KR102475326B1 - Novel Mimetic Peptide and Composition for Alzheimer's disease - Google Patents
Novel Mimetic Peptide and Composition for Alzheimer's disease Download PDFInfo
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- KR102475326B1 KR102475326B1 KR1020220012105A KR20220012105A KR102475326B1 KR 102475326 B1 KR102475326 B1 KR 102475326B1 KR 1020220012105 A KR1020220012105 A KR 1020220012105A KR 20220012105 A KR20220012105 A KR 20220012105A KR 102475326 B1 KR102475326 B1 KR 102475326B1
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- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- Health & Medical Sciences (AREA)
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Abstract
Description
본 발명은 신규한 펩타이드 유사체 및 이를 포함하는 알츠하이머 병 예방 조성물에 관한 것으로, 더욱 상세하게는 아밀로이드 베타 펩타이드의 아밀로이드 베타 피브릴 형성을 저해하는 신규한 펩타이드 유사체와 이를 포함하여 알츠하이머 병 예방에 유용한 조성물에 관한 것이다. The present invention relates to a novel peptide analog and a composition for preventing Alzheimer's disease containing the same, and more particularly, to a novel peptide analog inhibiting the formation of amyloid beta fibrils of amyloid beta peptide and a composition useful for preventing Alzheimer's disease including the same it's about
치매란 퇴행성 뇌질환 또는 뇌혈관계 질환 등에 의해 기억력, 언어능력, 판단력 및 수행능력 등의 인지기능 저하를 일으켜 일상생활에 지장을 초래하는 후천적인 다발성 장애를 말한다. 대표적인 증상으로는 기억장애, 언어장애, 방향감각 상실, 계산능력 저하, 성격 및 감정의 변화, 이상행동 등이 나타난다. Dementia refers to an acquired multiple disorder that interferes with daily life by causing deterioration in cognitive functions such as memory, language ability, judgment and performance ability due to degenerative brain disease or cerebrovascular disease. Typical symptoms include memory impairment, language impairment, disorientation, decline in calculation ability, personality and emotional changes, and abnormal behavior.
2017년 설문조사 결과, 질환 중 치매는 의료비 지출 부담이 가장 높고(34.3%), 환자·가족의 고통이 가장 크며(54.8%), 가장 발병 원인의 불확실성이 높으면서 치료 대안이 부족한(26.4%) 질병인 동시에 발병 시의 치사율/완치율에서도 암에 이어 두 번째로 위협적인(22.5%) 질환으로 인식되고 있다(참고: 국가과학기술자문회의 심의회의(2018), 제2차 보건의료기술육성기본계획(18~22)).According to the results of the 2017 survey, among the diseases, dementia has the highest burden of medical expenses (34.3%), the greatest pain for patients and their families (54.8%), and the highest uncertainty in the cause of disease and lack of treatment alternatives (26.4%). At the same time, it is recognized as the second most threatening (22.5%) disease after cancer in terms of mortality and cure rate at onset (Reference: National Science and Technology Advisory Council Council (2018), 2nd Health and Medical Technology Promotion Basic Plan ( 18-22)).
치매 유형별로는 신경퇴행성 질환인 알츠하이머 병이 70% 정도로 가장 흔하다. 알츠하이머 병은 아밀로이드 베타(amyloid β, 이하 "Aβ") 펩타이드와 타우 단백질(tau protein)이 비정상적으로 응집되어 신경세포를 손상시키는 질환이다.By type of dementia, Alzheimer's disease, a neurodegenerative disease, is the most common with about 70%. Alzheimer's disease is a disease in which amyloid β (hereinafter "Aβ") peptide and tau protein are abnormally aggregated to damage nerve cells.
알츠하이머 병은 현재 아리셉트(Aricept), 엑셀론(Exelon) 등의 아세틸콜린의 분해를 억제하는 약물이나 나멘다(Namenda)와 같은 글루탐산염 활동 조절제 등으로 치료 중인데, 이러한 약들은 근본적인 치료보다는 저하된 뇌 기능들을 개선시켜주는 데에 그치고 있다. Alzheimer's disease is currently being treated with drugs that inhibit the breakdown of acetylcholine, such as Aricept and Exelon, or glutamate activity modulators, such as Namenda. It's just about improving them.
치매 환자의 뇌에서 특이적으로 나타나는 아미로이드 플라크(amyloid plaque)는 아밀로이드 전구 단백질(Amyloid Precursor Protein, APP)의 비정상적인 분해에 의해 생성되는 Aβ 펩타이드가 응집하여 나타나는 현상이다. 아밀로이드 전구 단백질은 알파-세크레테아제(α-Secretase)와 감마-세크레테아제(γ-Secretase)에 의해 정상적인 경로로 분해되면서 그 기능을 하게 되는데, 알츠하이머 병 환자인 경우 베타-세크레테아제(β-Secretase)와 감마-세크레테아제에 의해 분해되면서 Aβ 모노머 (monomer)를 생성하게 된다. 아밀로이드 피브릴이 형성되는 메커니즘은 두 단계(two-step mechanism)로, 모노머들 간에 핵형성(nucleation)이 일어나고 핵이 응집이 되면서 섬유형태의 아밀로이드 피브릴이 성장한다(도 1 참조). 피브릴이 뭉쳐 반점처럼 생긴 덩어리 형태의 아밀로이드 플라크를 형성하고, 플라그 덩어리가 신경세포 외부에 쌓이면서 신경세포의 손상을 야기한다.Amyloid plaques, which appear specifically in the brains of patients with dementia, are a phenomenon caused by the aggregation of Aβ peptides produced by abnormal degradation of amyloid precursor protein (APP). Amyloid precursor protein functions as it is degraded in a normal pathway by alpha-secretase and gamma-secretase. In patients with Alzheimer's disease, beta-secretase (β -Secretase) and gamma-secretase to form Aβ monomers. The mechanism by which amyloid fibrils are formed is a two-step mechanism, in which nucleation occurs between monomers and nuclei aggregate, and fibrous amyloid fibrils grow (see FIG. 1). Fibrils aggregate to form amyloid plaques in the form of spot-like lumps, and plaque lumps accumulate on the outside of nerve cells, causing damage to nerve cells.
이에 아밀로이드 플라크를 효과적으로 감소시켜 알츠하이머 병에 대한 예방 또는 치료를 위한 기술들이 개발되었는데, 그 일 예로 한국등록특허 10-1802251호에는 Aβ 펩타이드 및 bvPLA2 (bee venom phospolipase A2)를 유효성분으로 포함하는 알츠하이머 병에 대한 예방 또는 치료용 백신 조성물이 개시되어 있다. Accordingly, technologies for preventing or treating Alzheimer's disease by effectively reducing amyloid plaques have been developed. For example, Korean Patent Registration No. 10-1802251 discloses Alzheimer's disease containing Aβ peptide and bvPLA2 (bee venom phospolipase A2) as active ingredients. A vaccine composition for the prevention or treatment of is disclosed.
또 다른 일예로 일본특허공개 2007-523848호에는 Aβ 응집 저해능을 가지는 펩타이드 및 그 유도체 또는 유사체를 개시하였는바, 구체적으로는 식 I: X1 [Lys X2 X3 Phe Gln]m Arg Gln Ile [Lys X4 Pro Phe Gln]n X (여기서 X1은 존재하지 않거나 또는 아세틸기이며; X2 및 X4는 독립적으로 Ileu 및 Leu로부터 선택되고; X3은 Pro 및 Trp로부터 선택되고; X는 1, 2, 3, 4, 5, 6, 7 및 8개의 아미노산으로부터 선택되는 길이로, 적어도 1개의 알칼리성 아미노산을 포함해, C－말단에서 아미드화된 펩티드부이며; m은 0 및 1로부터 선택되는 정수이며; n은 1 및 2로부터 선택되는 정수이다.)의 아미노산 배열을 가지는 펩타이드 및 그 염이, Aβ 아밀로이드 응집체의 형성에 대하여 저해 효과가 있음을 확인하였다.As another example, Japanese Patent Publication No. 2007-523848 discloses a peptide having an Aβ aggregation inhibitory ability and a derivative or analog thereof, specifically Formula I: X1 [Lys X2 X3 Phe Gln]m Arg Gln Ile [Lys X4 Pro Phe Gln]n X, wherein X1 is absent or an acetyl group; X2 and X4 are independently selected from Ileu and Leu; X3 is selected from Pro and Trp; and X is 1, 2, 3, 4, 5 , a peptide moiety selected from 6, 7 and 8 amino acids, containing at least one alkaline amino acid, amidated at the C-terminus; m is an integer selected from 0 and 1; n is 1 and 2 It was confirmed that the peptide having an amino acid sequence and a salt thereof have an inhibitory effect on the formation of Aβ amyloid aggregates.
이에 본 발명은 알츠하이머 병의 근본적인 원인이 되는 Aβ 펩타이드에 작용하여 아밀로이드 피브릴 형성을 저해하는 펩타이드 유사체 또는 이의 약학적으로 허용가능한 염을 제공하고자 한다. Accordingly, the present invention is intended to provide a peptide analog or a pharmaceutically acceptable salt thereof that inhibits the formation of amyloid fibrils by acting on the Aβ peptide, which is the fundamental cause of Alzheimer's disease.
또한 본 발명은 이러한 펩타이드 유사체를 포함하여 예방의학적으로 알츠하이머 병의 발병을 억제 내지 지연시킬 수 있는 매우 효과적인 조성물을 개발하고자 한다. In addition, the present invention is intended to develop a highly effective composition that can prevent or delay the onset of Alzheimer's disease, including these peptide analogues.
본 발명은 하기 화학식 1 내지 화학식 2로 표시되며, Aβ펩타이드의 아밀로이드 피브릴 형성을 저해하는, 펩타이드 유사체 또는 이의 약학적으로 허용가능한 염을 제공한다. The present invention provides peptide analogues or pharmaceutically acceptable salts thereof, which are represented by the following
상기 화학식 1 내지 2에 있어서, R은 -(CH2)n-페닐기 또는 -(CH2)n-사이클로헥실기이며, n은 3 내지 7의 정수이다. In
본 발명의 바람직한 일례에 따른 펩타이드 유사체 또는 이의 약학적으로 허용가능한 염은, 아밀로이드 베타42(이하"Aβ42") 펩타이드 또는 아밀로이드 베타40(이하"Aβ40") 펩타이드의 아밀로이드 피브릴 형성을 저해하는 것일 수 있다. Peptide analogues or pharmaceutically acceptable salts thereof according to a preferred embodiment of the present invention may inhibit the formation of amyloid fibrils of amyloid beta42 (hereinafter "Aβ42") peptide or amyloid beta40 (hereinafter "Aβ40") peptide. have.
본 발명의 구체적인 일례에 따른 펩타이드 유사체 또는 이의 약학적으로 허용가능한 염은, 다음 화학식 3 내지 6 중에서 선택된 단독 또는 2 이상의 혼합물일 수 있다.Peptide analogues or pharmaceutically acceptable salts thereof according to specific examples of the present invention may be selected from the following Chemical Formulas 3 to 6, or a mixture of two or more thereof.
본 발명의 일례에 따른 약학적으로 허용가능한 염은, 염산(Hydrochloric acid), 황산(Sulfuric acid), 질산(Nitric acid), 인산(Phosphoric acid), 브롬산(Bromic acid), 과염소산(Perchloric acid), 퓨마르산(Fumaric acid), 말레산(Maleic acid), 락트산(Lactic acid), 살리실산(Salicylic acid), 숙신산(Succinic acid), p-톨루엔술폰산(p-Toluenesulfonic acid), 메탄술폰산(Methanesulfonic acid), 포름산(Formic acid), 타르타르산(Tartaric acid), 시트르산(Citric acid), 아세트산(Acetic acid), 삼불화아세트산(Trifluoroacetic acid), 트리클로로아세트산(Trichloroacetic acid), 벤젠술폰산(Benzenesulfonic acid), 2-나프틸술폰산(2-Naphthylsulfonic acid), 벤조산(Benzoic acid), 말론산 (Malonic acid), 모노클로로아세트산(Monochloroacetic acid) 및 디클로로아세트산 (Dichloroacetic acid) 중에서 선택된 산염(acid salt), 나트륨(Sodium) 또는 마그네슘의 금속염, 및 탄소수 1 내지 10인 알킬(Alkyl) 또는 아릴(Aryl)기를 갖는 암모늄염 중에서 선택된 것일 수 있다.Pharmaceutically acceptable salts according to an example of the present invention are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, bromic acid, perchloric acid , Fumaric acid, Maleic acid, Lactic acid, Salicylic acid, Succinic acid, p - Toluenesulfonic acid, Methanesulfonic acid , Formic acid, Tartaric acid, Citric acid, Acetic acid, Trifluoroacetic acid, Trichloroacetic acid, Benzenesulfonic acid, 2- An acid salt selected from 2-Naphthylsulfonic acid, Benzoic acid, Malonic acid, Monochloroacetic acid and Dichloroacetic acid, Sodium or It may be selected from metal salts of magnesium and ammonium salts having an alkyl or aryl group having 1 to 10 carbon atoms.
본 발명은 또한 상기 일 구현 예들에 의한 펩타이드 유사체 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는, 알츠하이머 병 예방용 조성물을 제공한다.The present invention also provides a composition for preventing Alzheimer's disease comprising the peptide analog or a pharmaceutically acceptable salt thereof according to the above embodiments as an active ingredient.
본 발명의 일례에 따른 알츠하이머 병 예방용 약학 조성물은 비강, 피부, 구강 또는 피하주사로 투여할 수 있다. The pharmaceutical composition for preventing Alzheimer's disease according to an example of the present invention may be administered through nasal, dermal, oral or subcutaneous injection.
본 발명에 따르면 Aβ 펩타이드에 작용하여 아밀로이드 피브릴 형성을 저해하는 펩타이드 유사체를 제공할 수 있고, 이러한 펩타이드 유사체를 포함하여 예방의학적으로 알츠하이머 병의 발병을 억제 내지 지연시킬 수 있는 매우 효과적인 조성물을 제공할 수 있다.According to the present invention, it is possible to provide a peptide analog that inhibits the formation of amyloid fibrils by acting on the Aβ peptide, and a highly effective composition that can prevent or delay the onset of Alzheimer's disease, including such a peptide analog, can be provided. can
도 1은 Aβ 펩타이드의 아밀로이드 피브릴 형성 기전의 모식도.
도 2는 본 발명에 따른 신규한 펩타이드 유사체의 Aβ 펩타이드의 아밀로이드 피브릴 형성 저해 기전의 모식도.
도 3 내지 6은 합성된 화학식 3 내지 6으로 표시되는 펩타이드 유사체에 대한 역상 고성능 액체크로마토그래피(Reverse Phase High Performance Liquid Chromatography, RP-HPLC) 분석 그래프로, 도 3은 화학식 3 화합물, 도 4는 화학식 4 화합물, 도 5는 화학식 5 화합물, 도 6은 화학식 6 화합물에 대한 RP-HPLC 분석그래프.
도 7 내지 도 8은 화학식 3 내지 6에 따른 펩타이드 유사체(각각 화3, 화4, 화5 및 화6으로 약칭하여 도시함)에 대한 ThT 분석(Thioflavin T Assay) 결과 그래프로, 도 7은 Aβ40에 대한 시간의 변화에 따른 형광강도 변화를 관측한 결과이며, 도 8은 Aβ42에 대한 시간의 변화에 따른 형광강도 변화를 관측한 결과그래프.
도 9 내지 13은 ThT 분석이 끝난 각 시료에 대한 TEM (Transmission Electron Microscopy) 이미지로, 도 9는 Aβ42 펩타이드, 도 10은 'Aβ42 펩타이드 + 화학식 3 화합물', 도 11은 'Aβ42 펩타이드 + 화학식 4 화합물', 도 12는 'Aβ42 펩타이드 + 화학식 5 화합물', 그리고 도 13은 'Aβ42 펩타이드 + 화학식 6 화합물' 시료에 대하여 그 상을 관찰한 TEM 이미지.1 is a schematic diagram of the formation mechanism of amyloid fibrils of Aβ peptides.
Figure 2 is a schematic diagram of the mechanism of inhibition of amyloid fibril formation by the Aβ peptide of the novel peptide analogue according to the present invention.
3 to 6 are reverse phase high performance liquid chromatography (RP-HPLC) analysis graphs for the synthesized peptide analogues represented by Formulas 3 to 6, Figure 3 is a compound of Formula 3, Figure 4 is a
7 to 8 are graphs of ThT analysis (Thioflavin T Assay) results for peptide analogs according to Chemical Formulas 3 to 6 (abbreviated as Flower 3,
9 to 13 are TEM (Transmission Electron Microscopy) images of each sample after ThT analysis, FIG. 9 is Aβ42 peptide, FIG. 10 is ‘Aβ42 peptide + compound of Formula 3’, and FIG. 11 is ‘Aβ42 peptide + compound of Formula 4’ ', Figure 12 is 'Aβ42 peptide +
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다. The present invention will be described in more detail as follows.
Aβ 펩타이드의 16 내지 21 영역인 KLVFFA (Lys-Leu-Val-Phe-Phe-Ala)는 β-sheet 형성 및 원섬유발생 동안의 Aβ의 분자간 상호작용의 원인이 된다. 이러한 KLVFFA 자체에 대하여 Aβ 응집 저해능을 ThT 분석한 결과 아밀로이드 피브릴의 응집은 거의 저해되지 않는다는 선행 연구결과가 있다[참고: Angew. Chem. Int. Ed. 2014, 53, 1 - 5]. KLVFFA (Lys-Leu-Val-Phe-Phe-Ala),
본 발명에서는 Aβ 응집의 핵 역할을 하는 KLVFFA (Lys-Leu-Val-Phe-Phe-Ala)의 유도체를 이용하여 Aβ 모노머의 핵 형성을 억제함으로써 아밀로이드 피브릴 형성을 지연 내지 억제하고자 한다. In the present invention, the formation of amyloid fibrils is delayed or suppressed by inhibiting the formation of nuclei of Aβ monomers using a derivative of KLVFFA (Lys-Leu-Val-Phe-Phe-Ala), which serves as a nucleus for Aβ aggregation.
구체적으로는 도 2로 도시한 바와 같이 Aβ의 핵형성을 저해하고 피브릴 성장 부분을 캡핑(capping)하여 피브릴 성장을 지연하는 기전을 갖도록 신규한 펩타이드 유사체를 설계하였다. KLVFFA의 골격(backbone)은 유지하여 Aβ와의 결합 친밀도(Binding affinity)를 유지한 채, FF(Phe-Phe)를 히스티딘 유도체로 교체하였다. 히스티딘 유도체는 이미다졸 링(Imidazol ring)의 아민(Amine)을 알킬렌 페닐기 또는 알킬렌 사이클로헥실기로 치환함으로써 부피가 큰(bulky) 치환기가 다른 Aβ모노머의 접근을 막아주는 역할을 한다. 따라서 아밀로이드 피브릴의 성장부분에 잘 결합하여 피브릴 응집체를 캡핑하는 구조를 갖는다.Specifically, as shown in FIG. 2, a novel peptide analog was designed to have a mechanism of inhibiting the nucleation of Aβ and delaying fibril growth by capping the fibril growth portion. The backbone of KLVFFA was maintained and binding affinity with Aβ was maintained, and FF (Phe-Phe) was replaced with a histidine derivative. In the histidine derivative, the amine of the imidazol ring is substituted with an alkylene phenyl group or an alkylene cyclohexyl group so that the bulky substituent serves to prevent access of other Aβ monomers. Therefore, it has a structure that binds well to the growing portion of amyloid fibrils and caps fibril aggregates.
구체적으로 본 발명에 따른 신규한 펩타이드 유사체는, 하기 화학식 1(서열번호 1) 내지 화학식 2(서열번호 2)로 표시되는 것이다.Specifically, the novel peptide analogues according to the present invention are those represented by Formula 1 (SEQ ID NO: 1) to Formula 2 (SEQ ID NO: 2).
화학식 1
화학식 2
상기 화학식 1 내지 2에 있어서, R은 -(CH2)n-페닐기 또는 -(CH2)n-사이클로헥실기이며, n은 3 내지 7의 정수이다. In
이와 같은 화학식 1 내지 2로 표시되는 펩타이드 유사체는 ThT 분석을 통한 형광강도 변화를 관찰한 결과 Aβ 펩타이드의 아밀로이드 피브릴 형성을 지연하거나 억제하는 우수한 활성을 확인하였다. 여기서, ThT는 아밀로이드 피브릴과 같이 crossed-β-sheet 구조를 가지는 단백질 응집체와 결합하여 형광을 발산하는 물질로 잘 알려져 있다. 따라서, ThT의 형광강도(intensity)와 λmax(형광강도가 최대일 때의 wavelength)의 변화로부터 펩타이드 유사체의 아밀로이드 피브릴 형성 저해효능을 평가할 수 있다. As a result of observing the change in fluorescence intensity of the peptide analogues represented by Chemical Formulas 1 and 2 through ThT analysis, it was confirmed that the Aβ peptide has excellent activity in delaying or inhibiting the formation of amyloid fibrils. Here, ThT is well known as a substance that emits fluorescence by binding to protein aggregates having a crossed-β-sheet structure, such as amyloid fibrils. Therefore, the ability of the peptide analogues to inhibit formation of amyloid fibrils can be evaluated from changes in ThT fluorescence intensity and λmax (wavelength at which fluorescence intensity is maximum).
한편, 일반적으로 펩타이드 저해제의 경우 생체 내에서 프로테아제 (Protease)에 의한 분해가 문제가 된다. 이에 본 발명에서는 상기 화학식 1 내지 2로 표시되는 바와 같이 KLVFFA의 골격은 유지하면서, FF (Phe-Phe)를 히스티딘 유도체로 바꾸고, 여기에 -(CH2)n-페닐기 또는 -(CH2)n-사이클로헥실기를 도입하였다. Meanwhile, in the case of peptide inhibitors, in vivo degradation by proteases is a problem. Accordingly, in the present invention, as shown in
이와 관련하여 한국등록특허 10-1381285호에는 히스티딘 유도체를 포함한 펩타이드에 있어서 프로테아제 처리 후에도 항균 활성이 유지됨을 확인한 바 있다.In this regard, Korean Patent Registration No. 10-1381285 confirmed that antibacterial activity is maintained even after protease treatment in peptides including histidine derivatives.
구체적으로 한국등록특허 10-1381285호에는 다음 화학식 7로 표시되는 이미다졸기의 N(π)와 N(τ) 위치가 모두 치환된 히스티딘 유도체와 아르기닌을 함유하는 것을 특징으로 하는 펩티드, 이의 항균 및 항염증 활성과 관련하여 개시하고 있으며, 이는 프로테아제 처리 후에도 항균 활성이 유지되어 종래 펩타이드 항균제들의 불안정성으로 인한 항균제 개발의 문제점을 해소할 수 있는 것으로 기재하고 있다. Specifically, Korean Patent Registration No. 10-1381285 discloses a peptide characterized by containing a histidine derivative in which both the N(π) and N(τ) positions of the imidazole group represented by Formula 7 are substituted and arginine, the antibacterial and It is disclosed in relation to anti-inflammatory activity, and it is disclosed that the antibacterial activity is maintained even after protease treatment, thereby solving the problem of antimicrobial agent development due to the instability of conventional peptide antimicrobial agents.
화학식 7Formula 7
이때 R=-(CH2)n-CH3, -(CH2)n-Ph 또는 -(CH2)n-Cyclohexyl, n=1~7인 정수이다).In this case, R=-(CH 2 ) n -CH 3 , -(CH 2 ) n -Ph or -(CH 2 ) n -Cyclohexyl, n = 1 to 7).
본 발명자들은 Aβ 아밀로이드가 피브릴을 형성하는데 그 아미노산 서열 중 core region인 KLVFFA (Lys-Leu-Val-Phe-Phe-Ala)가 핵심역할을 하는 것으로 판단되어 서열 중에서 FF (Phe-Phe) 대신에 상기 화학식 7로 표시되는 히스티딘 유도체를 포함하는 다양한 펩타이드 유사체를 합성하였다. 이 중 상기 화학식 1 또는 2로 표시되는 펩타이드 유사체에 대해 아밀로이드 피브릴 형성 저해 활성을 확인한 바, Aβ42 또는 Aβ40의 아밀로이드 피브릴 형성 저해 활성을 가짐이 확인되어 본 발명에 이르게 되었다. The present inventors believe that KLVFFA (Lys-Leu-Val-Phe-Phe-Ala), a core region in the amino acid sequence, plays a key role in Aβ amyloid forming fibrils, so instead of FF (Phe-Phe) in the sequence Various peptide analogs including the histidine derivative represented by Chemical Formula 7 were synthesized. Among them, as a result of confirming the amyloid fibril formation inhibitory activity of the peptide analog represented by
예측컨대, 본 발명의 펩타이드 유사체는 Aβ42 또는 Aβ40의 아밀로이드 피브릴 형성 저해 활성은, 생체조건 하에서도 프로테아제 저항성이 높을 것으로 기대할 수 있는데, 이는 상기 화학식 7로 표시되는 히스티딘 유도체가 포함된 서열이기 때문이며, 이로써 본 발명에 따른 펩타이드 유사체는 프로테아제 처리 후에도 아밀로이드 피브릴 형성 저해효능이 유지되어 알츠하이머 병 예방제 개발에 유용할 것임을 기대할 수 있다.Predictably, the amyloid fibril formation inhibitory activity of Aβ42 or Aβ40 in the peptide analogs of the present invention can be expected to have high protease resistance even under in vivo conditions. This is because the sequence contains the histidine derivative represented by Formula 7, Accordingly, it can be expected that the peptide analogue according to the present invention will be useful for the development of an agent for preventing Alzheimer's disease because the effect of inhibiting amyloid fibril formation is maintained even after protease treatment.
한편, Aβ는 정상적인 세포내 대사과정을 거치면서 생성되어 Aβ40과 Aβ42 형태로 주로 존재하고, 수용성 단백질의 형태로 뇌척수액으로 흘러 들어간다. Aβ 응집체인 아밀로이드 피브릴이 뭉쳐서 형성되는 불용성의 플라크와 인산화된 타우(Tau) 응집체가 침착되어 형성된 neurofibrillary tangle은 알츠하이머 병을 앓고 있는 환자의 뇌에서 나타나는 특징이다. On the other hand, Aβ is produced through normal intracellular metabolism, exists mainly in the form of Aβ40 and Aβ42, and flows into the cerebrospinal fluid in the form of a water-soluble protein. Insoluble plaques formed by aggregation of amyloid fibrils, which are Aβ aggregates, and neurofibrillary tangles formed by deposition of phosphorylated tau aggregates are characteristics of the brains of patients suffering from Alzheimer's disease.
본 발명에 따른 신규한 펩타이드 유사체는 이러한 Aβ40 또는 Aβ42의 아밀로이드 피브릴 형성을 저해하며, 특히 바람직하게는 Aβ40와 Aβ42의 아밀로이드 피브릴 형성을 모두 저해하는 것일 수 있다. The novel peptide analog according to the present invention inhibits the formation of amyloid fibrils of Aβ40 or Aβ42, and particularly preferably may inhibit the formation of amyloid fibrils of both Aβ40 and Aβ42.
본 발명에 다른 바람직한 펩타이드 유사체 또는 이의 약학적으로 허용 가능한 염의 일례는 보다 구체적으로, 다음 화학식 3 내지 6 중에서 선택된 단독 또는 2 이상의 혼합물일 수 있다. More specifically, one example of a preferred peptide analog or a pharmaceutically acceptable salt thereof according to the present invention may be selected from the following formulas 3 to 6 alone or in a mixture of two or more.
화학식 3Formula 3
화학식 4
화학식 5
화학식 6
상기 화학식 3으로 표시되는 펩타이드 유사체는 Aβ 피브릴 core region인 KLVFFA (Lys-Leu-Val-Phe-Phe-Ala)의 서열에 있어서, FF 대신에 이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Ph기로 치환된 히스티딘 유도체를 갖는 구조의 화합물이다(서열번호 3). In the sequence of KLVFFA (Lys-Leu-Val-Phe-Phe-Ala), which is an Aβ fibril core region, the peptide analogue represented by Formula 3 contains N(π) and N(τ) of the imidazole group instead of FF. It is a compound having a structure having a histidine derivative in which all positions are substituted with -(CH 2 ) 3 -Ph groups (SEQ ID NO: 3).
상기 화학식 4로 표시되는 펩타이드 유사체는 Aβ 피브릴 core region인 KLVFFA (Lys-Leu-Val-Phe-Phe-Ala)의 서열에 있어서, FF 대신에 이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체를 갖는 구조의 화합물이다(서열번호 4). In the sequence of KLVFFA (Lys-Leu-Val-Phe-Phe-Ala), which is an Aβ fibril core region, the peptide analog represented by
상기 화학식 5(서열번호 5) 및 6(서열번호 6)으로 표시되는 펩타이드 유사체는 고리형의 펩타이드 유사체로, 이는 Aβ 피브릴 core region인 KLVFFA( Lys-Leu-Val-Phe-Phe-Ala)의 서열에 있어서, FF 대신에 이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Ph기 또는 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체를 갖는 구조의 고리형 펩타이드이다. 이는 특히 티오에테르(CH2-S-CH2) 결합을 갖는 고리형 펩타이드로, 이와 같은 티오에테르 결합은 N-말단 브로모아세트산(Bromoacetic acid, Br-CH2-COOH)와 C-말단의 시스테인(Cys)의 곁사슬인 CH2-SH와 결합하여 이루어진 결합이다. The peptide analogs represented by Formulas 5 (SEQ ID NO: 5) and 6 (SEQ ID NO: 6) are cyclic peptide analogs, which are the Aβ fibril core region of KLVFFA (Lys-Leu-Val-Phe-Phe-Ala). In the sequence, both the N(π) and N(τ) positions of the imidazole group in place of FF have a structure having a histidine derivative in which -(CH 2 ) 3 -Ph group or -(CH 2 ) 3 -Cyclohexyl group is substituted. It is a cyclic peptide. This is especially a cyclic peptide having a thioether (CH 2 -S-CH 2 ) bond, and such a thioether bond is composed of N-terminal bromoacetic acid (Br-CH 2 -COOH) and C-terminal cysteine. It is a bond formed by combining with (Cys) side chain CH 2 -SH.
경우에 따라 선형의 펩타이드 유사체 보다 고리형의 펩타이드 유사체가 아밀로이드 피브릴 형성 저해 활성에 있어서 보다 우수할 수 있다. In some cases, cyclic peptide analogues may be superior to linear peptide analogues in their amyloid fibril formation inhibitory activity.
또한, 경우에 따라 히스티딘 유도체에 있어서 방향족기를 가지는 펩타이드 유사체가 그렇지 않은 경우와 대비하여 아밀로이드 피브릴 형성 저해 활성이 보다 우수할 수 있다. In addition, in some cases, histidine derivatives may have more excellent amyloid fibril formation inhibitory activity than peptide analogues having an aromatic group.
상기 화학식 3 내지 6으로 표시되는 화합물들의 경우 히스티딘 유도체에 있어서 이미다졸기의 N(π) 및 N(τ) 위치의 치환체의 알킬렌 사슬의 길이가 3인 경우의 일례들로, 알킬렌 사슬의 길이가 3 내지 7까지 아밀로이드 피브릴 형성 저해 활성이 우수하다. 그러나, 알킬렌 사슬의 길이가 3보다 작은 경우는 활성이 감소하는 문제가 있을 수 있으며, 7보다 큰 경우도 활성이 감소하는 문제가 있을 수 있다. 상술한 측면에서 가장 아밀로이드 피브릴 형성 저해 활성이 우수한 펩타이드 유사체는 상기 화학식 5로 표시되는 것일 수 있다. In the case of the compounds represented by Chemical Formulas 3 to 6, examples of cases where the length of the alkylene chain of the N(π) and N(τ) position substituents of the imidazole group in the histidine derivative are 3, It is excellent in amyloid fibril formation inhibitory activity from 3 to 7 in length. However, if the length of the alkylene chain is less than 3, there may be a problem of reducing activity, and if it is greater than 7, there may be a problem of reducing activity. In terms of the above, the peptide analogue having the most excellent amyloid fibril formation inhibitory activity may be one represented by
한편, 본 발명에 따른 펩타이드 유사체는 약학적으로 허용되는 염을 포함할 수 있는데, 이때의 염은 무기산, 유기산 및 염기로부터 유도된 염을 포함할 수 있다. 구체적으로는, 염산(Hydrochloric acid), 황산(Sulfuric acid), 질산(Nitric acid), 인산(Phosphoric acid), 브롬산(Bromic acid), 과염소산(Perchloric acid), 퓨마르산(Fumaric acid), 말레산(Maleic acid), 락트산(Lactic acid), 살리실산(Salicylic acid), 숙신산(Succinic acid), p-톨루엔술폰산(p-Toluenesulfonic acid), 메탄술폰산(Methanesulfonic acid), 포름산(Formic acid), 타르타르산(Tartaric acid), 시트르산(Citric acid), 아세트산(Acetic acid), 삼불화아세트산(Trifluoroacetic acid), 트리클로로아세트산(Trichloroacetic acid), 벤젠술폰산(Benzenesulfonic acid), 2-나프틸술폰산(2-Naphthylsulfonic acid), 벤조산(Benzoic acid), 말론산(Malonic acid), 모노클로로아세트산(Monochloroacetic acid), 디클로로아세트산(Dichloroacetic acid) 중에서 선택된 산염(acid salt) 일 수 있으며, 염기로부터 유도된 염은 나트륨(Sodium) 또는 마그네슘 등의 알카리 금속염, 및 탄소수 1 내지 10인 알킬(Alkyl)기 또는 아릴(Aryl)기를 갖는 암모늄염 등을 포함할 수 있다.Meanwhile, the peptide analogue according to the present invention may include a pharmaceutically acceptable salt, and the salt may include salts derived from inorganic acids, organic acids, and bases. Specifically, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, bromic acid, perchloric acid, fumaric acid, maleic acid (Maleic acid), lactic acid, salicylic acid, succinic acid, p -Toluenesulfonic acid, methanesulfonic acid, formic acid, tartaric acid acid), citric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, 2-naphthylsulfonic acid, It may be an acid salt selected from benzoic acid, malonic acid, monochloroacetic acid, and dichloroacetic acid, and a salt derived from a base is sodium or magnesium Alkali metal salts such as the like, and ammonium salts having an alkyl group or an aryl group having 1 to 10 carbon atoms.
본 발명에 따른 상기 화학식 1 내지 2로 대별되는 신규한 펩타이드 유사체 또는 이의 약학적으로 허용 가능한 염을 합성하는 방법은 한정이 있는 것은 아니며, 당 업계에 알려진 기술을 사용하여 제조할 수 있음은 물론이다. The method for synthesizing the novel peptide analogs or pharmaceutically acceptable salts thereof classified into
대표적인 합성 방법을 아래에 설명하고 있으나, 본 발명이 이러한 예에 제한되는 것은 아니며, 당 업계에 알려진 기술의 범위 내에서 당 업자가 적절히 변형하여 사용할 수 있다.Representative synthesis methods are described below, but the present invention is not limited to these examples, and those skilled in the art may appropriately modify and use them within the scope of technology known in the art.
일례로 펩타이드 유사체의 합성은 고상 합성법 (Solid Phase Peptide Synthesis, SPPS)을 이용할 수 있는데, 화학식 1로 표시되는 펩타이드 유사체의 경우는 다음의 반응식 1로 나타내는 방법에 따라 얻어질 수 있다. For example, solid phase peptide synthesis (SPPS) may be used for the synthesis of peptide analogues. In the case of the peptide analogue represented by
(반응식 1)(Scheme 1)
다른 한편으로, 화학식 2로 표시되는 고리형 펩타이드 유사체의 경우는 고상과 액상 합성법을 병용하여 제조할 수 있는데, 이는 간략히 다음의 반응식 2로 나타낼 수 있다. On the other hand, in the case of the cyclic peptide analog represented by
(반응식 2)(Scheme 2)
이와 같은 합성법에 있어서 다양한 보호기를 사용할 수 있음은 물론인데, 일례로 아민 보호기는 아세트아미노메틸(Acetaminomethyl)기, 벤질옥시카보닐 (Benzyloxycarbonyl)기, 터트-부틸옥시카르보닐(tert-Butyloxycarbonyl)기, 아세틸 (acetyl)기, 벤조일(Benzoyl)기, 파라-니트로벤조일(para-Nitrobenzoyl)기, 파라-메톡시벤조일기(para-Methoxybenzoyl) 등을 예시할 수 있으며, 벤질옥시카보닐 (Benzyloxycarbonyl)기 또는 터트-부틸옥시카르보닐(tert-Butyloxycarbonyl)기가 바람직할 수 있다. Of course, various protecting groups can be used in this synthesis method. For example, an amine protecting group includes an acetaminomethyl group, a benzyloxycarbonyl group, a tert -butyloxycarbonyl group, An acetyl group, a benzoyl group, a para -nitrobenzoyl group, a para -methoxybenzoyl group, and the like can be exemplified, and a benzyloxycarbonyl group or A tert-Butyloxycarbonyl group may be preferred.
티올 보호기는 메톡시메틸(Methoxymethyl)기, 벤질옥시메틸(Benzyloxymethyl)기, 트리페닐메틸(Triphenylmethyl)기, 터트-부틸디메틸실릴(tert-Butyldimethylsilyl)기, 트리페닐실릴(Triphenylsilyl)기, 트리이소프로필실릴(Triisopropylsilyl)기, 파라-메톡시벤질(para-Methyloxybenzyl)기, 테트라히드로피란(Tetrahydropyran)기, 테트라히드로퓨란(Tetrahydrofuran)기, 터트-부틸(tert-Butyl)기, 디페닐메틸(Diphenylmethyl)기, 2-클로로트리틸(2-Chlorotrityl)기, 벤질(Benzyl)기, 4-메톡시벤질(4-Methoxybenzyl)기, 알릴(Allyl)기, 터트-부틸옥시카르보닐(tert-Butyloxycarbonyl)기, 아세틸(Acetyl)기, 벤조일(Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸(Methoxymethyl)기, 벤질옥시메틸(Benzyloxymethyl)기, 2-클로로트리틸(2-Chlorotrityl)기, 트리페닐메틸(Triphenylmethyl)기, 터트-부틸디메틸실릴(tert-Butyldimethylsilyl)기, 트리페닐실릴(Triphenylsilyl)기 또는 트리이소프로필실릴(Triisopropylsilyl)기인 것이 바람직할 수 있고, 2-클로로트리틸(2-Chlorotrityl)기 또는 트리페닐메틸(Triphenylmethyl)기인 것이 보다 바람직하며, 트리페닐메틸(Triphenylmethyl)기인 것이 가장 바람직하지만 이에 국한되는 것은 아니다.The thiol protecting group is a methoxymethyl group, a benzyloxymethyl group, a triphenylmethyl group, a tert -butyldimethylsilyl group, a triphenylsilyl group, and a triisopropyl group. Silyl group, para -methoxybenzyl group, tetrahydropyran group, tetrahydrofuran group, tert -butyl group, diphenylmethyl group group, 2-chlorotrityl group, benzyl group, 4-methoxybenzyl group, allyl group, tert -butyloxycarbonyl group , Acetyl group, Benzoyl group, etc. can be exemplified, and methoxymethyl group, benzyloxymethyl group, 2-chlorotrityl group, triphenylmethyl (Triphenylmethyl) group, tert -butyldimethylsilyl group, triphenylsilyl group or triisopropylsilyl group may be preferred, and 2-chlorotrityl group Alternatively, it is more preferably a triphenylmethyl group, and most preferably a triphenylmethyl group, but is not limited thereto.
카르복시산의 수산기 보호기는 메톡시메틸(Methoxymethyl)기, 벤질옥시메틸(Benzyloxymethyl)기, 트리페닐메틸(Triphenylmethyl)기, 터트-부틸디메틸실릴(tert-Butyldimethylsilyl)기, 트리페닐실릴(Triphenylsilyl)기, 트리이소프로필실릴(Triisopropylsilyl)기, 파라-메톡시벤질(para-Methyloxybenzyl)기, 테트라히드로피란(Tetrahydropyran)기, 테트라히드로퓨란(Tetrahydrofuran)기, 터트-부틸(tert-Butyl)기, 디페닐메틸(Diphenylmethyl)기, 2-클로로트리틸(2-Chlorotrityl)기, 벤질(Benzyl)기, 4-메톡시벤질(4-Methoxybenzyl)기, 알릴(Allyl)기, 터트-부틸옥시카르보닐(tert-Butyloxycarbonyl)기, 아세틸(Acetyl)기, 벤조일(Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸(Methoxymethyl)기, 벤질옥시메틸(Benzyloxymethyl)기, 트리페닐메틸(Triphenylmethyl)기, 터트-부틸디메틸실릴(tert-Butyldimethylsilyl)기, 트리페닐실릴(Triphenylsilyl)기 또는 트리이소프로필실릴(Triisopropylsilyl)기인 것이 바람직하고, 터트-부틸(tert-Butyl)기 또는 트리페닐메틸(Triphenylmethyl)기인 것이 보다 바람직하며, 터트-부틸(tert-Butyl)기인 것이 가장 바람직하지만 이에 국한되는 것은 아니다.The hydroxyl protecting group of carboxylic acid is a methoxymethyl group, a benzyloxymethyl group, a triphenylmethyl group, a tert -butyldimethylsilyl group, a triphenylsilyl group, and a triphenylsilyl group. Isopropylsilyl group, para -methoxybenzyl group, tetrahydropyran group, tetrahydrofuran group, tert -butyl group, diphenylmethyl ( Diphenylmethyl) group, 2-chlorotrityl group, benzyl group, 4-methoxybenzyl group, allyl group, tert-butyloxycarbonyl ( tert -Butyloxycarbonyl ) group, acetyl group, benzoyl group, etc. may be exemplified, and methoxymethyl group, benzyloxymethyl group, triphenylmethyl group, tert-butyldimethylsilyl ( tert -Butyldimethylsilyl) group, triphenylsilyl (Triphenylsilyl) group or triisopropylsilyl (Triisopropylsilyl) group is preferred, tert-butyl ( tert -Butyl) group or triphenylmethyl (Triphenylmethyl) group is more preferred, tert -Butyl ( tert -Butyl) group is most preferred, but is not limited thereto.
상기 및 이하의 기재에서 작용기에 대한 보호기는 "Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991)"에 상세히 기재되어 있다.In the above and below description, protecting groups for functional groups are described in detail in "Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991)".
한편, 사용할 수 있는 레진으로는 2-클로로트리틸클로라이드 레진(2-Chlorotritylchloride Resin), 왕 레진(Wang Resin), 디에이치피피 레진(DHPP Resin, 4-(1',1'-dimethyl-1'-hydroxypropyl)phenoxyacetyl alanyl aminomethyl polystyrene), 피디디엠 레진(PDDM Resin, Diphenyldiazomethane Resin), 사스린 레진 (SASRIN Resin, 2-Methoxy-4-alkoxybenzyl alcohol Resin)으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다. On the other hand, resins that can be used include 2-Chlorotritylchloride Resin, Wang Resin, and DHPP Resin, 4-(1',1'-dimethyl-1' -hydroxypropyl) phenoxyacetyl alanyl aminomethyl polystyrene), PDDM Resin (Diphenyldiazomethane Resin), and SASRIN Resin (2-Methoxy-4-alkoxybenzyl alcohol Resin).
용매로는 디클로로메탄(Dichloromethane), N,N-디메틸포름아마이드(N,N-Dimethylformamide), N,N-디메틸아세트아마이드(N,N-Dimethylacetamide), N-메틸피롤리돈(N-Methylpyrrolidone), 디메틸설폭시드(Dimethylsulfoxide), 클로로포름(Chloroform), 1,2-디클로로에탄(1,2-Dichloroethane), 테트라히드로퓨란(Tetrahydrofurane), 1,4-디옥산(1,4-Dioxane), 메탄올(Methanol), 에탄올(Ethanol), 이소프로판올(Isopropanol), 에틸렌 글리콜(Ethylene glycol), 메틸 아세테이트(Methyl acetate), 에틸 아세테이트(Ethyl acetate) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.As a solvent, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone , Dimethylsulfoxide, Chloroform, 1,2-Dichloroethane, Tetrahydrofurane, 1,4-Dioxane, Methanol ( methanol, ethanol, isopropanol, ethylene glycol, methyl acetate, ethyl acetate, and the like.
사용되는 보호기를 제거하는 염기로는 피페리딘(Piperidine), 피롤리딘(Pyrrolidine), 피페라진(Piperazine), 하이드라진 하이드레이트(Hydrazine hydrate), DBU, 4-메틸피페리딘(4-Methylpiperidine), 1-메틸-3-부틸이미다졸리윰 테트라플로오로보란(1-Methyl-3-butyl imidazolium BF4), 에탄올아민(Ethanolamine), 시클로헥실아민(Cyclohexylamine), 트리스(2-아미노에틸)아민(Tris(2-aminoethyl)amine), 1,3-디시클로헥산비스-(메틸아민)(1,3-Dicyclohexanebis-(methylamine)), 1,4-비스-(3-아미노프로필)피페라진(1,4-Bis-(3-aminopropyl)piperazine), 디에틸아민(Diethylamine), 4-디메틸아미노피리딘(4-Dimethylaminopyridine) 등의 유기 염기 및 수산화 리튬(Lithium hydroxide), 수산화 나트륨(Sodium Hydroxide), 수산화 칼슘(Calcium Hydroxide), 수산화 칼륨(Potassium Hydroxide) 등의 무기염기로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.Bases used to remove protecting groups include Piperidine, Pyrrolidine, Piperazine, Hydrazine hydrate, DBU, 4-Methylpiperidine, 1-Methyl-3-butylimidazolium tetrafluoroborane (1-Methyl-3-butyl imidazolium BF4), ethanolamine (Ethanolamine), cyclohexylamine (Cyclohexylamine), tris (2-aminoethyl) amine (Tris (2-aminoethyl)amine), 1,3-Dicyclohexanebis-(methylamine)), 1,4-bis-(3-aminopropyl)piperazine (1, Organic bases such as 4-Bis-(3-aminopropyl)piperazine, Diethylamine, and 4-Dimethylaminopyridine, as well as Lithium hydroxide, Sodium Hydroxide, and Calcium Hydroxide and at least one selected from the group consisting of inorganic bases such as (Calcium Hydroxide) and Potassium Hydroxide (Potassium Hydroxide).
보호화된 아미노산이 결합할 때 사용하는 시약으로는 DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (Ethyl cyano(hydooxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N',N',-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroboratemethanaminium), CDI (carbonyldiimidazole), COMU (1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin-2-yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDC·HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony-2-ethoxy-1,2-dihydro-quinoline), T3P (2-Propanephosphonic acid anhydride), DEPBT (3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate), HOBt (1-Hydroxybenzotriazole), HOOBt (HODhbt, Hydroxy-3,4-dihydro-4-ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1'-Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt (1-Hydroxyazabenzotriazole), HOSu (N-Hydroxysuccinimide) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.Reagents used for binding of protected amino acids include DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate) , PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (Ethyl cyano(hydooxyimino)acetato-O2 )-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H-benzotriazol-1-yl) -N,N,N',N',-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide), TBTU (O -(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethy luroniumtetrafluoroboratemethanaminium), carbonyldiimidazole (CDI), COMU (1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin-2 -yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDC HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony-2 -ethoxy-1,2-dihydro-quinoline), T3P (2-propanephosphonic acid anhydride), DEPBT (3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate) , HOBt (1-Hydroxybenzotriazole), HOOBt (HODhbt, Hydroxy-3,4-dihydro-4-ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1' -Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt (1-Hydroxyazabenzotriazole), HOSu (N-Hydroxysuccinimide), and the like.
레진 및 아미노산의 보호기를 동시에 제거하는 과정은 산성 용액의 존재 하에서 수행할 수 있다. 이때 산성 용액은 TFA/phenol/water/TIPS(88/5/5/2), TFA/phenol/water/thioanisole/EDT(82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/1-decanethiol(82.5/5/5/5/2.5), TFA/DTT/water/TIPS(88/5/5/2), TFA/phenol(95/5), TFA/phenol/Methanesulfonic acid(95/2.5/2.5), TFA/thioanisole/EDT/anisole(90/5/3/2), TFA/TES(95/5), TFA/water(95/5), TFA/DCM/indole(70/28/2), TFA/TIPS/water(95/2.5/2.5) 등의 용액을 예시할 수 있다.The process of simultaneously removing the protective group of the resin and amino acid may be performed in the presence of an acidic solution. At this time, the acidic solution is TFA/phenol/water/TIPS (88/5/5/2), TFA/phenol/water/thioanisole/EDT (82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/ 1-decanethiol (82.5/5/5/5/2.5), TFA/DTT/water/TIPS (88/5/5/2), TFA/phenol (95/5), TFA/phenol/Methanesulfonic acid (95/ 2.5/2.5), TFA/thioanisole/EDT/anisole (90/5/3/2), TFA/TES (95/5), TFA/water (95/5), TFA/DCM/indole (70/28/ 2), solutions such as TFA/TIPS/water (95/2.5/2.5) can be exemplified.
Crude 펩타이드를 정제할 때 사용하는 용매로는 메탄올(Methanol), 에탄올(Ethanol), 이소프로판올(Isopropanol), 아세토니트릴(Acetonitrile) 및 정제수의 혼합용액을 들 수 있고, 사용하는 산으로는 삼불화아세트산(Trifluoroacetic acid), 아세트산(Acetic acid), 포름산(Formic acid)을 0.1% 내지 5% 이내로 사용하여 정제할 수 있다. Solvents used when purifying crude peptides include a mixed solution of methanol, ethanol, isopropanol, acetonitrile, and purified water, and the acid used is trifluoroacetic acid ( Trifluoroacetic acid), acetic acid, and formic acid can be purified using within 0.1% to 5%.
상기 및 이하의 기재에서 "펩타이드"는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미하는 것으로 이해될 것이다. In the above and below description, "peptide" will be understood to mean a linear molecule formed by linking amino acid residues to each other by a peptide bond.
본 명세서에서 특별한 표시가 없는 한, 아미노산 및 보호기의 지정에 사용되는 약어는 IUPAC-IUB의 생화학 용어 위원회(Commission of Biochemical Nomenclature)에서 권장하는 용어에 기초한다(Biochemistry, 11:1726-1732(1972); Pure & Appl. Chem., Vol. 56, No. 5, pp. 595-624, 1984).Abbreviations used in the designation of amino acids and protecting groups herein, unless otherwise indicated, are based on terms recommended by the Commission of Biochemical Nomenclature of IUPAC-IUB ( Biochemistry, 11:1726-1732 (1972)). ( Pure & Appl. Chem., Vol. 56, No. 5, pp. 595-624, 1984).
본 발명에 따라 얻어진 신규한 펩타이드 유사체 또는 이의 약학적으로 허용 가능한 염은 알츠하이머 병 예방용 조성물의 유효성분으로 유용할 수 있다.The novel peptide analogue or pharmaceutically acceptable salt thereof obtained according to the present invention may be useful as an active ingredient of a composition for preventing Alzheimer's disease.
상기 및 이하의 기재에서 "알츠하이머 병 예방용"이라는 표현은, 알츠하이머 병에 대한 지연 또는 억제, 나아가 치료적 의미를 모두 포함하는 것으로 이해되어져야 할 것이다. In the above and below description, the expression "for preventing Alzheimer's disease" should be understood to include both delay or suppression of Alzheimer's disease and furthermore therapeutic meaning.
일명, 알츠하이머 병으로 불리는 노인성 치매는, 최근 고령 인구의 증가와 더불어 사회적 경제적으로 큰 문제로 대두되고 있다. 알츠하이머 병에 걸리면 기억 등의 인지 기능과 관련된 해마와 대뇌피질 신경세포에 심각한 소실이 발견되며, 이에 따라 심한 기억력 쇠퇴와 운동 및 감각체계의 이상이 동반된다. Aβ 펩타이드는 알츠하이머 병의 병리현상을 일으키는 주요 단백질로 잘 알려져 있는데, 아밀로이드 피브릴 형성과 같이 Aβ 펩타이드의 응집이 알츠하이머 병의 가장 주요한 병리학적 특징으로 알려져 있다. 이러한 점에서 본 발명에 다른 신규한 펩타이드 유사체 또는 이의 약학적으로 허용 가능한 염은 알츠하이머 병 예방용 조성물에 있어서 유효성분으로 작용할 수 있다. Senile dementia, also known as Alzheimer's disease, has recently emerged as a major social and economic problem along with the increase in the elderly population. In Alzheimer's disease, severe loss of neurons in the hippocampus and cerebral cortex related to cognitive functions such as memory is found, which is accompanied by severe memory decline and motor and sensory system abnormalities. Aβ peptide is well known as a major protein that causes the pathology of Alzheimer's disease, and aggregation of Aβ peptide, such as the formation of amyloid fibrils, is known as the most important pathological feature of Alzheimer's disease. In this regard, the novel peptide analogs or pharmaceutically acceptable salts thereof according to the present invention can act as an active ingredient in a composition for preventing Alzheimer's disease.
이러한 알츠하이머 병 예방용 조성물은 약학 조성물일 수 있는데, 이러한 경우 약제학적 분야에서 공지의 방법에 의하여 제조될 수 있으며, 그 자체 또는 약학적으로 허용되는 담체(carrier), 부형제(forming agent) 내지 희석제 등과 혼합하여 분말, 과립, 정제, 캡슐제 또는 주사제 등의 제형으로 제조될 수 있음은 물론이다. 또한, 이들을 경구 또는 비경구 투여용 제제와 같은 단위투여형 또는 수회 투여형 제제로 제형화하여 알츠하이머 병 예방제로써 사용할 수 있다. Such a composition for preventing Alzheimer's disease may be a pharmaceutical composition. In this case, it may be prepared by a method known in the pharmaceutical field, and may include itself or a pharmaceutically acceptable carrier, forming agent, diluent, etc. Of course, it can be prepared into formulations such as powders, granules, tablets, capsules, or injections by mixing. In addition, they can be formulated into a unit dosage type or multiple dosage type preparation such as a preparation for oral or parenteral administration and used as an agent for preventing Alzheimer's disease.
구체적인 일례로 본 발명의 알츠하이머 병 예방용 약학 조성물은 비강, 피부, 구강 또는 피하주사로 투여할 수 있음은 물론이다.As a specific example, the pharmaceutical composition for preventing Alzheimer's disease according to the present invention can be administered through nasal, dermal, oral or subcutaneous injection.
알츠하이머 병 예방용 조성물에 있어서 상기 화학식 1 내지 2로 표시되는 펩타이드 유사체의 유효성분 투여량은 체내에서 활성 성분의 흡수도, 물활성화율 및 배설속도, 환자의 연령, 성별, 상태, 치매의 중증 정도 등에 따라 적절히 선택될 수 있음은 물론이다.In the composition for preventing Alzheimer's disease, the dosage of the active ingredient of the peptide analogues represented by
이하, 본 발명을 실시 예에 의해 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시 예에 의해 제한되지 않는다는 것은 당 업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by way of examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
<실시예 1 내지 2> 고상 합성법을 이용한 선형 펩타이드 유사체의 합성(반응식 1 참조)<Examples 1 and 2> Synthesis of linear peptide analogues using solid phase synthesis (see Scheme 1)
- 실시예 1: 화학식 3으로 표시되는 펩타이드 유사체: Lys-Leu-Val-Hm-Ala( 여기서, Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Phenyl기로 치환된 히스티딘 유도체) - Example 1: Peptide analog represented by Formula 3: Lys-Leu-Val-H m -Ala (where H m = both N(π) and N(τ) positions of the imidazole group are -(CH 2 ) Histidine derivative substituted with 3 -Phenyl group)
- 실시예 2: 화학식 4로 표시되는 펩타이드 유사체: Lys-Leu-Val-Hm-Ala(여기서, Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체) - Example 2: Peptide analog represented by Formula 4 : Lys-Leu-Val-H m -Ala (where H m = both N(π) and N(τ) positions of the imidazole group are -(CH 2 ) Histidine derivative substituted with 3- Cyclohexyl group)
NH2-Ala-2-CTC resin 200mg(102umol, 0.51mmol/g)을 N,N-디메틸포름아마이드(N,N-Dimethylformamide, DMF)에 45분간 부풀린 후 감압여과를 통하여 용매를 제거하였다. NH 2 -Ala-2-CTC resin 200mg (102umol, 0.51mmol/g) was inflated in N, N -dimethylformamide (DMF) for 45 minutes, and then the solvent was removed through vacuum filtration.
다음 잔기에 오는 His 유사체(Hm, 0.197g, 3 당량)를 DMF 용액 2ml에 녹인 후 1-O-벤조트리아졸-N,N,N'N'-테트라메틸우로니움 헥사플루오로인산(1-O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, HBTU)(0.11g, 3 당량), 1-하이드록시벤조트리아졸(1-Hydroxybenzotriazole, HOBt)(0.04g, 3 당량), N,N-다이이소프로필에틸아민(N,N-Diisopropylethylamine, DIEA)(47ul, 3 당량)을 넣어서 2분간 활성화시켰다. 이때, 실시예 1의 경우는 His 유사체로서 이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Phenyl기로 치환된 것을 사용하였고, 실시예 2의 경우는 이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 것을 사용하였다. The His analog (Hm, 0.197 g, 3 equivalents) coming to the next residue was dissolved in 2 ml of DMF solution, and then 1-O-benzotriazole- N,N,N'N' -tetramethyluronium hexafluorophosphate (1 -O-Benzotriazole- N,N,N',N' -tetramethyluronium hexafluorophosphate, HBTU) (0.11 g, 3 eq.), 1-Hydroxybenzotriazole (HOBt) (0.04 g, 3 eq.), N,N -diisopropylethylamine ( N,N -Diisopropylethylamine, DIEA) (47ul, 3 equivalents) was added and activated for 2 minutes. At this time, in the case of Example 1, as a His analogue, both the N(π) and N(τ) positions of the imidazole group were substituted with -(CH 2 ) 3 -Phenyl groups, and in the case of Example 2, the imidazole group was used. A sol group in which both the N(π) and N(τ) positions were substituted with a -(CH 2 ) 3 -cyclohexyl group was used.
이후 활성화된 용액을 레진과 섞고 1시간 동안 상온에서 교반하였다. 1시간 후 교반된 용액을 감압을 이용하여 제거하였다. 용액 제거 후 DMF 2ml을 반응용기에 넣고 3분간 vortex 한 후 감압으로 제거하였다. 이러한 반응을 3번 반복하였다.Then, the activated solution was mixed with resin and stirred at room temperature for 1 hour. After 1 hour, the stirred solution was removed using reduced pressure. After removing the solution, 2 ml of DMF was added to the reaction vessel, vortexed for 3 minutes, and then removed under reduced pressure. This reaction was repeated 3 times.
그 다음 Fmoc 그룹을 제거하기 위하여 20%의 피페리딘(Piperidine) 2ml을 반응용기에 첨가하였다. 여기서, 20% 피페리딘은 160ml의 DMF에 40ml의 피페리딘을 혼합하여 제조한 것이다. 5분간 반응 후 감압을 이용하여 용매를 제거한 다음 20% 피페리딘 2ml를 첨가한 후 3분간 교반하였다. 반응시간이 끝나면 DMF 2ml를 반응 용기에 넣고 3분간 vortex한 후 감압으로 제거하였다. 이 반응을 2번 더 반복하였다. Then, 2 ml of 20% piperidine was added to the reaction vessel to remove the Fmoc group. Here, 20% piperidine is prepared by mixing 40 ml of piperidine in 160 ml of DMF. After reacting for 5 minutes, the solvent was removed using reduced pressure, and then 2ml of 20% piperidine was added and stirred for 3 minutes. After the reaction time was over, 2 ml of DMF was added to the reaction vessel, vortexed for 3 minutes, and then removed under reduced pressure. This reaction was repeated two more times.
그 이후 Val-Leu-Lys 순으로 아미노산 서열에 따른 Fmoc 보호화된 아미노산으로 반응을 수행하였다. After that, the reaction was performed with Fmoc-protected amino acids according to the amino acid sequence in the order of Val-Leu-Lys.
전체 아미노산 서열의 합성이 완료된 다음에 레진은 DMF, 메탄올, 디클로로메탄 및 에테르에 의해서 세정된 이후 진공에서 건조하였다.After the synthesis of the entire amino acid sequence was completed, the resin was washed with DMF, methanol, dichloromethane and ether and then dried in vacuo.
건조가 완료된 레진에 2.5% 트라이이소프로필실란(Triisopropylsilane, TIPS) 및 2.5%의 물이 함유된 트리플루오르아세트산(Trifluoroacetic acid, TFA)을 첨가하여 펩타이드 유사체를 레진에서 분리하였다. 레진에서 분리된 펩타이드 유사체는 냉각된 에테르를 이용하여 침전시킨 후 여과시켰다. Peptide analogues were separated from the resin by adding 2.5% triisopropylsilane (TIPS) and trifluoroacetic acid (TFA) containing 2.5% water to the dried resin. Peptide analogues isolated from the resin were precipitated using cooled ether and then filtered.
그 이후 합성된 펩타이드는 Vydac C18컬럼(10mm × 250mm, 5mL/min, B buffer:10-90/30min., 0.05% TFA/CH3CN)을 이용하여 역상 HPLC(RP-HPLC)로 정제하였다. Then, the synthesized peptide was purified by reverse phase HPLC (RP-HPLC) using a Vydac C 18 column (10 mm × 250 mm, 5 mL/min, B buffer: 10-90/30 min., 0.05% TFA/CH 3 CN). .
펩타이드의 순도는 역상 HPLC(Vydac C18컬럼 (4.6mm × 250mm, 1.5mL/min, B buffer:10-90/30min., 0.05% TFA/CH3CN)로 측정하였으며 그 결과를 도 3(화학식 3) 내지 4(화학식 4)로 나타내었다. 도 3으로부터 DMSO peak가 용출시간 9.20분에서, Product 피크가 용출시간 21.28분에서 얻어짐을 확인하였다(순도 99%). 도 4로부터 DMSO 피크가 용출시간 9.23분에서, Product 피크가 용출시간 24.58분에 얻어짐을 확인하였다(순도 99%). The purity of the peptide was measured by reverse phase HPLC (Vydac C 18 column (4.6 mm × 250 mm, 1.5 mL/min, B buffer: 10-90/30 min., 0.05% TFA/CH 3 CN), and the results were measured in FIG. 3 (Formula 3) to 4 (Formula 4). From Figure 3, it was confirmed that the DMSO peak was obtained at the elution time of 9.20 minutes and the product peak was obtained at the elution time of 21.28 minutes (99% purity). At 9.23 minutes, it was confirmed that the Product peak was obtained at an elution time of 24.58 minutes (99% purity).
최종적인 펩타이드의 분자량을 MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-time-of-flight Mass spectrometry)로 측정하여 다음 표 1에 나타내었으며, 합성된 펩타이드 및 펩타이드 유사체의 명명은 다음 표 1에 나타낸 바와 같다.The molecular weight of the final peptide was measured by MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-time-of-flight Mass Spectrometry) and shown in Table 1. The names of synthesized peptides and peptide analogs are shown in Table 1 below. same as bar
<실시예 3 내지 4> 고상/액상 합성법을 이용한 고리형 펩타이드 유사체의 합성(반응식 2 참조)<Examples 3 to 4> Synthesis of cyclic peptide analogs using solid/liquid phase synthesis (see Scheme 2)
- 실시예 3: 화학식 5로 표시되는 펩타이드 유사체: cyclo-Lys-Leu-Val-Hm-Ala-Cys(여기서, Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Phenyl기로 치환된 히스티딘 유도체) - Example 3: Peptide analog represented by Formula 5 : cyclo-Lys-Leu-Val-H m -Ala-Cys (Where, H m = both N(π) and N(τ) positions of the imidazole group are - (CH 2 ) Histidine derivative substituted with 3 -Phenyl group)
- 실시예 4: 화학식 6으로 표시되는 펩타이드 유사체: cyclo-Lys-Leu-Val-Hm-Ala-Cys(여기서, Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체) - Example 4: Peptide analog represented by Formula 6 : cyclo-Lys-Leu-Val-H m -Ala-Cys (where H m = both the N(π) and N(τ) positions of the imidazole group are - (CH 2 ) Histidine derivative substituted with 3 -Cyclohexyl group)
NH2-Cys(Trt)-CTC-resin(200mg(102umol, 0.51mmol/g)을 N,N-디메틸포라마이드(N,N-dimethylforamide, DMF)에 45분간 부풀린 후 감압 여과를 통하여 용매를 제거하였다. 두 번째 아미노산인 Ala을 도입하기 위하여 Fmoc-Ala-OH (0.1g, 3 당량)을 2ml의 DMF 용액에 녹인 후 HBTU(0.11g, 3당량), HOBt(0.04g, 3 당량), DIEA(47㎕, 3 당량)를 넣어서 2분간 활성화시켰다.NH 2 -Cys(Trt)-CTC-resin (200mg (102umol, 0.51mmol/g) was inflated in N,N - dimethylforamide (DMF) for 45 minutes, and then the solvent was removed by filtration under reduced pressure. To introduce the second amino acid, Ala, Fmoc-Ala-OH (0.1 g, 3 equiv) was dissolved in 2 ml of DMF solution, followed by HBTU (0.11 g, 3 equiv), HOBt (0.04 g, 3 equiv), and DIEA. (47 μl, 3 equivalents) was added and activated for 2 minutes.
이후 활성화된 용액을 레진과 섞고 1시간 동안 상온에서 교반하였다. 1시간 후 교반된 용액은 감압을 이용하여 제거하였다. 용액 제거 후 DMF 2ml을 반응 용기에 넣고 3분간 vortex 한 후 감압으로 제거하였다. 이러한 반응을 3번 반복하였다.Then, the activated solution was mixed with resin and stirred at room temperature for 1 hour. After 1 hour, the stirred solution was removed using reduced pressure. After removing the solution, 2ml of DMF was added to the reaction vessel, vortexed for 3 minutes, and then removed under reduced pressure. This reaction was repeated 3 times.
그 다음 단계인 Fmoc 그룹을 제거하기 위하여 20% 피페리딘(Piperidine) 2ml을 반응 용기에 첨가하였다. 첨가 후 5분간 반응 후 감압을 이용하여 용매를 제거한 후 다시 한 번 더 20% 피페리딘 2ml를 첨가한 후 3분간 교반하였다. 반응 시간이 끝나면 DMF 2ml을 반응 용기에 넣고 3분간 vortex 한 후 감압으로 제거하였다. 이 반응을 2번 더 반복하였다. In order to remove the Fmoc group, which is the next step, 2 ml of 20% piperidine was added to the reaction vessel. After reacting for 5 minutes after addition, the solvent was removed using reduced pressure, and then 2ml of 20% piperidine was added once more, followed by stirring for 3 minutes. After the reaction time was over, 2 ml of DMF was added to the reaction vessel, vortexed for 3 minutes, and then removed under reduced pressure. This reaction was repeated two more times.
그 이후 히스티딘 유도체-Val-Leu-Lys 순으로 아미노산 서열에 따른 Fmoc 보호화된 아미노산으로 반응을 수행한 뒤, Fmoc 그룹을 제거하였다.Thereafter, the reaction was performed with Fmoc-protected amino acids according to the amino acid sequence in the order of histidine derivative-Val-Leu-Lys, and then the Fmoc group was removed.
마지막으로 브로모아세트산(BrCH2COOH) 도입하기 위하여 BrCH2COOH(0.04g, 3 당량)을 2ml의 DMF 용액에 녹인 후 HBTU(0.11g, 3 당량), HOBt(0.04g, 3 당량), DIEA(47㎕, 3 당량)를 넣어서 2분간 활성화시켰다.Finally, to introduce bromoacetic acid (BrCH 2 COOH), BrCH 2 COOH (0.04 g, 3 equivalents) was dissolved in 2 ml of DMF solution, followed by HBTU (0.11 g, 3 equivalents), HOBt (0.04 g, 3 equivalents), and DIEA (47 μl, 3 equivalents) was added and activated for 2 minutes.
이후 활성화된 용액을 레진과 섞고 1시간 동안 상온에서 교반하였다. 1시간후 교반된 용액을 감압을 이용하여 제거하였다. 용액 제거 후 DMF 2ml을 반응용기에 넣고 3분간 vortex 한 후 감압으로 제거하였다. 이러한 반응을 3번 반복하였다. 전체 아미노산 서열의 합성이 완료된 다음에 레진은 DMF, 메탄올, 디클로로메탄 및 에테르에 의해서 세정된 이후 진공에서 건조하였다. 합성이 완료된 펩타이드는 2.5% 트라이이소프로필실란(Triisopropylsilane, TIPS) 및 2.5%의 물이 함유된 트리플루오르아세트산(Trifluoroacetic acid, TFA)을 이용하여 레진에서 분리하였다. 레진에서 분리된 펩타이드 유사체는 냉각된 에테르를 이용하여 침전시킨 후 여과시켰다. Then, the activated solution was mixed with resin and stirred at room temperature for 1 hour. After 1 hour, the stirred solution was removed using reduced pressure. After removing the solution, 2 ml of DMF was added to the reaction vessel, vortexed for 3 minutes, and then removed under reduced pressure. This reaction was repeated 3 times. After the synthesis of the entire amino acid sequence was completed, the resin was washed with DMF, methanol, dichloromethane and ether and then dried in vacuo. The synthesized peptide was separated from the resin using 2.5% triisopropylsilane (TIPS) and 2.5% water-containing trifluoroacetic acid (TFA). Peptide analogues isolated from the resin were precipitated using cooled ether and then filtered.
그 이후 펩타이드는 Vydac C18컬럼 (10mm × 250mm,5mL/min, B buffer:10-90/30min., 0.05% TFA/CH3CN)을 이용하여 역상 HPLC(RP-HPLC)로 정제하였다. 정제된 펩타이드는 동결 건조하였다. After that, the peptide was purified by reverse phase HPLC (RP-HPLC) using a Vydac C 18 column (10 mm × 250 mm, 5 mL/min, B buffer: 10-90/30 min., 0.05% TFA/CH 3 CN). Purified peptides were freeze-dried.
다음으로, Thioether 결합에 의한 고리형 펩타이드(cyclic peptide)를 합성하기 위하여 상기로부터 얻어진 선형 펩타이드(linear peptide) 2mg을 phosphate buffer (pH=8.5, 2mL)에 녹인 후 2시간 동안 반응시켰다. 합성진행을 HPLC로 모니터링하였으며 반응이 완료 후 Vydac C18컬럼 (10mm × 250mm,5mL/min, B buffer:10-90/30min., 0.05% TFA/CH3CN)을 이용하여 역상 HPLC로 정제하였다. Next, in order to synthesize a cyclic peptide by thioether bond, 2 mg of the linear peptide obtained above was dissolved in phosphate buffer (pH = 8.5, 2 mL) and reacted for 2 hours. The progress of the synthesis was monitored by HPLC, and after the reaction was completed, it was purified by reverse phase HPLC using a Vydac C 18 column (10 mm × 250 mm, 5 mL/min, B buffer: 10-90/30 min., 0.05% TFA/CH 3 CN). .
최종적으로 얻어진 고리형 펩타이드의 순도는 역상 HPLC (Vydac C18컬럼 (4.6mm × 250mm, 1.5mL/min, B buffer:10-90/30min., 0.05% TFA/CH3CN)로 측정하여 그 결과를 각각 도 5(화학식 5 화합물) 내지 6(화학식 6 화합물)으로 나타내었다. 도 5로부터 Product 피크가 용출시간 16.88분에서 얻어짐을 확인하였다(순도 99%). 도 6으로부터 Product 피크가 용출시간 18.22분에 얻어짐을 확인하였다(순도 99%). The purity of the finally obtained cyclic peptide was measured by reverse phase HPLC (Vydac C 18 column (4.6mm × 250mm, 1.5mL/min, B buffer: 10-90/30min., 0.05% TFA/CH 3 CN)) and the result 5 (compound of Formula 5) to 6 (compound of Formula 6), respectively. From Figure 5, it was confirmed that the Product peak was obtained at an elution time of 16.88 minutes (purity 99%). From Figure 6, the Product peak had an elution time of 18.22 It was confirmed that it was obtained in minutes (purity 99%).
최종적인 펩타이드의 분자량은 MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-time-of-flight Mass spectrometry)로 측정하여 그 결과를 다음 표 1에 기재였으며, 합성된 펩타이드 및 펩타이드 유사체의 명명은 다음 표 1에 나타낸 바와 같다.The molecular weight of the final peptide was measured by MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-time-of-flight Mass Spectrometry), and the results are shown in Table 1. The names of synthesized peptides and peptide analogs are listed in the following table. As shown in 1.
화학식 3
Formula 3
(Lys-Leu-Val-Hm-Ala: Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Phenyl기로 치환된 히스티딘 유도체)KLVH m A
(Lys-Leu-Val-H m -Ala: H m = Histidine derivative in which both N(π) and N(τ) positions of the imidazole group are substituted with -(CH 2 ) 3 -Phenyl groups)
802.44
802.44
화학식 4
(Lys-Leu-Val-Hm-Ala-Cys: Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체)KLVH m A
(Lys-Leu-Val-H m -Ala-Cys: H m = Histidine derivative in which both N(π) and N(τ) positions of the imidazole group are substituted with -(CH 2 ) 3 -Cyclohexyl groups)
814.55
814.55
화학식 5
(cyclo[Lys-Leu-Val-Hm-Ala-Cys]: Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Phenyl기로 치환된 히스티딘 유도체)Cyclo [KLVH m AC]
(cyclo[Lys-Leu-Val-H m -Ala-Cys]: H m = histidine derivative in which both N(π) and N(τ) positions of the imidazole group are substituted with -(CH 2 ) 3 -Phenyl groups)
946.52
946.52
화학식 6
(cyclo[Lys-Leu-Val-Hm-Ala-Cys]: Hm=이미다졸기의 N(π) 및 N(τ) 위치가 모두 -(CH2)3-Cyclohexyl기로 치환된 히스티딘 유도체)Cyclo [KLVH m AC]
(cyclo[Lys-Leu-Val-H m -Ala-Cys]: H m = histidine derivative in which both N(π) and N(τ) positions of the imidazole group are substituted with -(CH 2 ) 3 -cyclohexyl groups)
958.51
958.51
<실험예 1> ThT 분석(Thioflavin T Assay)<Experimental Example 1> ThT assay (Thioflavin T Assay)
ThT는 Aβ와 같이 crossed-β-sheet 구조를 가지는 물질과 결합하여 형광변화를 가지는 물질로 잘 알려져 있다. Aβ가 ThT 에 결합할 때 주변 환경에 따른 λmax와 형광강도(Intensity)의 변화로부터 아밀로이드 피브릴 형성의 저해효능을 평가할 수 있다. ThT is well known as a substance having a fluorescence change when combined with a substance having a crossed-β-sheet structure such as Aβ. When Aβ binds to ThT, the inhibitory effect on amyloid fibril formation can be evaluated from changes in λmax and fluorescence intensity according to the surrounding environment.
본 발명에 따른 펩타이드 유도체의 Aβ의 아밀로이드 피브릴 형성 저해 효능을 평가하기 위하여 다음과 같은 방법으로 실험하였다. In order to evaluate the efficacy of the peptide derivatives according to the present invention to inhibit A[beta] from forming amyloid fibrils, the following method was tested.
구체적으로, Aβ42 또는 Aβ40 파우더를 암모니아 수용액으로 용해시키고, ThT는 물에 용해, 펩타이드 유도체는 DMSO에 용해하여 각각 stock solution을 준비하였다. 이를 최종적으로, cuvette 내에 Phosphate Buffer 용액(20 mM Sodium phosphate buffer pH 7.5, 100 mM NaCl, 5μM DMSO) 내에서 Aβ 5μM, ThT 5μM, 각각의 펩타이드 유사체 50μM 농도가 되도록 준비하였다. Specifically, stock solutions were prepared by dissolving Aβ42 or Aβ40 powder in aqueous ammonia, dissolving ThT in water, and dissolving peptide derivatives in DMSO, respectively. Finally, it was prepared in a cuvette in a Phosphate Buffer solution (20 mM Sodium phosphate buffer pH 7.5, 100 mM NaCl, 5 μM DMSO) to have
37 ℃, 180 rpm의 교반 조건 하에서 Aβ 피브릴 형성에 대하여, Multi-mode microplate reader (Molecular Devices, U. S. A.)를 이용하여 시간에 따른 ThT의 실시간 형광강도 변화로써 측정하여 평가하였다. The formation of Aβ fibrils under stirring conditions of 37 °C and 180 rpm was evaluated by measuring the real-time fluorescence intensity change of ThT over time using a multi-mode microplate reader (Molecular Devices, USA ).
이때 대조군의 경우 상기 펩타이드 유사체를 첨가하지 않고 ThT, Aβ 만을 처리한 것을 제외하고는 동일하게 실시하였다. 여기(exitation)파장 및 발광(emission)파장을 각각 445 nm 및 480 nm로 하여 아밀로이드 피브릴의 가장 적합한 형광강도를 측정하였다. At this time, in the case of the control group, the same procedure was performed except that only ThT and Aβ were treated without adding the peptide analog. The most suitable fluorescence intensity of amyloid fibrils was measured by setting the excitation and emission wavelengths to 445 nm and 480 nm, respectively.
측정결과의 분석은, ThT 형광강도가 증대한다면 아밀로이드 피브릴 형성을 검증할 수 있고, 펩타이드 유사체들을 첨가하여 ThT 형광강도가 저하된다면 아밀로이드 피브릴 형성을 저해하는 데 있어서 활성을 갖는 것으로 판단할 수 있다.Analysis of the measurement results can verify the formation of amyloid fibrils if the ThT fluorescence intensity increases, and if the ThT fluorescence intensity decreases by adding peptide analogs, it can be judged to have activity in inhibiting the formation of amyloid fibrils. .
Aβ40 에 대한 실험 결과를 요약하면 다음 표 2와 같고, 구체적으로는 도 7과 같다.A summary of the experimental results for Aβ40 is shown in Table 2 below, and specifically shown in FIG. 7.
Aβ42 에 대한 실험 결과를 요약하면 다음 표 3과 같고, 구체적으로는 도 8과 같다.A summary of the experimental results for Aβ42 is shown in Table 3 below, and specifically shown in FIG. 8.
상기 표 2 내지 3 및 도 7 내지 8의 결과로 볼 때, Aβ42와 Aβ40에서 모두 화학식 5로 표시되는 고리형 펩타이드 유사체가 아밀로이드 피브릴 형성의 지연 내지 억제 효능이 뛰어남을 알 수 있다. Judging from the results of Tables 2 to 3 and FIGS. 7 to 8, In both Aβ42 and Aβ40, it can be seen that the cyclic peptide analog represented by
피브릴 형성 저해능은 화학식 5 > 화학식 4 > 화학식 3 화합물순으로 나타났으며, 화학식 6 화합물의 경우 Aβ42의 아밀로이드 피브릴 형성을 저해하나 Aβ40의 아밀로이드 피브릴 형성 저해 활성은 없음을 확인할 수 있다. The ability to inhibit fibril formation was shown in the order of
<실험예 2> TEM (Transmission Electron Microscopy) Analysis <Experimental Example 2> TEM (Transmission Electron Microscopy) Analysis
ThT assay가 끝난 Aβ 샘플 용액을 피펫으로 균일하게 현탁시킨 뒤 5㎕의 샘플을 채취하였다. 채취한 Aβ 샘플을 카본으로 코팅한 구리 그리드(carbon-coated copper grid)에 올려 15초간 상온에서 인큐베이션을 실시했다. 그리드에 흡착이 되지 않은 Aβ 샘플을 제거하기 위해서 10μL의 증류수로 3번 세척하였다. 세척이 끝난 Aβ 샘플을 2%(w/v) 우라닐 아세테이트(Uranyl acetate) 10㎕로 염색하였다. 건조된 그리드 샘플을 TEM(120 kV) 분석을 통해 그 상을 관찰하였다. After the ThT assay was completed, the Aβ sample solution was uniformly suspended with a pipette, and a sample of 5 μl was collected. The collected Aβ sample was placed on a carbon-coated copper grid and incubated at room temperature for 15 seconds. In order to remove the Aβ sample that was not adsorbed on the grid, it was washed three times with 10 μL of distilled water. After washing, the Aβ sample was stained with 10 μl of 2% (w/v) uranyl acetate. The phase of the dried grid sample was observed through TEM (120 kV) analysis.
그 결과를 도 9 내지 13으로 도시하였는바, 도 9는 Aβ42 펩타이드, 도 10은 'Aβ42 펩타이드 + 화학식 3 화합물', 도 11은 'Aβ42 펩타이드 + 화학식 4 화합물', 도 12는 'Aβ42 펩타이드 + 화학식 5 화합물', 그리고 도 13은 'Aβ42 펩타이드 + 화학식 6 화합물' 시료에 대하여 그 상을 관찰한 TEM 이미지로, 도 12로 도시한 것과 같이 화학식 5 화합물의 Aβ 아밀로이드 피브릴 형성 저해 활성이 가장 우수한 것을 확인할 수 있다. The results are shown in Figures 9 to 13, Figure 9 is Aβ42 peptide, Figure 10 is 'Aβ42 peptide + Formula 3 compound', Figure 11 is 'Aβ42 peptide +
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당 업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As above, specific parts of the present invention have been described in detail, and it will be clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> WellPep Co., Ltd. <120> Novel Mimetic Peptide and Composition for Alzheimer's disease <130> P210226 <140> 10-2022-0012105 <141> 2022-01-27 <160> 6 <170> KoPatentIn 3.0 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Xaa: His(R)2, R= -(CH2)n-phenyl or -(CH2)n-cyclohexyl <400> 1 Lys Leu Val Xaa Ala 1 5 <210> 2 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> (1) Cyclic Acetyl(CH2) 1-7(Cys), (2) Xaa: His(R)2, R=-(CH2)n-phenyl or -(CH2)n-cyclohexyl <400> 2 Lys Leu Val Xaa Ala Cys 1 5 <210> 3 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Xaa:His(Bis-phenylpropyl) <400> 3 Lys Leu Val Xaa Ala 1 5 <210> 4 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Xaa:His(Bis-cyclohexylpropyl) <400> 4 Lys Leu Val Xaa Ala 1 5 <210> 5 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> (1) Cyclic, 1(Acetyl(CH2))-7(Cys), (2) Xaa: His(Bis-phenylpropyl)2 <400> 5 Lys Leu Val Xaa Ala Cys 1 5 <210> 6 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> (1) Cyclic, 1(Acetyl(CH2))-7(CyS), (2) Xaa: His(Bis-cyclohexylpropyl)2 <400> 6 Lys Leu Val Xaa Ala 1 5 <110> WellPep Co., Ltd. <120> Novel Mimetic Peptide and Composition for Alzheimer's disease <130> P210226 <140> 10-2022-0012105 <141> 2022-01-27 <160> 6 <170> KoPatentIn 3.0 <210> 1 <211> 5 <212> PRT <213> artificial sequence <220> <223> Xaa: His(R)2, R=-(CH2)n-phenyl or -(CH2)n-cyclohexyl <400> 1 Lys Leu Val Xaa Ala 1 5 <210> 2 <211> 6 <212> PRT <213> artificial sequence <220> <223> (1) Cyclic Acetyl (CH2) 1-7 (Cys), (2) Xaa: His (R) 2, R=-(CH2)n-phenyl or -(CH2)n-cyclohexyl <400> 2 Lys Leu Val Xaa Ala Cys 1 5 <210> 3 <211> 5 <212> PRT <213> artificial sequence <220> <223> Xaa:His(Bis-phenylpropyl) <400> 3 Lys Leu Val Xaa Ala 1 5 <210> 4 <211> 5 <212> PRT <213> artificial sequence <220> <223> Xaa:His(Bis-cyclohexylpropyl) <400> 4 Lys Leu Val Xaa Ala 1 5 <210> 5 <211> 6 <212> PRT <213> artificial sequence <220> <223> (1) Cyclic, 1(Acetyl(CH2))-7(Cys), (2) Xaa: His(Bis-phenylpropyl)2 <400> 5 Lys Leu Val Xaa Ala Cys 1 5 <210> 6 <211> 5 <212> PRT <213> artificial sequence <220> <223> (1) Cyclic, 1(Acetyl(CH2))-7(CyS), (2) Xaa: His(Bis-cyclohexylpropyl)2 <400> 6 Lys Leu Val Xaa Ala 1 5
Claims (7)
아밀로이드 베타 펩타이드의 아밀로이드 피브릴 형성을 저해하는, 펩타이드 유사체 또는 이의 약학적으로 허용된 염.
화학식 5
Represented by Formula 5 below,
A peptide analog or pharmaceutically acceptable salt thereof that inhibits the formation of amyloid fibrils of amyloid beta peptide.
Formula 5
The method of claim 3, wherein the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, bromic acid, perchloric acid, Fumaric acid, Maleic acid, Lactic acid, Salicylic acid, Succinic acid, p - Toluenesulfonic acid, Methanesulfonic acid, Formic acid, Tartaric acid, Citric acid, Acetic acid, Trifluoroacetic acid, Trichloroacetic acid, Benzenesulfonic acid, 2-Nap An acid salt selected from among 2-Naphthylsulfonic acid, Benzoic acid, Malonic acid, Monochloroacetic acid and Dichloroacetic acid, Sodium or Magnesium A peptide analog or a pharmaceutically acceptable salt thereof, characterized in that it is selected from metal salts of, and ammonium salts having an alkyl or aryl group having 1 to 10 carbon atoms.
A pharmaceutical composition for preventing Alzheimer's disease comprising the peptide analog or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 4 as an active ingredient.
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|---|---|---|---|---|
| JP2007523848A (en) * | 2003-04-30 | 2007-08-23 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | Beta amyloid inhibitors and uses thereof |
| KR101381285B1 (en) * | 2012-09-12 | 2014-04-04 | 한국기초과학지원연구원 | Novel Peptide having Antimicrobial Activity and Anti-inflammatory Activity |
| JP2020505926A (en) * | 2017-01-30 | 2020-02-27 | ナショナル リサーチ カウンシル オブ カナダ | Blood-brain barrier transfer compounds and uses thereof |
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2022
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007523848A (en) * | 2003-04-30 | 2007-08-23 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | Beta amyloid inhibitors and uses thereof |
| KR101381285B1 (en) * | 2012-09-12 | 2014-04-04 | 한국기초과학지원연구원 | Novel Peptide having Antimicrobial Activity and Anti-inflammatory Activity |
| JP2020505926A (en) * | 2017-01-30 | 2020-02-27 | ナショナル リサーチ カウンシル オブ カナダ | Blood-brain barrier transfer compounds and uses thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230141551A (en) * | 2022-03-29 | 2023-10-10 | 웰펩 주식회사 | peptidomimetic compound having an ability to inhibit the formation of dementia-inducing beta-amyloid aggregates and a composition for preventing or treating dementia containing the same |
| KR102589266B1 (en) * | 2022-03-29 | 2023-10-16 | 웰펩 주식회사 | peptidomimetic compound having an ability to inhibit the formation of dementia-inducing beta-amyloid aggregates and a composition for preventing or treating dementia containing the same |
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