CN104877015B - 一种三萜-多肽缀合物、其药物组合物及用途 - Google Patents
一种三萜-多肽缀合物、其药物组合物及用途 Download PDFInfo
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Classifications
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- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
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- Chemical Kinetics & Catalysis (AREA)
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- Gastroenterology & Hepatology (AREA)
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Abstract
本发明属于生物医药领域,涉及一种三萜‑多肽缀合物、其药物组合物及用途。具体地,本发明涉及式I所示的缀合物、其衍生物、其立体异构体、或其可药用盐。本发明还涉及含有上述的式I缀合物、其衍生物、其立体异构体、或其可药用盐的药物组合物,以及式I缀合物、其衍生物、其立体异构体、或其可药用盐在治疗或预防HIV感染所致相关疾病尤其是获得性免疫缺陷综合征(AIDS,即艾滋病)的用途。本发明的化合物具有抑制HIV细胞融合例如抑制HIV‑1细胞融合的活性。XA1‑L1–P–K(L2‑XA2)式Ⅰ。
Description
技术领域
本发明属于生物医药领域,涉及一种三萜-多肽缀合物、其药物组合物及用途。具体地,本发明涉及式I所示的缀合物、其衍生物、其立体异构体、或其可药用盐。本发明还涉及含有上述的式I缀合物、其衍生物、其立体异构体、或其可药用盐的药物组合物,以及式I缀合物、其衍生物、其立体异构体、或其可药用盐在治疗或预防HIV感染所致相关疾病尤其是获得性免疫缺陷综合征(AIDS,即艾滋病)的用途。
XA1-L1–P–K(L2-XA2) 式Ⅰ。
背景技术
艾滋病主要是由于人免疫缺陷病毒Ⅰ型(HIV-1)感染导致的致死性传染疾病,在全球范围流行。目前临床上应用的抗HIV-1药物,辅以高效抗逆转录病毒疗法,可以在一定程度上延长HIV感染者的生存时间和改善其生活质量。但是,由于HIV疫苗研究进展缓慢以及耐药性问题日益明显,研发新型抗HIV药物仍是当务之急。HIV融合抑制剂(HIV fusioninhibitors)是干扰病毒进入靶细胞的新型抗HIV药物,其在感染的初始环节切断病毒的传播,这对于预防及控制HIV-1感染具有特殊意义,因而成为新机制抗HIV药物研究的热点。
Gp41是介导HIV-1与靶细胞膜融合的特异性蛋白,是融合抑制剂的作用靶标。Gp41的胞外区存在着两个与膜融合密切相关的螺旋结构功能区,即N末端重复序列(HR1)和C末端重复序列(HR2)。在膜融合过程中,HR2与HR1相互作用,形成一个六螺旋体核心结构(6-HB)。T20是衍生于gp41 HR2区域的具有36个氨基酸残基的融合抑制多肽,于2003年经美国FDA批准上市,是目前唯一上市的HIV-1融合抑制剂。T20能竞争性的和HR1构成的螺旋三聚体结合,占据HR2的作用位点,进而抑制6-HB的形成,使得膜融合过程不能完成。
T20的上市开辟了多肽类药物控制HIV-1的新领域。但是,T20本身存在着一些缺陷和不足。首先是耐药性问题:由于T20完全衍生于天然HR2序列,对靶标突变的抵抗力低,容易产生耐药性。HR1第36-45位残基(GIVQQQNNLL)是T20结合的主要部位,单个残基的突变导致T20敏感度下降5-10倍,两个残基突变则会导致敏感度下降100倍。其次,T20体内稳定性差,易被蛋白酶降解,生物利用度低。再次,T20具有较高的合成成本。因此,在保证生物活性的前提下如何解决耐药性、提高酶解稳定性以及降低多肽类HIV-1融合抑制剂的合成成本是新型HIV-1融合抑制剂研究的主要方向。
基于上述问题,目前主要的解决策略是避开T20的靶标结合部位,引入不同于T20的新的功能序列来克服耐药性;同时,加入螺旋形成及稳定因子,提高序列的螺旋性及稳定性,提高酶解稳定性及抑制活性。如第二代多肽类融合抑制剂T-1249,在其N端增加了与N-trimer疏水性口袋结合序列(WQEWEQKI),使其活性比T20提高了一个数量级;又如第三代融合抑制剂T-1144,和T20的靶标作用位点完全不同,主要为HR1的疏水性口袋区(WEAWERAI)。Ⅰ期临床研究结果表明,T-1144能够显著抑制T20耐药性毒株,同时比T20显示了更高的活性及更好的药代动力学性质。此外,5HR系列多肽开创了基于靶标gp41 HR1螺旋三聚体的三维晶体结构应用计算机辅助设计完全非天然α螺旋肽的新思路。以5HR为先导结构,在其N端引入口袋结合区(WMEWDRE),C端引入脂膜结合区(WASLWNWF),使得抑制融合活性得到了显著提高。
萜类化合物是指分子式为异戊二烯单位倍数的烃类及其含氧衍生物。萜类化合物可以单独存在,也可以以苷元的形式存在于皂苷分子当中。萜类化合物广泛存在于自然界中,具有多种生理活性。近年研究发现,某些萜类化合物具有一定的抗HIV活性。桦木酸(betulinic acid,BA)属于五环三萜类化合物。1994年Fujioka等首先发现了BA的抗HIV活性,可抑制HIV在H9细胞中复制。随后的研究表明,一些BA的类似物,如熊果酸(Ursolicacid,UA)和齐墩果酸(Oleanic acid,OA)同样具有抗HIV活性。在桦木酸的3位羟基上引入一个3,3-二甲基琥珀酰基团可显著提高其抗HIV活性。实验表明该类化合物是通过结合于Gag蛋白,干扰其裂解过程,抑制病毒蛋白的组装。在桦木酸的28位羧基上修饰同样具有较好的抗HIV活性。有实验表明它的这种抗HIV活性是通过抑制膜融合过程的后融合阶段实现的。
萜类化合物可以单独存在,也可以以苷元的形式存在于皂苷分子当中。皂苷是由苷元和糖两部分组成的,它在自然界的分布极为广泛。苷元主要包括萜类、甾体和甾体生物碱等结构;糖链的结构很多,但是糖基组成比较简单。长期以来,皂苷一直是天然有机化学和药物化学的重要研究对象,但多数研究仅仅局限在苷元上面,而忽略了糖的作用。近年来,随着分离技术和结构研究方法的进展,皂苷的构效关系得到了进一步的阐明。初步研究表明,皂苷中的糖链与其生物活性有着密切的关系。另外,许多皂苷化合物都具有广谱的抗病毒活性,但是活性都较弱。这主要和皂苷与病毒中特异性靶标的结合能力不强有关。
目前尚需要新的思路来开发新的HIV融合抑制剂。
发明内容
本发明人经过深入的研究和创造性的劳动,将衍生于gp41 HR2的肽类药效团与三萜类药效团缀合,设计全新结构HIV融合抑制剂,探索抑制耐药性,得到了一种化合物(如式I所示)即三萜-多肽缀合物。本发明人惊奇地发现,本发明的化合物具有良好的抑制HIV融合活性。由此提供了下述发明:
本发明的一个方面涉及式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,
XA1-L1–P-K(L2-XA2) 式Ⅰ
其中,
XA1和XA2为相互独立的三萜类化合物,并且XA1和XA2至少存在其中一个;
L1为连接多肽P与XA1间的连接臂,或者L1缺失,并且L1缺失时XA1也同时缺失;
P是氨基酸序列为NNYTSLIHSLIEESQNQQEKNEQELL(SEQ ID NO:1)或者INNYTSLIHSLIEESQNQQEKNEQELL(SEQ ID NO:2)的多肽;
K为赖氨酸,其侧链与L2-XA2连接,或者K缺失,并且K缺失时L2-XA2也同时缺失;
L2为连接赖氨酸K与XA2分子间的连接臂;
L2与L1相同或不同。
所述“XA1和XA2为相互独立的”表示XA1和XA2可以相同或不同。
所述“XA1和XA2至少存在其中一个”包括如下情况:仅存在XA1,仅存在XA2,或者XA1和XA2同时存在。
不拘于理论的限制,L1或L2为使得小分子能够保持空间灵活性而与靶标结合的连接臂。
不拘于理论的限制,在多肽P的羧基端引入K的目的是为了引入(L2-XA2)。
根据权利要求1本发明任一项所述的式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,其中,L1的一端与多肽P通过酰胺键连接,另一端通过1,2,3-三氮唑基团与XA1连接;具体地,所述1,2,3-三氮唑基团为L1上的叠氮基与XA1上的炔基通过“click反应”形成;和/或
L2的一端与赖氨酸K的侧链氨基通过酰胺键连接,另一端通过1,2,3-三氮唑基团与XA2连接;具体地,所述1,2,3-三氮唑基团为L2上的叠氮基与XA2上的炔基通过“click反应”形成。
根据本发明任一项所述的式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,其中,所述三萜类化合物为五环三萜类化合物或四环三萜类化合物,优选为五环三萜类化合物。
根据本发明任一项所述的式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,其中:
XA1和XA2独立地选自如下的12个结构式中的任意一个:
不拘于理论的限制,上面12个结构式中的炔基与L1或L2的叠氮基通过“click反应”形成1,2,3-三氮唑基团,通过1,2,3-三氮唑将L1或L2与上面的结构式(12个中的任一个)相连接。
根据本发明的任一项所述的式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,其中:
L1与L2独立地为叠氮乙酸与天然或非天然氨基酸缩合形成的化合物,或者叠氮乙酸与一端为氨基,一端为羧基的聚乙二醇缩合形成的化合物。
不拘于理论的限制,L1的一端与多肽P通过酰胺键连接;L1的另一端为叠氮基。叠氮基能够与XA1上的炔基通过“click反应”形成1,2,3-三氮唑基团,将XA1与L1连接。
不拘于理论的限制,L2的一端与K的侧链氨基通过酰胺键连接;L2的另一端为叠氮基。叠氮基能够与XA2上的炔基通过“click反应”形成1,2,3-三氮唑基团,将XA2与L2连接。
根据本发明的任一项所述的式Ⅰ所示的化合物、其衍生物、其立体异构体、或其可药用盐,其中:
所述天然或非天然氨基酸选自:
L型或D型的甘氨酸(Gly),丙氨酸(Ala),亮氨酸(Leu),异亮氨酸(Ile),谷氨酸(Glu),谷酰胺(Gln),天冬氨酸(Asp),天冬酰胺(Asn),缬氨酸(Val),赖氨酸(Lys),丝氨酸(Ser),苏氨酸(Thr),精氨酸(Arg),组氨酸(His),色氨酸(Trp),苯丙氨酸(Phe),酪氨酸(Tyr),半胱氨酸(Cys),甲硫氨酸(Met);
β-丙氨酸(βAla);
γ-氨基丁酸(GABA);
6-氨基己酸(Aca);
乙二酸,丙二酸,丁二酸,戊二酸,己二酸;
乙二胺,丙二胺,丁二胺,戊二胺,己二胺;
乙二醇,丙二醇,丁二醇,戊二醇,己二醇;
NH2-CH2CH2-O-CH2CH2-COOH(PEG1);
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG2);和
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG3)。
为了便于理解,这里仅以βAla为示例(并不表示对本发明进行限制),L1或L2为下式的虚线部分所示的结构:
根据本发明的任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐,其中,所述式Ⅰ化合物选自如下的化合物:
(1)BAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(2)UAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(3)OAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(4)BAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(5)UAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(6)OAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(7)BApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(8)UApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(9)OApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(10)BApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(11)UApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(12)OApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL;
(13)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-Bac);
(14)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(15)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(16)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(17)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(18)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(19)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(20)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(21)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(22)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(23)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(24)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApo);
(25)BAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(26)UAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(27)OAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(28)BAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(29)UAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(30)OAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(31)BApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(32)UApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(33)OApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(34)BApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(35)UApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(36)OApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApo);
(37)BAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(38)UAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(39)OAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(40)BAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(41)UAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(42)OAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApo);
(43)BAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(44)UAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(45)OAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(46)BAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(47)UAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(48)OAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(49)BApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(50)UApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(51)OApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(52)BApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(53)UApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(54)OApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL;
(55)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(56)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(57)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(58)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(59)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(60)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(61)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(62)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(63)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(64)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(65)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(66)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApo);
(67)BAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(68)UAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(69)OAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(70)BAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(71)UAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(72)OAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(73)BApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(74)UApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(75)OApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(76)BApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(77)UApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(78)OApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApo);
(79)BAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(80)UAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApc);
(81)OAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OApc);
(82)BAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(83)UAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UApo);
(84)OAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-Oapo)。
本发明的另一方面涉及一种药物组合物,其含有至少一种本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐,以及任选的药学上可接受的辅料。
本发明的再一方面涉及一种HIV融合抑制剂,其含有至少一种本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐。
本发明的再一方面涉及本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐在制备HIV融合抑制剂中的用途。
本发明的再一方面涉及本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐在制备用于治疗和/或预防和/辅助治疗HIV感染相关疾病尤其是艾滋病的药物中的用途。
本发明的再一方面涉及一种在体内或体外抑制HIV融合的方法,包括使用有效量的本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐的步骤。
在本发明的一个实施方案中,所述在体外抑制HIV融合的方法是非治疗目的的。
本发明的再一方面涉及一种治疗和/或预防和/或辅助治疗HIV感染相关疾病尤其是艾滋病的方法,包括使用有效量的本发明中任一项所述的式Ⅰ化合物、其衍生物、其立体异构体、或其可药用盐的步骤。
在本发明中,术语“天然”是指自然存在的,未经人为修饰的,如HIV-1gp41本身的氨基酸序列等。
在本发明中,术语“非天然”是指人为设计的,与天然不同的,如对直接衍生的天然序列经改造、修饰后的序列等。
在本发明中,术语“疏水性氨基酸”是指侧链为疏水性基团的氨基酸,包括:Ala,Val,Leu,Ile,Met,Phe,Trp等。
在本发明中,术语“亲水性氨基酸”是指侧链含有能与水作用形成氢键的亲水基团的氨基酸,包括:Ser,Thr,Cys,Asp,Asn,Glu,Gln,Arg,Lys,His,Tyr等。
在本发明中,术语“酸性氨基酸”是指侧链含羧基的氨基酸,包括:Glu,Asp等。
在本发明中,术语“碱性氨基酸”是指侧链含氨基或胍基的氨基酸,包括:Lys,Arg等。
发明的有益效果
本发明的化合物具有抑制HIV细胞融合例如抑制HIV-1细胞融合的活性。
附图说明
图1:样品配制说明。每个96孔样品板(每行12孔,共8行;Costar 3799,CorningIncorporation,USA)配制4个样品,每个样品重复1次。以第一行为例,将选定浓度的样品放置第S1孔,序列稀释4倍(即后一个孔的样品浓度是前一个孔的1/4),按此稀释10个浓度梯度。最后两个孔作为对照只含有培养基,其中第11孔含有靶细胞和效应细胞为100%融合对照(阳性对照),第12孔只含靶细胞为无融合背景对照(阴性对照)。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
在本发明中使用的缩写具有下面的含义:
实施例所用固相合成载体Rink酰胺树脂为天津南开合成责任有限公司产品;HBTU、HOBT、DIEA以及Fmoc保护的天然氨基酸或D型的非天然氨基酸为上海吉尔生化公司以及成都诚诺新技术有限责任公司产品。N-甲基吡咯烷酮(NMP)为ACROS公司产品;三氟乙酸(TFA)为北京博迈杰科技有限公司产品;3,4-二羟基苯乙酸、4-氨基水杨酸、5-氨基水杨酸、2,5-己二酮、叔丁醇以及溴代乙酸乙酯为ALFA公司产品;DMF、DCM为韩国三星公司产品;色谱纯乙腈为Fisher公司产品。其它试剂如无说明均为国产分析纯产品。
实施例1:化合物1的制备
1.1小分子化合物BAc的合成
中间体2的合成:
氮气保护下用2mlDMF溶解0.3g(0.66mmol)化合物1,0.11g咪唑及8mg DMAP。加入TBDPSCl 0.23mL(0.79mmol)。回流搅拌过夜。反应完成后加入25mL DCM,有机相分别用1N盐酸,饱和氯化钠溶液洗,无水硫酸钠干燥。柱层析分离纯化得白色固体,收率72%。
中间体3的合成:
将0.25g中间体2及40mg DMAP溶于10mL DCM中,加入0.11g戊炔酸。在搅拌下加入0.23g DIC,继续室温搅拌至反应完全。加入25mL DCM稀释后分别用10%柠檬酸、饱和碳酸氢钠及饱和氯化钠溶液洗三遍,无水硫酸钠干燥。柱层析分离纯化得白色固体,收率71%。
化合物4的合成:
氮气保护下将0.27g(0.34mmol)中间体3溶于5ml无水四氢呋喃中,加入TBAF0.14g(0.52mmol),室温搅拌3小时。反应结束后加入15mL DCM,有机相分别用1N HCl和饱和氯化钠洗三遍,无水硫酸钠干燥。柱层析分离纯化,得白色固体,收率80%。
1.2 BAc与肽缀合物(化合物1)的制备
多肽合成采用标准的Fmoc固相方法。选用Rink Amide树脂,肽链由C端向N端延长。缩合剂为HBTU/HOBt/DIEA。脱保护剂为哌啶/DMF溶液。利用CEM微波多肽合成仪合成肽序列,叠氮乙酸可以作为最后的残基与多肽N端氨基缩合。裂解剂为三氟乙酸(TFA),粗肽水溶解后冻干保存。用中压液相色谱法或高压液相色谱法(HPLC)进行分离纯化,纯肽含量>90%。基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
合成条件如下:
保护氨基酸或叠氮乙酸:0.2M的DMF溶液,
活化剂:0.45M HBTU/HOBt的DMF溶液,
活化碱:2M DIEA的NMP溶液,
脱保护剂:20%v/v哌啶的DMF溶液,
封闭试剂:20%v/v乙酸酐的DMF溶液。
称取Rink Amide树脂0.5g(0.25mmol)置入CEM微波多肽合成仪反应器中,然后将氨基酸,叠氮乙酸,活化剂,活化碱,脱保护试剂,封闭试剂按上述浓度配置好后,用CEM微波全自动多肽合成仪进行合成。完成后肽树脂用DMF洗涤3遍后用无水甲醇收缩,室温真空干燥,得肽树脂2.05g。
裂解液(体积百分比):三氟乙酸:乙二硫醇:间甲酚:水=82.5:10:5:2.5。
肽树脂的裂解:称取微波合成仪合成好的肽树脂2.05g,放入250ml茄形瓶中,冰浴,电磁搅拌。按1克肽树脂加入10ml的量配制裂解液。TFA需预先冰浴降温30min或者预先存放于冰箱中使用;将配制好的裂解液加入到冰浴条件下的肽树脂中,电磁搅拌,树脂变橙红色,冰浴条件下反应30min,然后,撤冰浴,室温再继续搅拌反应90min,反应完成。剧烈搅拌下向反应器中加入冷乙醚200ml,析出白色沉淀,继续搅拌30min;用G4的砂芯抽虑漏斗滤出析出物,用冷乙醚反复洗涤3遍,晾干。加入双蒸水50ml,乙腈5ml使固体充分溶解,抽虑,滤液冻干得N端连接叠氮乙酸的粗肽1.03g。
所得连接叠氮乙酸的粗肽用中压或高压色谱进行纯化。色谱柱为C8柱,洗脱剂为乙腈,水及少量乙酸。具体操作步骤:称取粗肽1.00g,加水20ml,乙腈5ml使固体溶解,离心10min(3000转/分钟),取上清液上样。色谱柱预先用15%乙腈/水/0.1%冰乙酸溶液200ml平衡。上样后继续用15%乙腈/水/0.1%冰乙酸溶液200ml冲洗,高效液相检测洗脱液成分。根据液相检测结果逐渐升高乙腈含量,直至所纯化的多肽缀合物主峰被洗脱出来。合并洗脱液,旋转蒸发去除大部分溶剂,冻干得纯的N端连有叠氮乙酸的多肽,HPLC检测含量大于90%。
Click化学制备缀合物:称取N端连有叠氮乙酸的多肽20mg,用1mL水溶解;称取BAc2mg,用1mL叔丁醇溶解。将溶解有BAc的叔丁醇溶液加到溶有肽的水溶液中,加入1mg五水合硫酸铜及1mg抗坏血酸,涡旋后置于超生仪中反应4小时。高效液相色谱检测反应。反应完成后用制备色谱分离纯化,分离方法如前所述。
实施例2-6:化合物2-3,43-45的制备
方法同实施例1,只是将与多肽N端缀合的BAc替换为UAc或OAc,或将多肽N端引入Ile,得化合物2-3,43-45。
实施例7:化合物4的制备
7.1小分子化合物BAo的合成
称取0.5g化合物1用10mL DMF溶解,加入0.46g碳酸钾及171微升溴丙炔。室温搅拌4小时,TLC监测反应。反应完成后过滤除盐滤液蒸干后柱层析分离纯化,得白色固体,收率65%。
7.2BAo与肽缀合物(化合物4)的制备:和化合物1的合成过程相
同,只是将肽链N端的小分子更换为BAo。
实施例8-12:化合物5-6,46-48的制备
方法同实施例7,只是将与多肽N端缀合的BAo替换为UAo或OAo,或将多肽N端引入Ile,得化合物5-6,46-48。
实施例13:化合物7的制备
13.1小分子化合物BApc的合成
称取1.0g化合物1用10mL DMF溶解,加入0.61g碳酸钾及284微升溴丙炔。室温搅拌4小时,TLC监测反应。反应完成后过滤除盐滤液蒸干后柱层析分离纯化,得中间体6,白色固体,收率65%。
称取0.15g中间体6及0.04g DMAP溶于6mL DCM中。依次加入戊炔酸0.09g及0.23gDIC。室温搅拌4小时,TLC检测反应。反应完成后一次用10%柠檬酸、饱和碳酸氢钠及饱和氯化钠溶液洗三遍,无水硫酸钠干燥。柱层析分离纯化得白色固体,收率70%。
13.2 BApc与肽缀合物(化合物7)的制备:和化合物1的合成过程相同,只是将肽链N端的小分子更换为BApc。
实施例14-18:化合物8-9,49-51的制备
方法同实施例13,只是将与多肽N端缀合的BApc替换为UApc或OApc,或将多肽N端引入Ile,得化合物8-9,49-51。
实施例19:化合物10的制备
19.1小分子化合物BApo的合成
称取4.0g化合物1置于茄瓶中,加入25mL吡啶及3.5mL乙酸酐室温搅拌过夜至澄清,TLC监测反应。反应完成后加入25mL水,继续搅拌30min。中间体8析出,抽滤得白色固体,收率80%。
称取1.0g中间体8用10mL DMF溶解,加入碳酸钾0.91g及溴丙炔342微升。室温搅拌4小时,TLC检测反应。反应完成后抽滤除去盐,减压浓缩。柱层析分离纯化得白色固体,收率78%。
19.2BApo与肽缀合物(化合物10)的制备:和化合物1的合成过程相同,只是将肽链N端的小分子更换为BApo。
实施例20-24:化合物11-12,52-54的制备
方法同实施例19,只是将与多肽N端缀合的BApo替换为UApo或OApo,或将多肽N端引入Ile,得化合物11-12,52-54。
实施例25:化合物13的制备
多肽合成采用标准的Fmoc固相方法。选用Rink Amide树脂,肽链由C端向N端延长。缩合剂为HBTU/HOBt/DIEA。脱保护剂为哌啶/DMF溶液。利用CEM微波多肽合成仪合成肽序列,第一个氨基酸残基选用Alloc保护侧链的赖氨酸与Rink Amide树脂相连。在多肽合成完成后,加入用2mL DCM/THF溶解的四三苯基膦钯(1eq)及5,5-二甲基环己基-1,3-二酮(10eq)溶液,避光搅拌6小时。用DIPEA/DMF洗树脂五次,后用DCM洗树脂5次。此时肽树脂中Alloc保护侧链的赖氨酸的Alloc基团脱除,侧链氨基暴露。此时用同样的多肽合成方法将叠氮乙酸与赖氨酸侧链氨基缩合。裂解剂为三氟乙酸(TFA),粗肽水溶解后冻干保存。用中压液相色谱法或高压液相色谱法(HPLC)进行分离纯化,纯肽含量>90%。基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
BAc的合成方法如前所述。用与制备化合物1相同的Click化学合成化合物13。
实施例26-48:化合物14-24,55-66的制备
方法同实施例25,只是将与多肽C端缀合的BA衍生物替换为UA或OA衍生物,或将多肽N端引入Ile,得化合物14-24,55-66。
实施例49:化合物25的制备
多肽合成采用标准的Fmoc固相方法。选用Rink Amide树脂,肽链由C端向N端延长。缩合剂为HBTU/HOBt/DIEA。脱保护剂为哌啶/DMF溶液。利用CEM微波多肽合成仪合成肽序列,第一个氨基酸残基选用Alloc保护侧链的赖氨酸与Rink Amide树脂相连。N端最后连接叠氮乙酸(与化合物1合成方法相同)。随后采用化合物13的合成方法脱除Alloc保护并将赖氨酸侧链与叠氮乙酸缩合。裂解剂为三氟乙酸(TFA),粗肽水溶解后冻干保存。用中压液相色谱法或高压液相色谱法(HPLC)进行分离纯化,纯肽含量>90%。基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
BAc的合成方法如前所述。用与制备化合物1相同的Click化学合成化合物25,区别在于BAc、五水合硫酸铜、抗坏血酸钠的投料量加倍。
实施例50-72:化合物26-36,67-78的制备
方法同实施例48,只是将与多肽C端缀合的BA衍生物替换为UA或OA衍生物,或将多肽N端引入Ile,得化合物26-36,67-78。
实施例73:化合物37的制备
71.1多肽中间体的合成
多肽合成采用标准的Fmoc固相方法。选用Rink Amide树脂,肽链由C端向N端延长。缩合剂为HBTU/HOBt/DIEA。脱保护剂为哌啶/DMF溶液。利用CEM微波多肽合成仪合成肽序列,第一个氨基酸残基选用半胱氨酸与Rink Amide树脂相连。N端最后连接叠氮乙酸(与化合物1合成方法相同)。裂解剂为三氟乙酸(TFA),粗肽水溶解后冻干保存。用中压液相色谱法或高压液相色谱法(HPLC)进行分离纯化,纯肽含量>90%。基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
71.2 BAc与多肽中间体N端缀合
BAc的合成方法如前所述。用与制备化合物1相同的Click化学合成化合物首先将BAc缀合在上述多肽中间体的N端。用中压液相色谱法或高压液相色谱法(HPLC)进行分离纯化,纯肽含量>90%。基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
71.3 BApc溴代乙酸酯(BApc-Br)的合成
依次称取溴乙酸6.95g,BApc7.73g,EDC·HCl 13.43g,DMAP 122mg加入500ml茄形瓶中,加入DCM 500ml,冰浴下搅拌,溶液呈黄色。30min后撤除冰浴,室温下反应24h,溶液呈红褐色。依次用饱和NaHCO3、饱和NaCl洗涤,无水MgSO4干燥。适当浓缩后用硅胶柱湿法装柱上样纯化。先用石油醚:乙酸乙酯=10:1作为洗脱剂洗脱500ml之后将洗脱剂更换为石油醚:乙酸乙酯=9:1,洗脱下产物,蒸除溶剂,真空干燥后得到白色固体6.3g,产率62%。
71.4将BApc缀合在BAc-多肽的C端
取纯化后的BAc-多肽(>90%)20mg溶于0.3ml DMSO中,分别加入0.2ml BApc-Br3.0mg的THF溶液,混合均匀后用滴管加入DIEA 2滴,室温反应3h,用C4半制备反相色谱柱分离纯化,MALDI-TOF-MS确证分子量。
实施例74-84:化合物38-42,79-84的制备
方法同实施例71,只是将与多肽C端缀合的BA衍生物替换为UA或OA衍生物,或将多肽N端引入Ile,得化合物38-42,79-84。
实施例85:化合物抑制HIV-1介导的细胞-细胞融合活性评价(IC50)
1.TZM-bl细胞和HL2/3细胞的复苏/冻存
将细胞冻存管从液氮中取出,37℃水浴迅速升温,取出细胞冻存液(1ml),加至15ml离心管,并加入1ml培养基,离心(800rpm,10min),除去培养基,重新加入1ml新鲜培养基,并轻吹使细胞均匀悬浮,将细胞悬浮液全部转移至含有15ml培养基的75cm2培养瓶中,在37℃、5%CO2下培养。
消化细胞并计数后,离心,弃上清,加冻存液轻吹使细胞均匀悬浮(100万/ml),分装至冻存管(1ml/管),分别置于4℃(30min)、-20℃(2h)、-80℃(12h)、-196℃保存。
2.传代培养
取出细胞培养瓶,倒去培养基,加入2ml消化液,轻晃使其在细胞表面平铺均匀,倒去消化液,重新加入2ml消化液,铺匀,37℃消化2min,加入4ml培养基终止消化,取出所有液体,离心,弃上清,加4ml培养基并轻吹使细胞均匀悬浮,取10μl计数,取40-50万细胞置于75cm2培养瓶中传代培养。
3.融合实验
A.取TZM-bl细胞(由美国NIH AIDS Research and Reference Reagent Program提供)悬浮液稀释至50万/ml,铺入96孔细胞培养板,50μl/孔,培养24h。
B.配样品:取待测化合物,先估计化合物的IC50值,以这个估计的值为基础,乘以两个4,再乘以6得到待测化合物的配制浓度,例如:估计样品的IC50为10nM,则样品的配制浓度为10*4*4*6=960nM,以此浓度为基础,在96孔板上第(1-10)列依次将待测化合物稀释四倍,11列和12列为空白溶剂(空白溶剂即只含培养基,不含待测样品,其中11列为阳性对照,为无样品抑制剂条件下以1:3浓度混合的TZM-bl细胞和HL2/3细胞;12列为阴性对照,为单一TZM-bl细胞的化学发光信号);DMSO含量≤6%。
样品配制说明(如附图1):每个96孔样品板(每行12孔,共8行;Costar 3799,Corning Incorporation,USA)配制4个样品,每个样品重复1次,如图1所示,以第一行为例将选定浓度的样品放置第S1孔,序列稀释4倍(即后一个孔的样品浓度是前一个孔的1/4),按此稀释10个浓度梯度。最后两个孔作为对照只含有培养基,其中第11孔含有靶细胞和效应细胞为100%融合对照(阳性对照),第12孔只含靶细胞为无融合背景对照(阴性对照)。
C.取HL2/3细胞(由美国NIH AIDS Research and Reference Reagent Program提供)悬浮液稀释至100万/ml,加入细胞板的(1-11)×(A-H),50μl/孔,第12×(A-H)补加50μl/孔培养基。
D.立即取步骤B中的20μl/孔样品加入细胞板,培养6h。
E.去除细胞板中每孔中的培养基(120μl/孔),以PBS洗2次,150μl/次。
加入稀释后的裂解液(1×),50μl/孔,裂解5min;其中稀释后的裂解液(1×)即将Luciferase试剂盒(Promega,USA)中(5×)的裂解液用水稀释,根据用量新鲜配制。
F.取20μl/孔细胞裂解液铺在96孔磷光板上。
G.将融化后的LA缓冲液(Luciferase Assay Buffer,Promega Cooperation,USA)加入LA底物(Luciferase Assay Substrate,Promega Cooperation,USA)中混匀,加40μl/孔于96孔磷光板中。
H.立即在酶标仪上检测发光。实验的阴性对照为单一TZM-bl细胞的化学发光信号,用Min表示;阳性对照为无样品抑制剂条件下以1:3浓度混合的TZM-bl细胞和HL2/3细胞,用Max表示;测定值为某一样品在某一浓度下的信号值,用X表示;细胞融合率=(X-Min)/(Max-Min)*100%。
按照上述方法,活性测定结果见下面的表1。
表1:抑制HIV-1介导的细胞融合活性(IC50)
由表1的活性结果可见,所有三萜-多肽缀合物均显示了抑制HIV-1细胞融合活性,其中化合物4、13、14、19、22、57、61、64、25、28、31、34、37、40、67、70、73、76、79、82抑制HIV融合活性达到较低的nM水平,与阳性对照药C34和T20相当甚至更好。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
序列表
Claims (12)
1.式Ⅰ所示的化合物或其可药用盐,
XA1-L1–P-K(L2-XA2) 式Ⅰ
其中,
仅存在XA2或者XA1和XA2同时存在;其中,仅存在XA2时,式Ⅰ为P-K(L2-XA2);
L1为连接多肽P与XA1间的连接臂;
P是氨基酸序列为NNYTSLIHSLIEESQNQQEKNEQELL(SEQ ID NO:1)或者INNYTSLIHSLIEESQNQQEKNEQELL(SEQ ID NO:2)的多肽;
K为赖氨酸,其侧链与L2-XA2连接;
L2为连接赖氨酸K与XA2分子间的连接臂;
L2与L1相同或不同;
XA1和XA2独立地选自如下的8个结构式中的任意一个:
2.根据权利要求1所述的式Ⅰ所示的化合物或其可药用盐,其中,L1的一端与多肽P通过酰胺键连接,另一端通过1,2,3-三氮唑基团与XA1连接;和/或
L2的一端与赖氨酸K的侧链氨基通过酰胺键连接,另一端通过1,2,3-三氮唑基团与XA2连接。
3.根据权利要求2所述的式Ⅰ所示的化合物或其可药用盐,其中,所述1,2,3-三氮唑基团为L1上的叠氮基与XA1上的炔基通过“click反应”形成。
4.根据权利要求2所述的式Ⅰ所示的化合物或其可药用盐,其中,所述1,2,3-三氮唑基团为L2上的叠氮基与XA2上的炔基通过“click反应”形成。
5.根据权利要求1至4中任一项所述的式Ⅰ所示的化合物或其可药用盐,其中:
L1与L2独立地为叠氮乙酸与天然或非天然氨基酸缩合形成的化合物,或者叠氮乙酸与一端为氨基,一端为羧基的聚乙二醇缩合形成的化合物。
6.根据权利要求5所述的式Ⅰ所示的化合物或其可药用盐,其中,
所述天然或非天然氨基酸选自:
甘氨酸(Gly),L型或D型的丙氨酸(Ala),L型或D型的亮氨酸(Leu),L型或D型的异亮氨酸(Ile),L型或D型的谷氨酸(Glu),L型或D型的谷酰胺(Gln),L型或D型的天冬氨酸(Asp),L型或D型的天冬酰胺(Asn),L型或D型的缬氨酸(Val),L型或D型的赖氨酸(Lys),L型或D型的丝氨酸(Ser),L型或D型的苏氨酸(Thr),L型或D型的精氨酸(Arg),L型或D型的组氨酸(His),L型或D型的色氨酸(Trp),L型或D型的苯丙氨酸(Phe),L型或D型的酪氨酸(Tyr),L型或D型的半胱氨酸(Cys),L型或D型的甲硫氨酸(Met);
β-丙氨酸(βAla);
γ-氨基丁酸(GABA);
6-氨基己酸(Aca);
乙二酸,丙二酸,丁二酸,戊二酸,己二酸;
乙二胺,丙二胺,丁二胺,戊二胺,己二胺;
乙二醇,丙二醇,丁二醇,戊二醇,己二醇;
NH2-CH2CH2-O-CH2CH2-COOH(PEG1);
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG2);和
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG3)。
7.根据权利要求1至4中任一项所述的式Ⅰ化合物或其可药用盐,其选自如下的化合物:
(13)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(14)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(15)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(16)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(17)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(18)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(19)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(22)NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(25)BAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(26)UAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(27)OAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(28)BAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(29)UAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(30)OAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(31)BApc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(34)BApo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(37)BAc-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(40)BAo-βAla-NNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(55)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(56)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(57)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(58)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(59)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(60)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(61)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(64)INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(67)BAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAc);
(68)UAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAc);
(69)OAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAc);
(70)BAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BAo);
(71)UAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-UAo);
(72)OAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-OAo);
(73)BApc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(76)BApo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
(79)BAc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApc);
(82)BAo-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-K(βAla-BApo);
或者上述化合物的可药用盐。
8.一种药物组合物,其含有至少一种权利要求1至7中任一项所述的式Ⅰ化合物或其可药用盐,以及任选的药学上可接受的辅料。
9.一种HIV融合抑制剂,其含有至少一种权利要求1至7中任一项所述的式Ⅰ化合物或其可药用盐。
10.权利要求1至7中任一项所述的式Ⅰ化合物或其可药用盐在制备HIV融合抑制剂,或者在制备用于治疗和/或预防和/辅助治疗HIV感染相关疾病的药物中的用途。
11.根据权利要求10所述的用途,其中,所述HIV感染相关疾病为艾滋病。
12.一种在体外抑制HIV融合的方法,包括使用有效量的权利要求1至7中任一项所述的式Ⅰ化合物或其可药用盐的步骤。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5769828A (en) * | 1996-06-13 | 1998-06-23 | Medtronic, Inc. | Two-stage venous cannula with expandable reinforcing member |
US20040097436A1 (en) * | 2000-09-29 | 2004-05-20 | Regents Of The University Of Minnesota | Triterpenes having antibacterial activity |
WO2009155789A1 (zh) * | 2008-06-25 | 2009-12-30 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的多肽及其衍生物 |
CN103122025A (zh) * | 2011-11-21 | 2013-05-29 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
CN103127135A (zh) * | 2011-11-22 | 2013-06-05 | 北京大学 | 三萜衍生物,其制备方法和用途 |
CN103483428A (zh) * | 2012-06-11 | 2014-01-01 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5769828A (en) * | 1996-06-13 | 1998-06-23 | Medtronic, Inc. | Two-stage venous cannula with expandable reinforcing member |
US20040097436A1 (en) * | 2000-09-29 | 2004-05-20 | Regents Of The University Of Minnesota | Triterpenes having antibacterial activity |
WO2009155789A1 (zh) * | 2008-06-25 | 2009-12-30 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的多肽及其衍生物 |
CN103122025A (zh) * | 2011-11-21 | 2013-05-29 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
CN103127135A (zh) * | 2011-11-22 | 2013-06-05 | 北京大学 | 三萜衍生物,其制备方法和用途 |
CN103483428A (zh) * | 2012-06-11 | 2014-01-01 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
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