 19 <210> 1550 <211> 19 <212> RNA <213> Homo sapiens <400> 1550 uuggagagua uagucuaua 19 <210> 1551 <211> 19 <212> RNA <213> Homo sapiens <400> 1551 uggagaguau agucuauac 19 <210> 1552 <211> 19 <212> RNA <213> Homo sapiens <400> 1552 ggagaguaua gucuauaca 19 <210> 1553 <211> 19 <212> RNA <213> Homo sapiens <400> 1553 gagaguauag ucuauacau 19 <210> 1554 <211> 19 <212> RNA <213> Homo sapiens <400> 1554 agaguauagu cuauacauu 19 <210> 1555 <211> 19 <212> RNA <213> Homo sapiens <400> 1555 gaguauaguc uauacauug 19 <210> 1556 <211> 19 <212> RNA <213> Homo sapiens <400> 1556 aguauagucu auacauugg 19 <210> 1557 <211> 19 <212> RNA <213> Homo sapiens <400> 1557 guauagucua uacauugga 19 <210> 1558 <211> 19 <212> RNA <213> Homo sapiens <400> 1558 gucuauacau uggaagaca 19 <210> 1559 <211> 19 <212> RNA <213> Homo sapiens <400> 1559 cuauacauug gaagacaca 19 <210> 1560 <211> 19 <212> RNA <213> Homo sapiens <400> 1560 uauacauugg aagacacaa 19 <210> 1561 <211> 19 <212> RNA <213> Homo sapiens <400> 1561 auacauugga agacacaaa 19 <210> 1562 <211> 19 <212> RNA <213> Homo sapiens <400> 1562 acauuggaag acacaaagu 19 <210> 1563 <211> 19 <212> RNA <213> Homo sapiens <400> 1563 cauuggaaga cacaaaguu 19 <210> 1564 <211> 19 <212> RNA <213> Homo sapiens <400> 1564 auuggaagac acaaaguua 19 <210> 1565 <211> 19 <212> RNA <213> Homo sapiens <400> 1565 uggaagacac aaaguuaca 19 <210> 1566 <211> 19 <212> RNA <213> Homo sapiens <400> 1566 ggaagacaca aaguuacau 19 <210> 1567 <211> 19 <212> RNA <213> Homo sapiens <400> 1567 gaagacacaa aguuacauc 19 <210> 1568 <211> 19 <212> RNA <213> Homo sapiens <400> 1568 aagacacaaa guuacaucc 19 <210> 1569 <211> 19 <212> RNA <213> Homo sapiens <400> 1569 agacacaaag uuacaucca 19 <210> 1570 <211> 19 <212> RNA <213> Homo sapiens <400> 1570 gacacaaagu uacauccaa 19 <210> 1571 <211> 19 <212> RNA <213> Homo sapiens <400> 1571 acacaaaguu acauccaaa 19 <210> 1572 <211> 19 <212> RNA <213> Homo sapiens <400> 1572 cacaaaguua cauccaaag 19 <210> 1573 <211> 19 <212> RNA <213> Homo sapiens <400> 1573 caaaguuaca uccaaaguu 19 <210> 1574 <211> 19 <212> RNA <213> Homo sapiens <400> 1574 aaaguuacau ccaaaguua 19 <210> 1575 <211> 19 <212> RNA <213> Homo sapiens <400> 1575 aaguuacauc caaaguuau 19 <210> 1576 <211> 19 <212> RNA <213> Homo sapiens <400> 1576 aguuacaucc aaaguuauc 19 <210> 1577 <211> 19 <212> RNA <213> Homo sapiens <400> 1577 guuacaucca aaguuaucg 19 <210> 1578 <211> 19 <212> RNA <213> Homo sapiens <400> 1578 uuacauccaa aguuaucga 19 <210> 1579 <211> 19 <212> RNA <213> Homo sapiens <400> 1579 uacauccaaa guuaucgaa 19 <210> 1580 <211> 19 <212> RNA <213> Homo sapiens <400> 1580 acauccaaag uuaucgaaa 19 <210> 1581 <211> 19 <212> RNA <213> Homo sapiens <400> 1581 cauccaaagu uaucgaaaa 19 <210> 1582 <211> 19 <212> RNA <213> Homo sapiens <400> 1582 auccaaaguu aucgaaaag 19 <210> 1583 <211> 19 <212> RNA <213> Homo sapiens <400> 1583 uccaaaguua ucgaaaagu 19 <210> 1584 <211> 19 <212> RNA <213> Homo sapiens <400> 1584 ccaaaguuau cgaaaaguu 19 <210> 1585 <211> 19 <212> RNA <213> Homo sapiens <400> 1585 caaaguuauc gaaaaguuc 19 <210> 1586 <211> 19 <212> RNA <213> Homo sapiens <400> 1586 cgaaaaguuc ccggcucca 19 <210> 1587 <211> 19 <212> RNA <213> Homo sapiens <400> 1587 aaaaguuccc ggcuccagu 19 <210> 1588 <211> 19 <212> RNA <213> Homo sapiens <400> 1588 cccggcucca gugcacauc 19 <210> 1589 <211> 19 <212> RNA <213> Homo sapiens <400> 1589 cggcuccagu gcacaucug 19 <210> 1590 <211> 19 <212> RNA <213> Homo sapiens <400> 1590 ggcuccagug cacaucugu 19 <210> 1591 <211> 19 <212> RNA <213> Homo sapiens <400> 1591 gcuccagugc acaucugug 19 <210> 1592 <211> 19 <212> RNA <213> Homo sapiens <400> 1592 cuccagugca caucugugu 19 <210> 1593 <211> 19 <212> RNA <213> Homo sapiens <400> 1593 ccagugcaca ucuguguga 19 <210> 1594 <211> 19 <212> RNA <213> Homo sapiens <400> 1594 gugcacaucu gugugagcu 19 <210> 1595 <211> 19 <212> RNA <213> Homo sapiens <400> 1595 gcacaucugu gugagcugg 19 <210> 1596 <211> 19 <212> RNA <213> Homo sapiens <400> 1596 acaucugugu gagcuggga 19 <210> 1597 <211> 19 <212> RNA <213> Homo sapiens <400> 1597 aucuguguga gcugggagu 19 <210> 1598 <211> 19 <212> RNA <213> Homo sapiens <400> 1598 ugugugagcu gggaguccu 19 <210> 1599 <211> 19 <212> RNA <213> Homo sapiens <400> 1599 gugugagcug ggaguccuc 19 <210> 1600 <211> 19 <212> RNA <213> Homo sapiens <400> 1600 agcugggagu ccucaucag 19 <210> 1601 <211> 19 <212> RNA <213> Homo sapiens <400> 1601 gcugggaguc cucaucagg 19 <210> 1602 <211> 19 <212> RNA <213> Homo sapiens <400> 1602 cugggagucc ucaucaggu 19 <210> 1603 <211> 19 <212> RNA <213> Homo sapiens <400> 1603 ugggaguccu caucaggua 19 <210> 1604 <211> 19 <212> RNA <213> Homo sapiens <400> 1604 gggaguccuc aucagguau 19 <210> 1605 <211> 19 <212> RNA <213> Homo sapiens <400> 1605 ggaguccuca ucagguauu 19 <210> 1606 <211> 19 <212> RNA <213> Homo sapiens <400> 1606 gaguccucau cagguauug 19 <210> 1607 <211> 19 <212> RNA <213> Homo sapiens <400> 1607 guccucauca gguauugcu 19 <210> 1608 <211> 19 <212> RNA <213> Homo sapiens <400> 1608 uccucaucag guauugcug 19 <210> 1609 <211> 19 <212> RNA <213> Homo sapiens <400> 1609 ccucaucagg uauugcuga 19 <210> 1610 <211> 19 <212> RNA <213> Homo sapiens <400> 1610 cucaucaggu auugcugaa 19 <210> 1611 <211> 19 <212> RNA <213> Homo sapiens <400> 1611 ucaucaggua uugcugaau 19 <210> 1612 <211> 19 <212> RNA <213> Homo sapiens <400> 1612 caucagguau ugcugaauu 19 <210> 1613 <211> 19 <212> RNA <213> Homo sapiens <400> 1613 aucagguauu gcugaauuu 19 <210> 1614 <211> 19 <212> RNA <213> Homo sapiens <400> 1614 ucagguauug cugaauuuu 19 <210> 1615 <211> 19 <212> RNA <213> Homo sapiens <400> 1615 cagguauugc ugaauuuug 19 <210> 1616 <211> 19 <212> RNA <213> Homo sapiens <400> 1616 agguauugcu gaauuuugg 19 <210> 1617 <211> 19 <212> RNA <213> Homo sapiens <400> 1617 gguauugcug aauuuugga 19 <210> 1618 <211> 19 <212> RNA <213> Homo sapiens <400> 1618 guauugcuga auuuuggau 19 <210> 1619 <211> 19 <212> RNA <213> Homo sapiens <400> 1619 auugcugaau uuuggauca 19 <210> 1620 <211> 19 <212> RNA <213> Homo sapiens <400> 1620 ugcugaauuu uggaucaau 19 <210> 1621 <211> 19 <212> RNA <213> Homo sapiens <400> 1621 gcugaauuuu ggaucaaug 19 <210> 1622 <211> 19 <212> RNA <213> Homo sapiens <400> 1622 cugaauuuug gaucaaugg 19 <210> 1623 <211> 19 <212> RNA <213> Homo sapiens <400> 1623 gaauuuugga ucaauggga 19 <210> 1624 <211> 19 <212> RNA <213> Homo sapiens <400> 1624 ggaucaaugg gacaccuuu 19 <210> 1625 <211> 19 <212> RNA <213> Homo sapiens <400> 1625 caaugggaca ccuuuggug 19 <210> 1626 <211> 19 <212> RNA <213> Homo sapiens <400> 1626 aaugggacac cuuugguga 19 <210> 1627 <211> 19 <212> RNA <213> Homo sapiens <400> 1627 augggacacc uuuggugaa 19 <210> 1628 <211> 19 <212> RNA <213> Homo sapiens <400> 1628 ugggacaccu uuggugaaa 19 <210> 1629 <211> 19 <212> RNA <213> Homo sapiens <400> 1629 gggacaccuu uggugaaaa 19 <210> 1630 <211> 19 <212> RNA <213> Homo sapiens <400> 1630 ggacaccuuu ggugaaaaa 19 <210> 1631 <211> 19 <212> RNA <213> Homo sapiens <400> 1631 accuuuggug aaaaagggu 19 <210> 1632 <211> 19 <212> RNA <213> Homo sapiens <400> 1632 ccuuugguga aaaaggguc 19 <210> 1633 <211> 19 <212> RNA <213> Homo sapiens <400> 1633 cuuuggugaa aaagggucu 19 <210> 1634 <211> 19 <212> RNA <213> Homo sapiens <400> 1634 ggugaaaaag ggucugcga 19 <210> 1635 <211> 19 <212> RNA <213> Homo sapiens <400> 1635 gugaaaaagg gucugcgac 19 <210> 1636 <211> 19 <212> RNA <213> Homo sapiens <400> 1636 ugaaaaaggg ucugcgaca 19 <210> 1637 <211> 19 <212> RNA <213> Homo sapiens <400> 1637 gaaaaagggu cugcgacag 19 <210> 1638 <211> 19 <212> RNA <213> Homo sapiens <400> 1638 aaagggucug cgacagggu 19 <210> 1639 <211> 19 <212> RNA <213> Homo sapiens <400> 1639 aagggucugc gacaggguu 19 <210> 1640 <211> 19 <212> RNA <213> Homo sapiens <400> 1640 agggucugcg acaggguua 19 <210> 1641 <211> 19 <212> RNA <213> Homo sapiens <400> 1641 gggucugcga caggguuac 19 <210> 1642 <211> 19 <212> RNA <213> Homo sapiens <400> 1642 ggucugcgac aggguuacu 19 <210> 1643 <211> 19 <212> RNA <213> Homo sapiens <400> 1643 gucugcgaca ggguuacuu 19 <210> 1644 <211> 19 <212> RNA <213> Homo sapiens <400> 1644 ucugcgacag gguuacuuu 19 <210> 1645 <211> 19 <212> RNA <213> Homo sapiens <400> 1645 cugcgacagg guuacuuug 19 <210> 1646 <211> 19 <212> RNA <213> Homo sapiens <400> 1646 ugcgacaggg uuacuuugu 19 <210> 1647 <211> 19 <212> RNA <213> Homo sapiens <400> 1647 gcgacagggu uacuuugua 19 <210> 1648 <211> 19 <212> RNA <213> Homo sapiens <400> 1648 cgacaggguu acuuuguag 19 <210> 1649 <211> 19 <212> RNA <213> Homo sapiens <400> 1649 gacaggguua cuuuguaga 19 <210> 1650 <211> 19 <212> RNA <213> Homo sapiens <400> 1650 acaggguuac uuuguagaa 19 <210> 1651 <211> 19 <212> RNA <213> Homo sapiens <400> 1651 caggguuacu uuguagaag 19 <210> 1652 <211> 19 <212> RNA <213> Homo sapiens <400> 1652 aggguuacuu uguagaagc 19 <210> 1653 <211> 19 <212> RNA <213> Homo sapiens <400> 1653 ggguuacuuu guagaagcu 19 <210> 1654 <211> 19 <212> RNA <213> Homo sapiens <400> 1654 gguuacuuug uagaagcuc 19 <210> 1655 <211> 19 <212> RNA <213> Homo sapiens <400> 1655 guuacuuugu agaagcuca 19 <210> 1656 <211> 19 <212> RNA <213> Homo sapiens <400> 1656 agaagcucag cccaagauu 19 <210> 1657 <211> 19 <212> RNA <213> Homo sapiens <400> 1657 gaagcucagc ccaagauug 19 <210> 1658 <211> 19 <212> RNA <213> Homo sapiens <400> 1658 aagcucagcc caagauugu 19 <210> 1659 <211> 19 <212> RNA <213> Homo sapiens <400> 1659 agcucagccc aagauuguc 19 <210> 1660 <211> 19 <212> RNA <213> Homo sapiens <400> 1660 cucagcccaa gauuguccu 19 <210> 1661 <211> 19 <212> RNA <213> Homo sapiens <400> 1661 agcccaagau uguccuggg 19 <210> 1662 <211> 19 <212> RNA <213> Homo sapiens <400> 1662 ccaagauugu ccuggggca 19 <210> 1663 <211> 19 <212> RNA <213> Homo sapiens <400> 1663 caagauuguc cuggggcag 19 <210> 1664 <211> 19 <212> RNA <213> Homo sapiens <400> 1664 agauuguccu ggggcagga 19 <210> 1665 <211> 19 <212> RNA <213> Homo sapiens <400> 1665 gauuguccug gggcaggaa 19 <210> 1666 <211> 19 <212> RNA <213> Homo sapiens <400> 1666 uuguccuggg gcaggaaca 19 <210> 1667 <211> 19 <212> RNA <213> Homo sapiens <400> 1667 uccuggggca ggaacagga 19 <210> 1668 <211> 19 <212> RNA <213> Homo sapiens <400> 1668 cuggggcagg aacaggauu 19 <210> 1669 <211> 19 <212> RNA <213> Homo sapiens <400> 1669 uggggcagga acaggauuc 19 <210> 1670 <211> 19 <212> RNA <213> Homo sapiens <400> 1670 ggggcaggaa caggauucc 19 <210> 1671 <211> 19 <212> RNA <213> Homo sapiens <400> 1671 ggcaggaaca ggauuccua 19 <210> 1672 <211> 19 <212> RNA <213> Homo sapiens <400> 1672 gcaggaacag gauuccuau 19 <210> 1673 <211> 19 <212> RNA <213> Homo sapiens <400> 1673 caggaacagg auuccuaug 19 <210> 1674 <211> 19 <212> RNA <213> Homo sapiens <400> 1674 ggaacaggau uccuauggg 19 <210> 1675 <211> 19 <212> RNA <213> Homo sapiens <400> 1675 gaacaggauu ccuaugggg 19 <210> 1676 <211> 19 <212> RNA <213> Homo sapiens <400> 1676 acaggauucc uaugggggc 19 <210> 1677 <211> 19 <212> RNA <213> Homo sapiens <400> 1677 caggauuccu augggggca 19 <210> 1678 <211> 19 <212> RNA <213> Homo sapiens <400> 1678 ggauuccuau gggggcaag 19 <210> 1679 <211> 19 <212> RNA <213> Homo sapiens <400> 1679 gauuccuaug ggggcaagu 19 <210> 1680 <211> 19 <212> RNA <213> Homo sapiens <400> 1680 auuccuaugg gggcaaguu 19 <210> 1681 <211> 19 <212> RNA <213> Homo sapiens <400> 1681 uuccuauggg ggcaaguuu 19 <210> 1682 <211> 19 <212> RNA <213> Homo sapiens <400> 1682 uccuaugggg gcaaguuug 19 <210> 1683 <211> 19 <212> RNA <213> Homo sapiens <400> 1683 ccuauggggg caaguuuga 19 <210> 1684 <211> 19 <212> RNA <213> Homo sapiens <400> 1684 cuaugggggc aaguuugau 19 <210> 1685 <211> 19 <212> RNA <213> Homo sapiens <400> 1685 uaugggggca aguuugaua 19 <210> 1686 <211> 19 <212> RNA <213> Homo sapiens <400> 1686 gggggcaagu uugauagga 19 <210> 1687 <211> 19 <212> RNA <213> Homo sapiens <400> 1687 ggggcaaguu ugauaggag 19 <210> 1688 <211> 19 <212> RNA <213> Homo sapiens <400> 1688 gggcaaguuu gauaggagc 19 <210> 1689 <211> 19 <212> RNA <213> Homo sapiens <400> 1689 ggcaaguuug auaggagcc 19 <210> 1690 <211> 19 <212> RNA <213> Homo sapiens <400> 1690 gcaaguuuga uaggagcca 19 <210> 1691 <211> 19 <212> RNA <213> Homo sapiens <400> 1691 caaguuugau aggagccag 19 <210> 1692 <211> 19 <212> RNA <213> Homo sapiens <400> 1692 aaguuugaua ggagccagu 19 <210> 1693 <211> 19 <212> RNA <213> Homo sapiens <400> 1693 uugauaggag ccaguccuu 19 <210> 1694 <211> 19 <212> RNA <213> Homo sapiens <400> 1694 ugauaggagc caguccuuu 19 <210> 1695 <211> 19 <212> RNA <213> Homo sapiens <400> 1695 gauaggagcc aguccuuug 19 <210> 1696 <211> 19 <212> RNA <213> Homo sapiens <400> 1696 auaggagcca guccuuugu 19 <210> 1697 <211> 19 <212> RNA <213> Homo sapiens <400> 1697 aggagccagu ccuuugugg 19 <210> 1698 <211> 19 <212> RNA <213> Homo sapiens <400> 1698 ggagccaguc cuuuguggg 19 <210> 1699 <211> 19 <212> RNA <213> Homo sapiens <400> 1699 gagccagucc uuuguggga 19 <210> 1700 <211> 19 <212> RNA <213> Homo sapiens <400> 1700 agccaguccu uugugggag 19 <210> 1701 <211> 19 <212> RNA <213> Homo sapiens <400> 1701 gccaguccuu ugugggaga 19 <210> 1702 <211> 19 <212> RNA <213> Homo sapiens <400> 1702 ccaguccuuu gugggagag 19 <210> 1703 <211> 19 <212> RNA <213> Homo sapiens <400> 1703 caguccuuug ugggagaga 19 <210> 1704 <211> 19 <212> RNA <213> Homo sapiens <400> 1704 aguccuuugu gggagagau 19 <210> 1705 <211> 19 <212> RNA <213> Homo sapiens <400> 1705 guccuuugug ggagagauu 19 <210> 1706 <211> 19 <212> RNA <213> Homo sapiens <400> 1706 uccuuugugg gagagauug 19 <210> 1707 <211> 19 <212> RNA <213> Homo sapiens <400> 1707 ccuuuguggg agagauugg 19 <210> 1708 <211> 19 <212> RNA <213> Homo sapiens <400> 1708 cuuuguggga gagauuggg 19 <210> 1709 <211> 19 <212> RNA <213> Homo sapiens <400> 1709 uugugggaga gauugggga 19 <210> 1710 <211> 19 <212> RNA <213> Homo sapiens <400> 1710 ugugggagag auuggggau 19 <210> 1711 <211> 19 <212> RNA <213> Homo sapiens <400> 1711 gugggagaga uuggggauu 19 <210> 1712 <211> 19 <212> RNA <213> Homo sapiens <400> 1712 ugggagagau uggggauuu 19 <210> 1713 <211> 19 <212> RNA <213> Homo sapiens <400> 1713 gggagagauu ggggauuug 19 <210> 1714 <211> 19 <212> RNA <213> Homo sapiens <400> 1714 ggagagauug gggauuugu 19 <210> 1715 <211> 19 <212> RNA <213> Homo sapiens <400> 1715 gagagauugg ggauuugua 19 <210> 1716 <211> 19 <212> RNA <213> Homo sapiens <400> 1716 agagauuggg gauuuguac 19 <210> 1717 <211> 19 <212> RNA <213> Homo sapiens <400> 1717 gagauugggg auuuguaca 19 <210> 1718 <211> 19 <212> RNA <213> Homo sapiens <400> 1718 agauugggga uuuguacau 19 <210> 1719 <211> 19 <212> RNA <213> Homo sapiens <400> 1719 ggggauuugu acauguggg 19 <210> 1720 <211> 19 <212> RNA <213> Homo sapiens <400> 1720 gggauuugua cauguggga 19 <210> 1721 <211> 19 <212> RNA <213> Homo sapiens <400> 1721 ggauuuguac augugggac 19 <210> 1722 <211> 19 <212> RNA <213> Homo sapiens <400> 1722 gauuuguaca ugugggacu 19 <210> 1723 <211> 19 <212> RNA <213> Homo sapiens <400> 1723 uguacaugug ggacucugu 19 <210> 1724 <211> 19 <212> RNA <213> Homo sapiens <400> 1724 guacaugugg gacucugug 19 <210> 1725 <211> 19 <212> RNA <213> Homo sapiens <400> 1725 acauguggga cucugugcu 19 <210> 1726 <211> 19 <212> RNA <213> Homo sapiens <400> 1726 gggacucugu gcugccccc 19 <210> 1727 <211> 19 <212> RNA <213> Homo sapiens <400> 1727 ggacucugug cugccccca 19 <210> 1728 <211> 19 <212> RNA <213> Homo sapiens <400> 1728 acucugugcu gcccccaga 19 <210> 1729 <211> 19 <212> RNA <213> Homo sapiens <400> 1729 cucugugcug cccccagaa 19 <210> 1730 <211> 19 <212> RNA <213> Homo sapiens <400> 1730 cugugcugcc cccagaaaa 19 <210> 1731 <211> 19 <212> RNA <213> Homo sapiens <400> 1731 ugugcugccc ccagaaaau 19 <210> 1732 <211> 19 <212> RNA <213> Homo sapiens <400> 1732 gugcugcccc cagaaaaua 19 <210> 1733 <211> 19 <212> RNA <213> Homo sapiens <400> 1733 gcugccccca gaaaauauc 19 <210> 1734 <211> 19 <212> RNA <213> Homo sapiens <400> 1734 cccccagaaa auauccugu 19 <210> 1735 <211> 19 <212> RNA <213> Homo sapiens <400> 1735 cccagaaaau auccugucu 19 <210> 1736 <211> 19 <212> RNA <213> Homo sapiens <400> 1736 ccagaaaaua uccugucug 19 <210> 1737 <211> 19 <212> RNA <213> Homo sapiens <400> 1737 cagaaaauau ccugucugc 19 <210> 1738 <211> 19 <212> RNA <213> Homo sapiens <400> 1738 gaaaauaucc ugucugccu 19 <210> 1739 <211> 19 <212> RNA <213> Homo sapiens <400> 1739 aaaauauccu gucugccua 19 <210> 1740 <211> 19 <212> RNA <213> Homo sapiens <400> 1740 aaauauccug ucugccuau 19 <210> 1741 <211> 19 <212> RNA <213> Homo sapiens <400> 1741 ccugucugcc uaucagggu 19 <210> 1742 <211> 19 <212> RNA <213> Homo sapiens <400> 1742 cugucugccu aucagggua 19 <210> 1743 <211> 19 <212> RNA <213> Homo sapiens <400> 1743 gucugccuau caggguacc 19 <210> 1744 <211> 19 <212> RNA <213> Homo sapiens <400> 1744 ugccuaucag gguaccccu 19 <210> 1745 <211> 19 <212> RNA <213> Homo sapiens <400> 1745 gccuaucagg guaccccuc 19 <210> 1746 <211> 19 <212> RNA <213> Homo sapiens <400> 1746 ccuaucaggg uaccccucu 19 <210> 1747 <211> 19 <212> RNA <213> Homo sapiens <400> 1747 cuaucagggu accccucuc 19 <210> 1748 <211> 19 <212> RNA <213> Homo sapiens <400> 1748 caggguaccc cucucccug 19 <210> 1749 <211> 19 <212> RNA <213> Homo sapiens <400> 1749 ggguaccccu cucccugcc 19 <210> 1750 <211> 19 <212> RNA <213> Homo sapiens <400> 1750 gguaccccuc ucccugcca 19 <210> 1751 <211> 19 <212> RNA <213> Homo sapiens <400> 1751 guaccccucu cccugccaa 19 <210> 1752 <211> 19 <212> RNA <213> Homo sapiens <400> 1752 uaccccucuc ccugccaau 19 <210> 1753 <211> 19 <212> RNA <213> Homo sapiens <400> 1753 ccccucuccc ugccaauau 19 <210> 1754 <211> 19 <212> RNA <213> Homo sapiens <400> 1754 cccucucccu gccaauauc 19 <210> 1755 <211> 19 <212> RNA <213> Homo sapiens <400> 1755 cugccaauau ccuggacug 19 <210> 1756 <211> 19 <212> RNA <213> Homo sapiens <400> 1756 ccaauauccu ggacuggca 19 <210> 1757 <211> 19 <212> RNA <213> Homo sapiens <400> 1757 caauauccug gacuggcag 19 <210> 1758 <211> 19 <212> RNA <213> Homo sapiens <400> 1758 uccuggacug gcaggcucu 19 <210> 1759 <211> 19 <212> RNA <213> Homo sapiens <400> 1759 ccuggacugg caggcucug 19 <210> 1760 <211> 19 <212> RNA <213> Homo sapiens <400> 1760 cuggacuggc aggcucuga 19 <210> 1761 <211> 19 <212> RNA <213> Homo sapiens <400> 1761 uggacuggca ggcucugaa 19 <210> 1762 <211> 19 <212> RNA <213> Homo sapiens <400> 1762 ggacuggcag gcucugaac 19 <210> 1763 <211> 19 <212> RNA <213> Homo sapiens <400> 1763 gacuggcagg cucugaacu 19 <210> 1764 <211> 19 <212> RNA <213> Homo sapiens <400> 1764 acuggcaggc ucugaacua 19 <210> 1765 <211> 19 <212> RNA <213> Homo sapiens <400> 1765 cuggcaggcu cugaacuau 19 <210> 1766 <211> 19 <212> RNA <213> Homo sapiens <400> 1766 uggcaggcuc ugaacuaug 19 <210> 1767 <211> 19 <212> RNA <213> Homo sapiens <400> 1767 ggcaggcucu gaacuauga 19 <210> 1768 <211> 19 <212> RNA <213> Homo sapiens <400> 1768 gcaggcucug aacuaugaa 19 <210> 1769 <211> 19 <212> RNA <213> Homo sapiens <400> 1769 caggcucuga acuaugaaa 19 <210> 1770 <211> 19 <212> RNA <213> Homo sapiens <400> 1770 aggcucugaa cuaugaaau 19 <210> 1771 <211> 19 <212> RNA <213> Homo sapiens <400> 1771 ggcucugaac uaugaaauc 19 <210> 1772 <211> 19 <212> RNA <213> Homo sapiens <400> 1772 gcucugaacu augaaauca 19 <210> 1773 <211> 19 <212> RNA <213> Homo sapiens <400> 1773 cucugaacua ugaaaucag 19 <210> 1774 <211> 19 <212> RNA <213> Homo sapiens <400> 1774 ucugaacuau gaaaucaga 19 <210> 1775 <211> 19 <212> RNA <213> Homo sapiens <400> 1775 gaacuaugaa aucagagga 19 <210> 1776 <211> 19 <212> RNA <213> Homo sapiens <400> 1776 aacuaugaaa ucagaggau 19 <210> 1777 <211> 19 <212> RNA <213> Homo sapiens <400> 1777 acuaugaaau cagaggaua 19 <210> 1778 <211> 19 <212> RNA <213> Homo sapiens <400> 1778 cuaugaaauc agaggauau 19 <210> 1779 <211> 19 <212> RNA <213> Homo sapiens <400> 1779 uaugaaauca gaggauaug 19 <210> 1780 <211> 19 <212> RNA <213> Homo sapiens <400> 1780 ugaaaucaga ggauauguc 19 <210> 1781 <211> 19 <212> RNA <213> Homo sapiens <400> 1781 gaaaucagag gauauguca 19 <210> 1782 <211> 19 <212> RNA <213> Homo sapiens <400> 1782 aaaucagagg auaugucau 19 <210> 1783 <211> 19 <212> RNA <213> Homo sapiens <400> 1783 aaucagagga uaugucauc 19 <210> 1784 <211> 19 <212> RNA <213> Homo sapiens <400> 1784 cagaggauau gucaucauc 19 <210> 1785 <211> 19 <212> RNA <213> Homo sapiens <400> 1785 agaggauaug ucaucauca 19 <210> 1786 <211> 19 <212> RNA <213> Homo sapiens <400> 1786 gaggauaugu caucaucaa 19 <210> 1787 <211> 19 <212> RNA <213> Homo sapiens <400> 1787 aggauauguc aucaucaaa 19 <210> 1788 <211> 19 <212> RNA <213> Homo sapiens <400> 1788 ggauauguca ucaucaaac 19 <210> 1789 <211> 19 <212> RNA <213> Homo sapiens <400> 1789 gauaugucau caucaaacc 19 <210> 1790 <211> 19 <212> RNA <213> Homo sapiens <400> 1790 augucaucau caaacccuu 19 <210> 1791 <211> 19 <212> RNA <213> Homo sapiens <400> 1791 caucaucaaa cccuuggug 19 <210> 1792 <211> 19 <212> RNA <213> Homo sapiens <400> 1792 ucaucaaacc cuuggugug 19 <210> 1793 <211> 19 <212> RNA <213> Homo sapiens <400> 1793 acccuuggug ugggucuga 19 <210> 1794 <211> 19 <212> RNA <213> Homo sapiens <400> 1794 cccuuggugu gggucugag 19 <210> 1795 <211> 19 <212> RNA <213> Homo sapiens <400> 1795 ccuuggugug ggucugagg 19 <210> 1796 <211> 19 <212> RNA <213> Homo sapiens <400> 1796 cuuggugugg gucugaggu 19 <210> 1797 <211> 19 <212> RNA <213> Homo sapiens <400> 1797 uggugugggu cugaggucu 19 <210> 1798 <211> 19 <212> RNA <213> Homo sapiens <400> 1798 gguguggguc ugaggucuu 19 <210> 1799 <211> 19 <212> RNA <213> Homo sapiens <400> 1799 gugugggucu gaggucuug 19 <210> 1800 <211> 19 <212> RNA <213> Homo sapiens <400> 1800 ugugggucug aggucuuga 19 <210> 1801 <211> 19 <212> RNA <213> Homo sapiens <400> 1801 gugggucuga ggucuugac 19 <210> 1802 <211> 19 <212> RNA <213> Homo sapiens <400> 1802 gggucugagg ucuugacuc 19 <210> 1803 <211> 19 <212> RNA <213> Homo sapiens <400> 1803 ggucugaggu cuugacuca 19 <210> 1804 <211> 19 <212> RNA <213> Homo sapiens <400> 1804 gucugagguc uugacucaa 19 <210> 1805 <211> 19 <212> RNA <213> Homo sapiens <400> 1805 cugaggucuu gacucaacg 19 <210> 1806 <211> 19 <212> RNA <213> Homo sapiens <400> 1806 ugaggucuug acucaacga 19 <210> 1807 <211> 19 <212> RNA <213> Homo sapiens <400> 1807 gaggucuuga cucaacgag 19 <210> 1808 <211> 19 <212> RNA <213> Homo sapiens <400> 1808 aggucuugac ucaacgaga 19 <210> 1809 <211> 19 <212> RNA <213> Homo sapiens <400> 1809 ggucuugacu caacgagag 19 <210> 1810 <211> 19 <212> RNA <213> Homo sapiens <400> 1810 gucuugacuc aacgagagc 19 <210> 1811 <211> 19 <212> RNA <213> Homo sapiens <400> 1811 ucuugacuca acgagagca 19 <210> 1812 <211> 19 <212> RNA <213> Homo sapiens <400> 1812 cuugacucaa cgagagcac 19 <210> 1813 <211> 19 <212> RNA <213> Homo sapiens <400> 1813 uugacucaac gagagcacu 19 <210> 1814 <211> 19 <212> RNA <213> Homo sapiens <400> 1814 ugacucaacg agagcacuu 19 <210> 1815 <211> 19 <212> RNA <213> Homo sapiens <400> 1815 gacucaacga gagcacuug 19 <210> 1816 <211> 19 <212> RNA <213> Homo sapiens <400> 1816 acucaacgag agcacuuga 19 <210> 1817 <211> 19 <212> RNA <213> Homo sapiens <400> 1817 cucaacgaga gcacuugaa 19 <210> 1818 <211> 19 <212> RNA <213> Homo sapiens <400> 1818 ucaacgagag cacuugaaa 19 <210> 1819 <211> 19 <212> RNA <213> Homo sapiens <400> 1819 caacgagagc acuugaaaa 19 <210> 1820 <211> 19 <212> RNA <213> Homo sapiens <400> 1820 aacgagagca cuugaaaau 19 <210> 1821 <211> 19 <212> RNA <213> Homo sapiens <400> 1821 acgagagcac uugaaaaug 19 <210> 1822 <211> 19 <212> RNA <213> Homo sapiens <400> 1822 cgagagcacu ugaaaauga 19 <210> 1823 <211> 19 <212> RNA <213> Homo sapiens <400> 1823 gagagcacuu gaaaaugaa 19 <210> 1824 <211> 19 <212> RNA <213> Homo sapiens <400> 1824 agagcacuug aaaaugaaa 19 <210> 1825 <211> 19 <212> RNA <213> Homo sapiens <400> 1825 gagcacuuga aaaugaaau 19 <210> 1826 <211> 19 <212> RNA <213> Homo sapiens <400> 1826 agcacuugaa aaugaaaug 19 <210> 1827 <211> 19 <212> RNA <213> Homo sapiens <400> 1827 gcacuugaaa augaaauga 19 <210> 1828 <211> 19 <212> RNA <213> Homo sapiens <400> 1828 cacuugaaaa ugaaaugac 19 <210> 1829 <211> 19 <212> RNA <213> Homo sapiens <400> 1829 acuugaaaau gaaaugacu 19 <210> 1830 <211> 19 <212> RNA <213> Homo sapiens <400> 1830 cuugaaaaug aaaugacug 19 <210> 1831 <211> 19 <212> RNA <213> Homo sapiens <400> 1831 uugaaaauga aaugacugu 19 <210> 1832 <211> 19 <212> RNA <213> Homo sapiens <400> 1832 ugaaaaugaa augacuguc 19 <210> 1833 <211> 19 <212> RNA <213> Homo sapiens <400> 1833 gaaaaugaaa ugacugucu 19 <210> 1834 <211> 19 <212> RNA <213> Homo sapiens <400> 1834 aaaaugaaau gacugucua 19 <210> 1835 <211> 19 <212> RNA <213> Homo sapiens <400> 1835 aaaugaaaug acugucuaa 19 <210> 1836 <211> 19 <212> RNA <213> Homo sapiens <400> 1836 aaugaaauga cugucuaag 19 <210> 1837 <211> 19 <212> RNA <213> Homo sapiens <400> 1837 augaaaugac ugucuaaga 19 <210> 1838 <211> 19 <212> RNA <213> Homo sapiens <400> 1838 ugaaaugacu gucuaagag 19 <210> 1839 <211> 19 <212> RNA <213> Homo sapiens <400> 1839 gaaaugacug ucuaagaga 19 <210> 1840 <211> 19 <212> RNA <213> Homo sapiens <400> 1840 aaaugacugu cuaagagau 19 <210> 1841 <211> 19 <212> RNA <213> Homo sapiens <400> 1841 augacugucu aagagaucu 19 <210> 1842 <211> 19 <212> RNA <213> Homo sapiens <400> 1842 ugacugucua agagaucug 19 <210> 1843 <211> 19 <212> RNA <213> Homo sapiens <400> 1843 gacugucuaa gagaucugg 19 <210> 1844 <211> 19 <212> RNA <213> Homo sapiens <400> 1844 acugucuaag agaucuggu 19 <210> 1845 <211> 19 <212> RNA <213> Homo sapiens <400> 1845 cugucuaaga gaucugguc 19 <210> 1846 <211> 19 <212> RNA <213> Homo sapiens <400> 1846 ugucuaagag aucugguca 19 <210> 1847 <211> 19 <212> RNA <213> Homo sapiens <400> 1847 gucuaagaga ucuggucaa 19 <210> 1848 <211> 19 <212> RNA <213> Homo sapiens <400> 1848 ucuaagagau cuggucaaa 19 <210> 1849 <211> 19 <212> RNA <213> Homo sapiens <400> 1849 cuaagagauc uggucaaag 19 <210> 1850 <211> 19 <212> RNA <213> Homo sapiens <400> 1850 uaagagaucu ggucaaagc 19 <210> 1851 <211> 19 <212> RNA <213> Homo sapiens <400> 1851 aagagaucug gucaaagca 19 <210> 1852 <211> 19 <212> RNA <213> Homo sapiens <400> 1852 agagaucugg ucaaagcaa 19 <210> 1853 <211> 19 <212> RNA <213> Homo sapiens <400> 1853 gagaucuggu caaagcaac 19 <210> 1854 <211> 19 <212> RNA <213> Homo sapiens <400> 1854 agaucugguc aaagcaacu 19 <210> 1855 <211> 19 <212> RNA <213> Homo sapiens <400> 1855 gaucugguca aagcaacug 19 <210> 1856 <211> 19 <212> RNA <213> Homo sapiens <400> 1856 aucuggucaa agcaacugg 19 <210> 1857 <211> 19 <212> RNA <213> Homo sapiens <400> 1857 ucuggucaaa gcaacugga 19 <210> 1858 <211> 19 <212> RNA <213> Homo sapiens <400> 1858 cuggucaaag caacuggau 19 <210> 1859 <211> 19 <212> RNA <213> Homo sapiens <400> 1859 uggucaaagc aacuggaua 19 <210> 1860 <211> 19 <212> RNA <213> Homo sapiens <400> 1860 ggucaaagca acuggauac 19 <210> 1861 <211> 19 <212> RNA <213> Homo sapiens <400> 1861 gucaaagcaa cuggauacu 19 <210> 1862 <211> 19 <212> RNA <213> Homo sapiens <400> 1862 ucaaagcaac uggauacua 19 <210> 1863 <211> 19 <212> RNA <213> Homo sapiens <400> 1863 caaagcaacu ggauacuag 19 <210> 1864 <211> 19 <212> RNA <213> Homo sapiens <400> 1864 aaagcaacug gauacuaga 19 <210> 1865 <211> 19 <212> RNA <213> Homo sapiens <400> 1865 aagcaacugg auacuagau 19 <210> 1866 <211> 19 <212> RNA <213> Homo sapiens <400> 1866 agcaacugga uacuagauc 19 <210> 1867 <211> 19 <212> RNA <213> Homo sapiens <400> 1867 gcaacuggau acuagaucu 19 <210> 1868 <211> 19 <212> RNA <213> Homo sapiens <400> 1868 caacuggaua cuagaucuu 19 <210> 1869 <211> 19 <212> RNA <213> Homo sapiens <400> 1869 aacuggauac uagaucuua 19 <210> 1870 <211> 19 <212> RNA <213> Homo sapiens <400> 1870 acuggauacu agaucuuac 19 <210> 1871 <211> 19 <212> RNA <213> Homo sapiens <400> 1871 cuggauacua gaucuuaca 19 <210> 1872 <211> 19 <212> RNA <213> Homo sapiens <400> 1872 uggauacuag aucuuacau 19 <210> 1873 <211> 19 <212> RNA <213> Homo sapiens <400> 1873 ggauacuaga ucuuacauc 19 <210> 1874 <211> 19 <212> RNA <213> Homo sapiens <400> 1874 gauacuagau cuuacaucu 19 <210> 1875 <211> 19 <212> RNA <213> Homo sapiens <400> 1875 auacuagauc uuacaucug 19 <210> 1876 <211> 19 <212> RNA <213> Homo sapiens <400> 1876 acuagaucuu acaucugca 19 <210> 1877 <211> 19 <212> RNA <213> Homo sapiens <400> 1877 cuagaucuua caucugcag 19 <210> 1878 <211> 19 <212> RNA <213> Homo sapiens <400> 1878 agaucuuaca ucugcagcu 19 <210> 1879 <211> 19 <212> RNA <213> Homo sapiens <400> 1879 gaucuuacau cugcagcuc 19 <210> 1880 <211> 19 <212> RNA <213> Homo sapiens <400> 1880 aucuuacauc ugcagcucu 19 <210> 1881 <211> 19 <212> RNA <213> Homo sapiens <400> 1881 ucuuacaucu gcagcucuu 19 <210> 1882 <211> 19 <212> RNA <213> Homo sapiens <400> 1882 cuuacaucug cagcucuuu 19 <210> 1883 <211> 19 <212> RNA <213> Homo sapiens <400> 1883 uuacaucugc agcucuuuc 19 <210> 1884 <211> 19 <212> RNA <213> Homo sapiens <400> 1884 uacaucugca gcucuuucu 19 <210> 1885 <211> 19 <212> RNA <213> Homo sapiens <400> 1885 acaucugcag cucuuucuu 19 <210> 1886 <211> 19 <212> RNA <213> Homo sapiens <400> 1886 caucugcagc ucuuucuuc 19 <210> 1887 <211> 19 <212> RNA <213> Homo sapiens <400> 1887 aucugcagcu cuuucuucu 19 <210> 1888 <211> 19 <212> RNA <213> Homo sapiens <400> 1888 ucugcagcuc uuucuucuu 19 <210> 1889 <211> 19 <212> RNA <213> Homo sapiens <400> 1889 cugcagcucu uucuucuuu 19 <210> 1890 <211> 19 <212> RNA <213> Homo sapiens <400> 1890 ugcagcucuu ucuucuuug 19 <210> 1891 <211> 19 <212> RNA <213> Homo sapiens <400> 1891 gcagcucuuu cuucuuuga 19 <210> 1892 <211> 19 <212> RNA <213> Homo sapiens <400> 1892 cagcucuuuc uucuuugaa 19 <210> 1893 <211> 19 <212> RNA <213> Homo sapiens <400> 1893 agcucuuucu ucuuugaau 19 <210> 1894 <211> 19 <212> RNA <213> Homo sapiens <400> 1894 gcucuuucuu cuuugaauu 19 <210> 1895 <211> 19 <212> RNA <213> Homo sapiens <400> 1895 cucuuucuuc uuugaauuu 19 <210> 1896 <211> 19 <212> RNA <213> Homo sapiens <400> 1896 ucuuucuucu uugaauuuc 19 <210> 1897 <211> 19 <212> RNA <213> Homo sapiens <400> 1897 cuuucuucuu ugaauuucc 19 <210> 1898 <211> 19 <212> RNA <213> Homo sapiens <400> 1898 uuucuucuuu gaauuuccu 19 <210> 1899 <211> 19 <212> RNA <213> Homo sapiens <400> 1899 uucuucuuug aauuuccua 19 <210> 1900 <211> 19 <212> RNA <213> Homo sapiens <400> 1900 ucuucuuuga auuuccuau 19 <210> 1901 <211> 19 <212> RNA <213> Homo sapiens <400> 1901 uucuuugaau uuccuaucu 19 <210> 1902 <211> 19 <212> RNA <213> Homo sapiens <400> 1902 ucuuugaauu uccuaucug 19 <210> 1903 <211> 19 <212> RNA <213> Homo sapiens <400> 1903 cuuugaauuu ccuaucugu 19 <210> 1904 <211> 19 <212> RNA <213> Homo sapiens <400> 1904 uuugaauuuc cuaucugua 19 <210> 1905 <211> 19 <212> RNA <213> Homo sapiens <400> 1905 uugaauuucc uaucuguau 19 <210> 1906 <211> 19 <212> RNA <213> Homo sapiens <400> 1906 ugaauuuccu aucuguaug 19 <210> 1907 <211> 19 <212> RNA <213> Homo sapiens <400> 1907 gaauuuccua ucuguaugu 19 <210> 1908 <211> 19 <212> RNA <213> Homo sapiens <400> 1908 auuuccuauc uguaugucu 19 <210> 1909 <211> 19 <212> RNA <213> Homo sapiens <400> 1909 uuuccuaucu guaugucug 19 <210> 1910 <211> 19 <212> RNA <213> Homo sapiens <400> 1910 uuccuaucug uaugucugc 19 <210> 1911 <211> 19 <212> RNA <213> Homo sapiens <400> 1911 uccuaucugu augucugcc 19 <210> 1912 <211> 19 <212> RNA <213> Homo sapiens <400> 1912 ccuaucugua ugucugccu 19 <210> 1913 <211> 19 <212> RNA <213> Homo sapiens <400> 1913 cuaucuguau gucugccua 19 <210> 1914 <211> 19 <212> RNA <213> Homo sapiens <400> 1914 uaucuguaug ucugccuaa 19 <210> 1915 <211> 19 <212> RNA <213> Homo sapiens <400> 1915 aucuguaugu cugccuaau 19 <210> 1916 <211> 19 <212> RNA <213> Homo sapiens <400> 1916 ucuguauguc ugccuaauu 19 <210> 1917 <211> 19 <212> RNA <213> Homo sapiens <400> 1917 cuguaugucu gccuaauua 19 <210> 1918 <211> 19 <212> RNA <213> Homo sapiens <400> 1918 uguaugucug ccuaauuaa 19 <210> 1919 <211> 19 <212> RNA <213> Homo sapiens <400> 1919 guaugucugc cuaauuaaa 19 <210> 1920 <211> 19 <212> RNA <213> Homo sapiens <400> 1920 uaugucugcc uaauuaaaa 19 <210> 1921 <211> 19 <212> RNA <213> Homo sapiens <400> 1921 augucugccu aauuaaaaa 19 <210> 1922 <211> 19 <212> RNA <213> Homo sapiens <400> 1922 ugucugccua auuaaaaaa 19 <210> 1923 <211> 19 <212> RNA <213> Homo sapiens <400> 1923 gucugccuaa uuaaaaaaa 19 <210> 1924 <211> 19 <212> RNA <213> Homo sapiens <400> 1924 ucugccuaau uaaaaaaau 19 <210> 1925 <211> 19 <212> RNA <213> Homo sapiens <400> 1925 cugccuaauu aaaaaaaua 19 <210> 1926 <211> 19 <212> RNA <213> Homo sapiens <400> 1926 ugccuaauua aaaaaauau 19 <210> 1927 <211> 19 <212> RNA <213> Homo sapiens <400> 1927 gccuaauuaa aaaaauaua 19 <210> 1928 <211> 19 <212> RNA <213> Homo sapiens <400> 1928 ccuaauuaaa aaaauauau 19 <210> 1929 <211> 19 <212> RNA <213> Homo sapiens <400> 1929 cuaauuaaaa aaauauaua 19 <210> 1930 <211> 19 <212> RNA <213> Homo sapiens <400> 1930 uaaaaaaaua uauauugua 19 <210> 1931 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1931 uaccuugugu uuucgagccu a 21 <210> 1932 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1932 ugccuacagc cucuucuccu a 21 <210> 1933 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1933 acagccucuu cuccuacaau a 21 <210> 1934 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1934 guccucauca gguauugcug a 21 <210> 1935 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1935 aggagccagu ccuuuguggg a 21 <210> 1936 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1936 gagccagucc uuugugggag a 21 <210> 1937 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1937 ccaguccuuu gugggagaga u 21 <210> 1938 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1938 caguccuuug ugggagagau u 21 <210> 1939 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1939 ugggagagau uggggauuug u 21 <210> 1940 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1940 gggagagauu ggggauuugu a 21 <210> 1941 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1941 gagagauugg ggauuuguac a 21 <210> 1942 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1942 uccugucugc cuaucagggu a 21 <210> 1943 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <400> 1943 caggcucuga acuaugaaau c 21 <210> 1944 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> cm <400> 1944 gaggauaugu caucaucaaa c 21 <210> 1945 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1945 ugggucugag gucuugacuc a 21 <210> 1946 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1946 acucaacgag agcacuugaa a 21 <210> 1947 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1947 cucaacgaga gcacuugaaa a 21 <210> 1948 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1948 ucaacgagag cacuugaaaa u 21 <210> 1949 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1949 aacgagagca cuugaaaaug a 21 <210> 1950 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1950 acgagagcac uugaaaauga a 21 <210> 1951 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1951 cgagagcacu ugaaaaugaa a 21 <210> 1952 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1952 gagagcacuu gaaaaugaaa u 21 <210> 1953 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 1953 agagcacuug aaaaugaaau g 21 <210> 1954 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1954 cuaagagauc uggucaaagc a 21 <210> 1955 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> cm <400> 1955 cuggucaaag caacuggaua c 21 <210> 1956 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1956 aagcaacugg auacuagauc u 21 <210> 1957 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1957 agcaacugga uacuagaucu u 21 <210> 1958 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1958 gcaacuggau acuagaucuu a 21 <210> 1959 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1959 aucuuacauc ugcagcucuu u 21 <210> 1960 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <400> 1960 uacaucugca gcucuuucuu c 21 <210> 1961 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1961 acaucugcag cucuuucuuc u 21 <210> 1962 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1962 caucugcagc ucuuucuucu u 21 <210> 1963 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1963 aucugcagcu cuuucuucuu u 21 <210> 1964 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 1964 ucugcagcuc uuucuucuuu g 21 <210> 1965 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1965 cugcagcucu uucuucuuug a 21 <210> 1966 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1966 ugcagcucuu ucuucuuuga a 21 <210> 1967 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1967 gcagcucuuu cuucuuugaa u 21 <210> 1968 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 1968 cagcucuuuc uucuuugaau u 21 <210> 1969 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <400> 1969 uugaauuucc uaucuguaug u 21 <210> 1970 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1970 uccuaucugu augucugccu a 21 <210> 1971 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1971 aucuguaugu cugccuaauu a 21 <210> 1972 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1972 ucuguauguc ugccuaauua a 21 <210> 1973 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1973 cuguaugucu gccuaauuaa a 21 <210> 1974 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 1974 gucugccuaa uuaaaaaaau a 21 <210> 1975 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1975 uaggcucgaa aacacaaggu aaa 23 <210> 1976 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 1976 uaggagaaga ggcuguaggc acg 23 <210> 1977 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 1977 uauuguagga gaagaggcug uag 23 <210> 1978 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1978 ucagcaauac cugaugagga cuc 23 <210> 1979 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1979 ucccacaaag gacuggcucc uau 23 <210> 1980 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1980 ucucccacaa aggacuggcu ccu 23 <210> 1981 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1981 aucucuccca caaaggacug gcu 23 <210> 1982 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1982 aaucucuccc acaaaggacu ggc 23 <210> 1983 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1983 acaaaucccc aaucucuccc aca 23 <210> 1984 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1984 uacaaauccc caaucucucc cac 23 <210> 1985 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1985 uguacaaauc cccaaucucu ccc 23 <210> 1986 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1986 uacccugaua ggcagacagg aua 23 <210> 1987 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1987 gauuucauag uucagagccu gcc 23 <210> 1988 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 1988 guuugaugau gacauauccu cug 23 <210> 1989 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1989 ugagucaaga ccucagaccc aca 23 <210> 1990 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1990 uuucaagugc ucucguugag uca 23 <210> 1991 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1991 uuuucaagug cucucguuga guc 23 <210> 1992 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1992 auuuucaagu gcucucguug agu 23 <210> 1993 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 1993 ucauuuucaa gugcucucgu uga 23 <210> 1994 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 1994 uucauuuuca agugcucucg uug 23 <210> 1995 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> um <400> 1995 uuucauuuuc aagugcucuc guu 23 <210> 1996 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1996 auuucauuuu caagugcucu cgu 23 <210> 1997 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 1997 cauuucauuu ucaagugcuc ucg 23 <210> 1998 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 1998 ugcuuugacc agaucucuua gac 23 <210> 1999 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> um <400> 1999 guauccaguu gcuuugacca gau 23 <210> 2000 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2000 agaucuagua uccaguugcu uug 23 <210> 2001 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> um <400> 2001 aagaucuagu auccaguugc uuu 23 <210> 2002 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> um <400> 2002 uaagaucuag uauccaguug cuu 23 <210> 2003 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2003 aaagagcugc agauguaaga ucu 23 <210> 2004 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2004 gaagaaagag cugcagaugu aag 23 <210> 2005 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2005 agaagaaaga gcugcagaug uaa 23 <210> 2006 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2006 aagaagaaag agcugcagau gua 23 <210> 2007 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2007 aaagaagaaa gagcugcaga ugu 23 <210> 2008 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2008 caaagaagaa agagcugcag aug 23 <210> 2009 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> gm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorocytosine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2009 ucaaagaaga aagagcugca gau 23 <210> 2010 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroguanine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2010 uucaaagaag aaagagcugc aga 23 <210> 2011 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2011 auucaaagaa gaaagagcug cag 23 <210> 2012 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2012 aauucaaaga agaaagagcu gca 23 <210> 2013 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2013 acauacagau aggaaauuca aag 23 <210> 2014 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2014 uaggcagaca uacagauagg aaa 23 <210> 2015 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2015 uaauuaggca gacauacaga uag 23 <210> 2016 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2016 uuaauuaggc agacauacag aua 23 <210> 2017 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2017 uuuaauuagg cagacauaca gau 23 <210> 2018 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2018 uauuuuuuua auuaggcaga cau 23 <210> 2019 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <400> 2019 uaccuugugu uuucgagccu a 21 <210> 2020 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(4) <223> cm <220> <221> modified_base <222> (5)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2020 uaccuugugu uuucgagccu a 21 <210> 2021 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2021 uaccuugugu uuucgagccu a 21 <210> 2022 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> um <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> cm <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2022 ugggucugag gucuugacuc a 21 <210> 2023 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> cm <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2023 ugggucugag gucuugacuc a 21 <210> 2024 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <400> 2024 agagcacuug aaaaugaaau g 21 <210> 2025 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(14) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2025 agagcacuug aaaaugaaau g 21 <210> 2026 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2026 agagcacuug aaaaugaaau g 21 <210> 2027 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <400> 2027 ucugcagcuc uuucuucuuu g 21 <210> 2028 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> um <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2028 ucugcagcuc uuucuucuuu g 21 <210> 2029 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2029 ucugcagcuc uuucuucuuu g 21 <210> 2030 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> gm <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> gm <220> <221> modified_base <222> (19)..(20) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2030 gcagcucuuu cuucuuugaa u 21 <210> 2031 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> gm <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> gm <220> <221> modified_base <222> (19)..(20) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2031 gcagcucuuu cuucuuugaa u 21 <210> 2032 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> gm <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> um <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(21) <223> um <400> 2032 cagcucuuuc uucuuugaau u 21 <210> 2033 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(21) <223> um <400> 2033 cagcucuuuc uucuuugaau u 21 <210> 2034 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> gm <220> <221> modified_base <222> (4)..(5) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> um <400> 2034 uugaauuucc uaucuguaug u 21 <210> 2035 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> um <400> 2035 uugaauuucc uaucuguaug u 21 <210> 2036 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 2036 agagcacuug aaaaugaaau a 21 <210> 2037 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2037 agagcacuug aaaaugaaau a 21 <210> 2038 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(14) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2038 agagcacuug aaaaugaaau a 21 <210> 2039 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2039 agagcacuug aaaaugaaau a 21 <210> 2040 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <400> 2040 ucugcagcuc uuucuucuuu a 21 <210> 2041 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2041 ucugcagcuc uuucuucuuu a 21 <210> 2042 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> um <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2042 ucugcagcuc uuucuucuuu a 21 <210> 2043 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2043 ucugcagcuc uuucuucuuu a 21 <210> 2044 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2044 uaggcucgaa aacacaaggu aaa 23 <210> 2045 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(4) <223> 2'-fluoroguanine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorouracil <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(19) <223> 2'-fluoroguanine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2045 uaggcucgaa aacacaaggu aaa 23 <210> 2046 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(23) <223> 2'-O-methyladenosine <400> 2046 uaggcucgaa aacacaaggu aaa 23 <210> 2047 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroguanine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-fluoroguanine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(8) <223> 2'-fluoroadenine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2047 ugagucaaga ccucagaccc aca 23 <210> 2048 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroguanine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2048 ugagucaaga ccucagaccc aca 23 <210> 2049 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2049 cauuucauuu ucaagugcuc ucg 23 <210> 2050 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorouracil <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2050 cauuucauuu ucaagugcuc ucg 23 <210> 2051 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2051 cauuucauuu ucaagugcuc ucg 23 <210> 2052 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2052 caaagaagaa agagcugcag aug 23 <210> 2053 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(4) <223> 2'-fluoroadenine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluoroadenine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2053 caaagaagaa agagcugcag aug 23 <210> 2054 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> um <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2054 caaagaagaa agagcugcag aug 23 <210> 2055 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-fluorocytosine <220> <221> modified_base <222> (5)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorocytosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2055 auucaaagaa gaaagagcug cag 23 <210> 2056 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2056 auucaaagaa gaaagagcug cag 23 <210> 2057 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(4) <223> 2'-fluorouracil <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(8) <223> 2'-fluoroadenine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorocytosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2057 aauucaaaga agaaagagcu gca 23 <210> 2058 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2058 aauucaaaga agaaagagcu gca 23 <210> 2059 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluorocytosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-fluorouracil <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorocytosine <220> <221> modified_base <222> (20)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2059 acauacagau aggaaauuca aag 23 <210> 2060 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluorocytosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(22) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2060 acauacagau aggaaauuca aag 23 <210> 2061 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 2061 uauuucauuu ucaagugcuc ucg 23 <210> 2062 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2062 uauuucauuu ucaagugcuc ucg 23 <210> 2063 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorouracil <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2063 uauuucauuu ucaagugcuc ucg 23 <210> 2064 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2064 uauuucauuu ucaagugcuc ucg 23 <210> 2065 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <400> 2065 uaaagaagaa agagcugcag aug 23 <210> 2066 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2066 uaaagaagaa agagcugcag aug 23 <210> 2067 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(4) <223> 2'-fluoroadenine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluoroadenine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2067 uaaagaagaa agagcugcag aug 23 <210> 2068 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(22) <223> um <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2068 uaaagaagaa agagcugcag aug 23 <210> 2069 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2069 uaccuugugu uuucgagccu a 21 <210> 2070 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2070 ccaguccuuu gugggagaga u 21 <210> 2071 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2071 gagagauugg ggauuuguac a 21 <210> 2072 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2072 ugggucugag gucuugacuc a 21 <210> 2073 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2073 agagcacuug aaaaugaaau g 21 <210> 2074 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2074 gcaacuggau acuagaucuu a 21 <210> 2075 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2075 ucugcagcuc uuucuucuuu g 21 <210> 2076 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2076 gcagcucuuu cuucuuugaa u 21 <210> 2077 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 2077 cagcucuuuc uucuuugaau u 21 <210> 2078 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2078 uugaauuucc uaucuguaug u 21 <210> 2079 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2079 uaccuugugu uuucgagccu a 21 <210> 2080 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2080 ccaguccuuu gugggagaga u 21 <210> 2081 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2081 gagagauugg ggauuuguac a 21 <210> 2082 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2082 ugggucugag gucuugacuc a 21 <210> 2083 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2083 agagcacuug aaaaugaaau g 21 <210> 2084 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroadenine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2084 gcaacuggau acuagaucuu a 21 <210> 2085 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2085 ucugcagcuc uuucuucuuu g 21 <210> 2086 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroguanine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2086 gcagcucuuu cuucuuugaa u 21 <210> 2087 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> um <400> 2087 cagcucuuuc uucuuugaau u 21 <210> 2088 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2088 uugaauuucc uaucuguaug u 21 <210> 2089 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <400> 2089 uaccuugugu uuucgagccu a 21 <210> 2090 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(4) <223> cm <220> <221> modified_base <222> (5)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2090 uaccuugugu uuucgagccu a 21 <210> 2091 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2091 uaccuugugu uuucgagccu a 21 <210> 2092 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> um <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> cm <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2092 ugggucugag gucuugacuc a 21 <210> 2093 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluoroguanine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> cm <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2093 ugggucugag gucuugacuc a 21 <210> 2094 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <400> 2094 agagcacuug aaaaugaaau g 21 <210> 2095 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(14) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2095 agagcacuug aaaaugaaau g 21 <210> 2096 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2096 agagcacuug aaaaugaaau g 21 <210> 2097 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <400> 2097 ucugcagcuc uuucuucuuu g 21 <210> 2098 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> um <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2098 ucugcagcuc uuucuucuuu g 21 <210> 2099 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <400> 2099 ucugcagcuc uuucuucuuu g 21 <210> 2100 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> gm <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> gm <220> <221> modified_base <222> (19)..(20) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2100 gcagcucuuu cuucuuugaa u 21 <210> 2101 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> gm <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorocytosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> gm <220> <221> modified_base <222> (19)..(20) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (21)..(21) <223> um <400> 2101 gcagcucuuu cuucuuugaa u 21 <210> 2102 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> gm <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> um <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(21) <223> um <400> 2102 cagcucuuuc uucuuugaau u 21 <210> 2103 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorouracil <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(21) <223> um <400> 2103 cagcucuuuc uucuuugaau u 21 <210> 2104 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(2) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> gm <220> <221> modified_base <222> (4)..(5) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> um <400> 2104 uugaauuucc uaucuguaug u 21 <210> 2105 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(2) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorouracil <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(11) <223> 2'-fluorouracil <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> um <400> 2105 uugaauuucc uaucuguaug u 21 <210> 2106 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroadenine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2106 agagcacuug aaaaugaaau a 21 <210> 2107 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(14) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> gm <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2107 agagcacuug aaaaugaaau a 21 <210> 2108 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2108 agagcacuug aaaaugaaau a 21 <210> 2109 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2109 ucugcagcuc uuucuucuuu a 21 <210> 2110 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> um <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> cm <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> cm <220> <221> modified_base <222> (15)..(16) <223> um <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2110 ucugcagcuc uuucuucuuu a 21 <210> 2111 <211> 21 <212> RNA <213> Artificial Sequence <220> <223> siRNA sense strand against APCS <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroguanine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (11)..(12) <223> 2'-fluorouracil <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> um <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <400> 2111 ucugcagcuc uuucuucuuu a 21 <210> 2112 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2112 uaggcucgaa aacacaaggu aaa 23 <210> 2113 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2113 aucucuccca caaaggacug gcu 23 <210> 2114 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 2114 uguacaaauc cccaaucucu ccc 23 <210> 2115 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2115 ugagucaaga ccucagaccc aca 23 <210> 2116 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2116 cauuucauuu ucaagugcuc ucg 23 <210> 2117 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> um <400> 2117 uaagaucuag uauccaguug cuu 23 <210> 2118 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2118 caaagaagaa agagcugcag aug 23 <210> 2119 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2119 auucaaagaa gaaagagcug cag 23 <210> 2120 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2120 aauucaaaga agaaagagcu gca 23 <210> 2121 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2121 acauacagau aggaaauuca aag 23 <210> 2122 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2122 uaggcucgaa aacacaaggu aaa 23 <210> 2123 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorocytosine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> cm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorocytosine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> um <400> 2123 aucucuccca caaaggacug gcu 23 <210> 2124 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(10) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> cm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> cm <400> 2124 uguacaaauc cccaaucucu ccc 23 <210> 2125 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> gm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2125 ugagucaaga ccucagaccc aca 23 <210> 2126 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2126 cauuucauuu ucaagugcuc ucg 23 <210> 2127 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> gm <220> <221> modified_base <222> (11)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> um <400> 2127 uaagaucuag uauccaguug cuu 23 <210> 2128 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorocytosine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2128 caaagaagaa agagcugcag aug 23 <210> 2129 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> um <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2129 auucaaagaa gaaagagcug cag 23 <210> 2130 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2130 aauucaaaga agaaagagcu gca 23 <210> 2131 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluoroadenine <220> <221> modified_base <222> (2)..(2) <223> cm <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroadenine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2131 acauacagau aggaaauuca aag 23 <210> 2132 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2132 uaggcucgaa aacacaaggu aaa 23 <210> 2133 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(4) <223> 2'-fluoroguanine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorouracil <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(19) <223> 2'-fluoroguanine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2133 uaggcucgaa aacacaaggu aaa 23 <210> 2134 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroguanine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> um <220> <221> modified_base <222> (7)..(7) <223> 2'-fluorocytosine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> cm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> gm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(23) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <400> 2134 uaggcucgaa aacacaaggu aaa 23 <210> 2135 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroguanine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-fluoroguanine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(8) <223> 2'-fluoroadenine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2135 ugagucaaga ccucagaccc aca 23 <210> 2136 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroguanine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> gm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> cm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> um <220> <221> modified_base <222> (14)..(14) <223> 2'-fluorocytosine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2136 ugagucaaga ccucagaccc aca 23 <210> 2137 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2137 cauuucauuu ucaagugcuc ucg 23 <210> 2138 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorouracil <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2138 cauuucauuu ucaagugcuc ucg 23 <210> 2139 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2139 cauuucauuu ucaagugcuc ucg 23 <210> 2140 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2140 caaagaagaa agagcugcag aug 23 <210> 2141 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(4) <223> 2'-fluoroadenine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluoroadenine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2141 caaagaagaa agagcugcag aug 23 <210> 2142 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> cm <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> um <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2142 caaagaagaa agagcugcag aug 23 <210> 2143 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> 2'-fluorocytosine <220> <221> modified_base <222> (5)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorocytosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2143 auucaaagaa gaaagagcug cag 23 <210> 2144 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> cm <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> gm <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroadenine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> cm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2144 auucaaagaa gaaagagcug cag 23 <210> 2145 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(4) <223> 2'-fluorouracil <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(8) <223> 2'-fluoroadenine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(10) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroadenine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorocytosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorouracil <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroguanine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2145 aauucaaaga agaaagagcu gca 23 <210> 2146 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorocytosine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroguanine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroguanine <220> <221> modified_base <222> (17)..(17) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluoroguanine <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(20) <223> um <220> <221> modified_base <222> (21)..(21) <223> gm <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> 2'-O-methyladenosine <400> 2146 aauucaaaga agaaagagcu gca 23 <210> 2147 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluorocytosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-fluorouracil <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorocytosine <220> <221> modified_base <222> (20)..(22) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2147 acauacagau aggaaauuca aag 23 <210> 2148 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (2)..(2) <223> 2'-fluorocytosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroadenine <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(10) <223> um <220> <221> modified_base <222> (11)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> gm <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (16)..(16) <223> 2'-fluoroadenine <220> <221> modified_base <222> (17)..(17) <223> um <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorouracil <220> <221> modified_base <222> (19)..(19) <223> cm <220> <221> modified_base <222> (20)..(22) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2148 acauacagau aggaaauuca aag 23 <210> 2149 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2149 uauuucauuu ucaagugcuc ucg 23 <210> 2150 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> 2'-fluorocytosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluorouracil <220> <221> modified_base <222> (20)..(20) <223> 2'-fluorocytosine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluorouracil <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorocytosine <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2150 uauuucauuu ucaagugcuc ucg 23 <210> 2151 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(2) <223> 2'-fluoroadenine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluorouracil <220> <221> modified_base <222> (4)..(4) <223> um <220> <221> modified_base <222> (5)..(5) <223> 2'-fluorouracil <220> <221> modified_base <222> (6)..(6) <223> cm <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> um <220> <221> modified_base <222> (9)..(9) <223> 2'-fluorouracil <220> <221> modified_base <222> (10)..(11) <223> um <220> <221> modified_base <222> (12)..(12) <223> 2'-fluorocytosine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroadenine <220> <221> modified_base <222> (15)..(15) <223> gm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> um <220> <221> modified_base <222> (20)..(20) <223> cm <220> <221> modified_base <222> (21)..(21) <223> um <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> cm <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2151 uauuucauuu ucaagugcuc ucg 23 <210> 2152 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> 2'-fluorouracil <220> <221> modified_base <222> (2)..(2) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (3)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2152 uaaagaagaa agagcugcag aug 23 <210> 2153 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(4) <223> 2'-fluoroadenine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> 2'-fluoroguanine <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> 2'-fluoroguanine <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-fluoroadenine <220> <221> modified_base <222> (20)..(20) <223> 2'-fluoroguanine <220> <221> modified_base <222> (21)..(21) <223> 2'-fluoroadenine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> 2'-fluorouracil <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2153 uaaagaagaa agagcugcag aug 23 <210> 2154 <211> 23 <212> RNA <213> Artificial Sequence <220> <223> siRNA antisense strand against APCS <220> <221> modified_base <222> (1)..(3) <223> 5'-phosphonothioate <220> <221> modified_base <222> (1)..(1) <223> um <220> <221> modified_base <222> (2)..(3) <223> 2'-fluoroadenine <220> <221> modified_base <222> (4)..(4) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (5)..(5) <223> 2'-fluoroguanine <220> <221> modified_base <222> (6)..(6) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (7)..(7) <223> 2'-fluoroadenine <220> <221> modified_base <222> (8)..(8) <223> gm <220> <221> modified_base <222> (9)..(9) <223> 2'-fluoroadenine <220> <221> modified_base <222> (10)..(11) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (12)..(12) <223> 2'-fluoroguanine <220> <221> modified_base <222> (13)..(13) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (14)..(14) <223> 2'-fluoroguanine <220> <221> modified_base <222> (15)..(15) <223> cm <220> <221> modified_base <222> (16)..(16) <223> 2'-fluorouracil <220> <221> modified_base <222> (17)..(17) <223> gm <220> <221> modified_base <222> (18)..(18) <223> 2'-fluorocytosine <220> <221> modified_base <222> (19)..(19) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (20)..(20) <223> gm <220> <221> modified_base <222> (21)..(21) <223> 2'-O-methyladenosine <220> <221> modified_base <222> (22)..(23) <223> 5'-phosphonothioate <220> <221> modified_base <222> (22)..(22) <223> um <220> <221> modified_base <222> (23)..(23) <223> gm <400> 2154 uaaagaagaa agagcugcag aug 23

Claims (27)

  1. 하기 식 1로 표시되는 핵산 복합체.
    식 1:
    Figure pct00230

    (식 1 중,
    X는 센스 사슬 및 안티센스 사슬을 포함하며, 적어도 11개의 염기쌍의 이중 사슬 영역을 포함하는 이중 사슬 핵산이고,
    상기 이중 사슬 핵산은, 상기 안티센스 사슬 중의, 17개∼30개의 뉴클레오티드 사슬 길이의 올리고뉴클레오티드 사슬에 있어서, 표 1-1∼표 1-13에 기재된 표적 APCS mRNA 서열의 어느 하나와 상보적이고,
    상기 센스 사슬의 3' 말단 또는 5' 말단은 S3에 결합하고,
    L1 및 L2는 각각 독립적으로 당(糖) 리간드이고,
    S1, S2 및 S3은 각각 독립적으로 링커이다.)
  2. 제1항에 있어서, 하기 식 2로 표시되는 구조를 갖는 핵산 복합체.
    식 2:
    Figure pct00231

    (식 2 중,
    X, L1, L2 및 S3은 각각 상기와 동의이고,
    P1, P2, P3, P4, P5 및 P6, 그리고 T1 및 T2는 각각 독립적으로 존재하지 않거나, 또는 -CO-, -NH-, -O-, -S-, -O-CO-, -S-CO-, -NH-CO-, -CO-O-, -CO-S- 혹은 -CO-NH-이고,
    Q1, Q2, Q3 및 Q4는 각각 독립적으로 존재하지 않거나, 또는 치환 혹은 무치환의 탄소수 1∼12의 알킬렌 또는 -(CH2CH2O)n-CH2CH2-이며, n은 0∼99의 정수이고,
    B1 및 B2는 각각 독립적으로 결합수(結合手)이거나 또는 하기 식 2-1로 표시되는 어느 하나의 구조이고, 각 구조에 있어서의 말단의 둥근 흑점은 각각 P2 또는 P3 혹은 P5 또는 P6과의 결합점이며, m1, m2, m3 및 m4는 각각 독립적으로 0∼10의 정수이고,
    식 2-1:
    Figure pct00232

    p1 및 p2는 각각 독립적으로 1, 2 또는 3의 정수이고,
    q1, q2, q3 및 q4는 각각 독립적으로 0∼10의 정수이고,
    단, p1 및 p2가 각각 2 또는 3의 정수일 때, 각각의 P3 및 P6, Q2 및 Q4, T1 및 T2, 그리고 L1 및 L2는 동일하더라도 또는 다르더라도 좋으며, q1∼q4가 2∼10일 때, 각각의 -[P2-Q1]-, -[Q2-P3]-, -[P5-Q3]-, -[Q4-P6]-의 조합은 동일하더라도 또는 다르더라도 좋다.)
  3. 제2항에 있어서, P1 및 P4가 각각 독립적으로 -CO-NH-, -NH-CO- 또는 -O-인 핵산 복합체.
  4. 제2항 또는 제3항에 있어서, -[P2-Q1]q1- 및 -[P5-Q3]q3-이 각각 독립적으로 존재하지 않거나 또는 하기 식 3-1∼식 3-3으로 표시되는 어느 하나의 구조인 핵산 복합체.
    식 3-1:
    Figure pct00233

    식 3-2:
    Figure pct00234

    식 3-3:
    Figure pct00235

    (식 3-1∼식 3-3 중,
    m5 및 m6은 각각 독립적으로 0∼10의 정수이고, 식 3-1∼식 3-3의 구조에 있어서의 말단의 둥근 흑점은 각각 B1 또는 B2 혹은 P1 또는 P4와의 결합점이다.)
  5. 제2항 내지 제4항 중 어느 한 항에 있어서, 하기 식 4-1∼식 4-9로 표시되는 어느 하나의 구조를 갖는 핵산 복합체.
    식 4-1:
    Figure pct00236

    식 4-2:
    Figure pct00237

    식 4-3:
    Figure pct00238

    식 4-4:
    Figure pct00239

    식 4-5:
    Figure pct00240

    식 4-6:
    Figure pct00241

    식 4-7:
    Figure pct00242

    식 4-8:
    Figure pct00243

    식 4-9:
    Figure pct00244

    (식 4-1∼4-9 중,
    X, L1, L2, S3, P3, P6, T1, T2, Q2, Q4, q2 및 q4는 각각 상기와 동의이다.)
  6. 제1항에 있어서, 하기 식 5로 표시되는 구조를 갖는 핵산 복합체.
    식 5:
    Figure pct00245

    (식 5 중,
    X, S3, P1, P2, P3, Q1, Q2, B1, T1, L1, p1, q1 및 q2는 각각 상기와 동의이다.)
  7. 제6항에 있어서, P1이 -CO-NH-, -NH-CO- 또는 -O-인 핵산 복합체.
  8. 제6항 또는 제7항에 있어서, 하기 식 6-1∼식 6-9로 표시되는 어느 하나의 구조를 갖는 핵산 복합체.
    식 6-1:
    Figure pct00246

    식 6-2:
    Figure pct00247

    식 6-3:
    Figure pct00248

    식 6-4:
    Figure pct00249

    식 6-5:
    Figure pct00250

    식 6-6:
    Figure pct00251

    식 6-7:
    Figure pct00252

    식 6-8:
    Figure pct00253

    식 6-9:
    Figure pct00254

    (식 6-1∼6-9 중,
    X, S3, P3, Q2, T1, L1 및 q2는 각각 상기와 동의이다.)
  9. 제2항 내지 제5항 중 어느 한 항에 있어서, 하기 식 7-1∼식 7-9로 표시되는 어느 하나의 구조를 갖는 핵산 복합체.
    식 7-1:
    Figure pct00255

    식 7-2:
    Figure pct00256

    식 7-3:
    Figure pct00257

    식 7-4:
    Figure pct00258

    식 7-5:
    Figure pct00259

    식 7-6:
    Figure pct00260

    식 7-7:
    Figure pct00261

    식 7-8:
    Figure pct00262

    식 7-9:
    Figure pct00263

    (식 7-1∼7-9 중,
    X, S3, L1 및 L2는 각각 상기와 동의이다.)
  10. 제1항 내지 제9항 중 어느 한 항에 있어서, 상기 당 리간드가 N-아세틸갈락토사민인 핵산 복합체.
  11. 제1항 내지 제10항 중 어느 한 항에 있어서, 상기 이중 사슬 핵산이 수식 뉴클레오티드를 포함하는 핵산 복합체.
  12. 제1항 내지 제11항 중 어느 한 항에 있어서, 센스 사슬의 3' 말단 및 안티센스 사슬의 5' 말단은 평활 말단을 형성하는 핵산 복합체.
  13. 제11항에 있어서, 상기 이중 사슬 핵산이 당부(糖部) 수식 뉴클레오티드를 포함하는 핵산 복합체.
  14. 제1항 내지 제13항 중 어느 한 항에 있어서, 하기 식 7-8-1로 표시되는 구조를 갖는 핵산 복합체.
    식 7-8-1:
    Figure pct00264

    (식 7-8-1 중, X는 상기와 동의이다.)
  15. 제1항 내지 제14항 중 어느 한 항에 있어서, X가 표 1-1∼표 1-13에 기재한 센스 사슬/안티센스 사슬로 이루어진 군에서 선택되는 한 쌍의 센스 사슬/안티센스 사슬인 핵산 복합체.
  16. 제1항 내지 제14항 중 어느 한 항에 있어서, X가 표 M1-1∼표 M1-3, 표 R-1∼표 R-2 및 표 R-3∼표 R-4에 기재한 센스 사슬/안티센스 사슬로 이루어진 군에서 선택되는 한 쌍의 센스 사슬/안티센스 사슬인 핵산 복합체.
  17. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체를 포함하는 의약 조성물.
  18. 제17항에 있어서, 세포 내에 도입하기 위한 의약 조성물.
  19. 제17항 또는 제18항에 있어서, 정맥내 투여 또는 피하 투여되는 의약 조성물.
  20. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체 또는 제17항 내지 제19항 중 어느 한 항에 기재한 의약 조성물을, 그것을 필요로 하는 환자에게 투여하는 것을 포함하는, 질환의 치료 또는 예방 방법.
  21. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체 또는 제17항 내지 제19항 중 어느 한 항에 기재한 의약 조성물을 이용하여 이중 사슬 핵산을 세포 내에 도입하는 것을 포함하는, APCS 유전자의 발현을 억제하는 방법.
  22. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체 또는 제17항 내지 제19항 중 어느 한 항에 기재한 의약 조성물을 포유동물에게 투여하는 것을 포함하는, 아밀로이드 관련 질환의 치료 방법.
  23. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체 또는 제17항 내지 제19항 중 어느 한 항에 기재한 의약 조성물을 포함하는, 아밀로이드 관련 질환의 치료에 이용하기 위한 의약.
  24. 제1항 내지 제16항 중 어느 한 항에 기재한 핵산 복합체 또는 제17항 내지 제19항 중 어느 한 항에 기재한 의약 조성물을 포함하는, 아밀로이드 관련 질환의 치료제.
  25. 제22항에 있어서, 아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 치료 방법.
  26. 제23항에 있어서, 아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 의약.
  27. 제24항에 있어서, 아밀로이드 관련 질환이 APCS를 포함한 아밀로이드 섬유에 의해 매개되는 장해에 의해서 야기되는 질환인 치료제.
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