CN105267211B - Aspochalasin类化合物在制备抗HIV潜伏药物和治疗艾滋病药物中的应用 - Google Patents
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Abstract
本发明公开了一种Aspochalasin类化合物在制备抗HIV潜伏药物和治疗艾滋病药物中的应用,Aspochalasin类化合物为式I结构,所述的R1、R2、R3、R4和R5为氢、羟基、羰基、双键、环氧、甲基、烷烃酰胺中的一种或两种以上,R1、R2、R3、R4和R5相同或者不相同。该Aspochalasin类化合物具有激活HIV潜伏的作用,可以与抗逆转录病毒药物联合使用,可清除被激活的潜伏感染的细胞,以此加速潜伏病毒库的清除,从而用于艾滋病的治疗。
Description
技术领域
本发明涉及治疗艾滋病药物的技术领域,具体涉及Aspochalasin类化合物在制备抗HIV潜伏药物和治疗艾滋病药物中的应用。
背景技术
获得性免疫缺陷综合征(AIDS)是由艾滋病毒(HIV)感染引起的一种严重危害人们生命健康的传染性疾病,目前临床采用的高效抗逆转录病毒疗法(Highly activeantiretroviral therapy,HAART),虽然能极大地提高艾滋病人的生存时间和质量,但是HIV感染人体后会与宿主细胞整合,形成无法被HAART清除的病毒库。这些潜伏病毒,在停止HAART后会重新激活并迅速反弹,因此艾滋患者需长期用药,而长期用药会引起病毒变异,耐药性增加,药物不良反应增加而使治疗失败(Ho,D.D.Toward HIV eradication orremission:the tasks ahead.Science,1998.280:1866–1867.)。研究显示,HIV难以在体内被完全清除的一个重要原因是HIV能够潜伏在静息的记忆CD4+T细胞中,该潜伏感染细胞是由一小部分HIV感染的活化CD4+T细胞转化而产生的,其整合的前病毒缺乏转录活性,因而,不会被免疫***和抗逆转录酶病毒的药物攻击。尽管感染个体携带潜伏感染细胞数量较少,但衰减率是如此之慢,以至于欲在个体生存期内仅靠HAART治疗将其彻底清除是不可能的。因此,HIV潜伏感染的静息CD4+T细胞是构成机体内病毒储藏库(reservoir)的主要部分,同时也是目前临床治疗不能彻底清除HIV的巨大障碍[Finzi,D.et al.Latentinfection of CD4+T cells provides a mechanism for lifelong persistence ofHIV-1,even in patients on effective combination therapy.Nature Med.1999,5,512–517]。
现实成功的个案提示,艾滋病的“功能性”治愈是可以实现的,而清除HIV潜伏病毒库是最有希望的方法[实现艾滋病的功能性治愈的策略,中国艾滋病性病,2015,21:253-256],因而探索激活和清除HIV潜伏库的方法以获得艾滋病临床功能性治愈,是当前艾滋病研究的热点。目前临床研究的HIV潜伏激活剂有细胞因子IL-2、细胞因子IL-7,组蛋白去乙酰化酶抑制剂伏立诺他,以及甲基化酶抑制剂。以上在研药物都存在不同的不足,如激活效果弱,不良反应明显等。因而,发现更加安全有效的HIV潜伏激活剂及相应的治疗方案已是当务之急。
发明内容
本发明提供了一种Aspochalasin类化合物在制备抗HIV潜伏药物和在制备治疗艾滋病药物中的应用。
Aspochalasin类化合物在制备抗HIV潜伏药物和在制备治疗艾滋病药物中的应用,本发明提供的Aspochalasin类化合物,为一种具有激活HIV潜伏作用的药物,为式I所示的结构,式II所示的结构是在式I结构的基础上,标注了A、B、C,本发明的Aspochalasin类化合物,A、B、C环形成5/6/11三环骈合结构,其C大环可有不同的取代。即所述的R1、R2、R3、R4和R5为氢、羟基、羰基、双键、环氧、甲基、烷烃酰胺等中的一种或两种以上(包括两种),R1、R2、R3、R4和R5相同或者不相同。
本发明提供的Aspochalasin类化合物,可以为混合物,也可以为单一的化合物,Aspochalasin类化合物可包括Aspochalasin E(R1、R2、R3、R4和R5分别为OH、OH、OH、H和H)、Aspochalasin M(R1、R2、R3、R4和R5分别为H、=O、OH、H和H)、Aspochalasin P(R1、R2、R3、R4和R5分别为H、OH、=O、H和H)、Aspochalasin C(R1、R2、R3分别为H、OH、OH,R4和R5形成双键)和19,20-dihydro-Aspochalasin C(R1、R2、R3、R4和R5分别为H、OH、OH、H和H)及其组合物。
即所述的Aspochalasin类化合物为Aspochalasin E、Aspochalasin M、Aspochalasin P、Aspochalasin C、19,20-dihydro-Aspochalasin C中的一种或两种以上,其中,Aspochalasin E中R1、R2、R3、R4和R5分别为OH、OH、OH、H和H,Aspochalasin M中R1、R2、R3、R4和R5分别为H、=O、OH、H和H,Aspochalasin P中R1、R2、R3、R4和R5分别为H、OH、=O、H和H,Aspochalasin C中R1、R2、R3分别为H、OH、OH,R4和R5形成双键,19,20-dihydro-AspochalasinC中R1、R2、R3、R4和R5分别为H、OH、OH、H和H。
进一步优选,所述的Aspochalasin类化合物为Aspochalasin C,Aspochalasin C中R1、R2、R3分别为H、OH、OH,R4和R5形成双键。在低浓度时即能明显使感染细胞内潜伏的HIV表达,相对激活率高,与抗逆转录病毒药物联合使用,可更好地清除被激活的潜伏感染的细胞,以此加速潜伏病毒库的清除,从而用于艾滋病的治疗。
Aspochalasin类化合物可以商业购买,也可以由曲丽穗霉Spicariaelegans(Eur.J.Org.Chem.2009,3045-3051)、或Trichodermagamsii(Fitoterapia,2012,541-544)、或黄柄曲霉Aspergillus flavipes(J.Nat.Prod.2004,328-332)等真菌发酵产物提取分离得到。
本发明采用HIV潜伏细胞模型进行活性筛选试验,结果显示Aspochalasin类化合物能使感染细胞内潜伏的HIV表达,具有干预HIV潜伏的作用,与抗逆转录病毒药物联合使用,可清除被激活的潜伏感染的细胞,以此加速潜伏病毒库的清除,为艾滋病的彻底治愈提供新的途径。
本发明提供的Aspochalasin类化合物和抗逆转录病毒药物联合在制备治疗艾滋病药物中的应用。
本发明提供的Aspochalasinl类化合物特别适合与其它抗HIV的药物联用。尤其是本发明的活性成分可与抗逆转录病毒药物联合使用,清除潜伏感染的细胞,从而用于艾滋病的治疗。所述的抗HIV药物包括:一、核苷类逆转录酶抑制剂:齐多夫定、地丹诺辛、扎西他滨、司他夫定、拉米夫定、阿巴卡韦;二、非核苷类逆转录酶抑制剂:奈韦拉平、地拉韦啶、依非韦伦;三、及蛋白酶抑制剂:沙奎那韦、茚地那韦、利托那韦、奈非那韦、安普那韦。即所述的抗逆转录病毒药物为齐多夫定、地丹诺辛、扎西他滨、司他夫定、拉米夫定、阿巴卡韦、奈韦拉平、地拉韦啶、依非韦伦、沙奎那韦、茚地那韦、利托那韦、奈非那韦、安普那韦中的一种或两种以上(包括两种)。
与现有技术相比,本发明的主要优点包括:
1.提出了Aspochalasin类化合物的新用途,其在低浓度时即能明显使感染细胞内潜伏的HIV表达。
2.所述的Aspochalasin类化合物可作为活性成分,制备具有激活HIV潜伏作用的药物。
3.所述的Aspochalasin类化合物可进一步可与抗逆转录病毒药物联合使用,为艾滋病的彻底治愈提供新的途径。
具体实施方式
实施例1
HIV潜伏诱导激活实验
将活性筛选用的细胞按每孔2×104个种植于96孔板,每孔加入100微升含10%FBS(胎牛血清,Gibco)的1640培养基(Gibco)。24小时后,加入一定浓度的Aspochalasin类化合物。药物处理细胞72小时后,在荧光显微镜下观察细胞GFP表达情况,并收集细胞进行流式细胞术检测,分析荧光细胞所占比例。
实施例2
用终浓度为20微克/毫升的Aspochalasin E(R1、R2、R3、R4和R5分别为OH、OH、OH、H和H)处理HIV潜伏感染细胞模型,在其作用3天后,通过对报告基因绿色荧光蛋白的荧光显微镜观察和流式细胞术检测,分析HIV潜伏感染细胞的激活效率,结果显示,HIV潜伏感染细胞经Aspochalasin E处理后相对激活率为62%。
实施例3
用终浓度为20微克/毫升的Aspochalasin C(R1、R2、R3分别为H、OH、OH,R4和R5形成双键)处理HIV潜伏感染细胞模型,在其作用3天后,通过对报告基因绿色荧光蛋白的荧光显微镜观察和流式细胞术检测,分析HIV潜伏感染细胞的激活效率,结果显示,HIV潜伏感染细胞经处理后相对激活率为80%。
实施例4
用终浓度为20微克/毫升的19,20-dihydro-Aspochalasin C(R1、R2、R3、R4和R5分别为H、OH、OH、H和H)处理HIV潜伏感染细胞模型,在其作用3天后,通过对报告基因绿色荧光蛋白的荧光显微镜观察和流式细胞术检测,分析HIV潜伏感染细胞的激活效率,结果显示,HIV潜伏感染细胞经19,20-dihydro-Aspochalasin C处理后相对激活率为56%。
实施例5
用终浓度为20微克/毫升的Aspochalasin类化合物的组合物,包括AspochalasinE(R1、R2、R3、R4和R5分别为OH、OH、OH、H和H)、Aspochalasin M(R1、R2、R3、R4和R5分别为H、=O、OH、H和H)和Aspochalasin P(R1、R2、R3、R4和R5分别为H、OH、=O、H和H),三者质量比1:1:1,处理HIV潜伏感染细胞模型,在其作用3天后,通过对报告基因绿色荧光蛋白的荧光显微镜观察和流式细胞术检测,分析HIV潜伏感染细胞的激活效率,结果显示,HIV潜伏感染细胞处理后激活率为51%。
实施例6
取Aspochalasin C(R1、R2、R3分别为H、OH、OH,R4和R5形成双键)4g与药用淀粉10g,灌制成胶囊,每粒净重200mg,该胶囊具有激活HIV潜伏的作用,在低浓度时即能明显使感染细胞内潜伏的HIV表达。
实施例7
取Aspochalasin C(R1、R2、R3分别为H、OH、OH,R4和R5形成双键)4g、齐多夫定4g、药用淀粉10g,灌制成胶囊,每粒净重200mg,该胶囊具有激活HIV潜伏的作用,与抗逆转录病毒药物齐多夫定联合使用,可清除被激活的潜伏感染的细胞,以此加速潜伏病毒库的清除,从而用于艾滋病的治疗。
Claims (2)
1.Aspochalasin类化合物在制备抗HIV潜伏药物中的应用,其特征在于,所述的Aspochalasin类化合物为式I所示的结构,
所述的Aspochalasin类化合物为Aspochalasin E、Aspochalasin P、Aspochalasin C、19,20-dihydro-Aspochalasin C中的一种或两种以上,其中,Aspochalasin E中R1、R2、R3、R4和R5分别为OH、OH、OH、H和H,Aspochalasin P中R1、R2、R3、R4和R5分别为H、OH、=O、H和H,Aspochalasin C中R1、R2、R3分别为H、OH、OH,R4和R5形成双键,19,20-dihydro-AspochalasinC中R1、R2、R3、R4和R5分别为H、OH、OH、H和H。
2.根据权利要求1所述的应用,其特征在于,所述的Aspochalasin类化合物为Aspochalasin C,Aspochalasin C中R1、R2、R3分别为H、OH、OH,R4和R5形成双键。
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