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喹诺酮抗HIV活性及其构效关系的研究进展
喹诺酮是近年来寻找抗HIV新药的重要结构骨架之一.通过结构修饰,可从中筛选出若干有希望的整合酶抑制剂、逆转录酶抑制剂以及双重(逆转录酶+整合酶)抑制剂.尤其是整合酶抑制剂elvitegravir即将上市,引起对抗HIV喹诺酮研发的关注.本文按喹诺酮的结构特征,从2-喹诺酮、4-喹诺酮、β-二酮酸和杂合体着手,综述了近年来这类化合物在抗HIV活性及其构效关系、作用机制等方面的研究进展.
关键词： 喹诺酮 逆转录酶抑制剂 整合酶抑制剂 双重抑制剂:构效关系:综述 -
HIV整合酶抑制剂体外筛选方法研究进展
为了评价HIV整合酶抑制剂体外筛选方法的特点和整合酶抑制剂研究进展,以常用的3'加工反应法、链转移反应法、改良ELISA法及基于结构的筛选为基础归类整合酶抑制剂.整合酶抑制剂按方法分为五类,并可推测其作用机制,通过比较可知以上方法各有利弊,需配合运用.整合酶抑制剂有研究价值.
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喹啉酮酸类HIV-1整合酶抑制剂的研究进展
整合酶是人类免疫缺陷病毒(HIV)进入宿主细胞复制过程中必不可少的一种酶,而人体组织中无此酶,因此,此酶成为高效、低毒的抗HIV药物研发的理想靶标.简介HIV-1整合酶及其抑制剂的作用机制,分类综述具有二酮酸药效团类似结构的喹啉酮酸类HIV-1整合酶抑制剂的研究进展.
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抗艾滋病药Dolutegravir
将自身基因整合到宿主细胞染色质中,是包括人类免疫缺陷病毒(HIV)在内的逆转录病毒复制过程中的一个关键步骤,由病毒整合酶介导.因此,整合酶可作为阻断HIV复制的合适靶标,由美国Shionogi-ViiV Healthcare公司开发的dolutegravir(代号:S/GSK-1349572)即为一种口服有效的整合酶抑制剂,其抗HIV活性显著.临床研究显示,对整合酶抑制剂raltegravir产生耐药性的HIV感染者可对本品应答.目前,本品正处于Ⅲ期临床研究阶段.
关键词： Dolutegravir 艾滋病 HIV-1 整合酶抑制剂 -
HIV-1整合酶抑制剂基因突变耐药研究
HIV在整合酶作用下进入人类基因组是病毒利用人类宿主细胞机制完成其自身复制和增殖的第一步,也是整个病毒感染周期的关键步骤.整合酶抑制剂以全新的作用机制在抗病毒中起到了有效作用,但也因其耐药问题的出现仍无法实现持久完全的病毒抑制.此文综述了目前主要的HIV-1整合酶抑制剂相关的耐药基因突变情况及耐药突变对整合酶效率和病毒复制适应性的影响.
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HIV-1整合酶抑制剂体外筛选方法研究进展
整合酶是HIV基因表达和复制所必需的酶,而且宿主细胞内不存在该酶的类似物.因此,HIV-1整合酶已成为设计、筛选抗HIV药物的理想靶点.迄今为止,Raltegravir仍是唯一上市的HIV整合酶抑制剂,而且临床上也已经出现耐药问题.研发新一代整合酶抑制剂非常必要.高通量、高灵敏度、简单易行的筛选方法是研究开发新一代HIV-1整合酶抑制剂的关键.目前,HIV-1整合酶抑制剂筛选方法有多种,各有优缺点,该文将对文献报道的整合酶抑制剂体外筛选方法的新进展做一介绍.
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HIV整合酶研究进展
HIV整合酶可催化病毒复制周期中的整合过程,即将HIV反转录产物cDNA整合入宿主基因组,它是病毒复制过程不可缺少的酶.抑制该酶活性将能有效抗HIV,迄今尚未在人体内发现整合酶的功能类似物,故整合酶成为抗HIV的理想靶点.本文综述了近年来整合酶的结构、催化活性及影响因素、整合酶抑制剂的研究进展.
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第一个喹诺酮类抗HIV药物埃替格韦
尽管抗逆转录病毒联合疗法能有效降低血液HIV RNA载量和增加CD4细胞计数,使机会感染的发病率和HIV/AIDS及其相关性肿瘤等的病死率降低,但由于药物本身存在毒副作用及代谢毒性,加之HIV耐药性逐年增加,这种治疗方案非常复杂.埃替格韦是继雷特格韦之后美国FDA批准的第二个HIV-1整合酶链转移抑制剂(INSTI),也第一个喹诺酮类抗HIV药物.本品具有良好的耐受性,可对病毒产生快速和持续的抑制作用.(埃替格韦+cobicistat+恩曲他滨+富马酸替诺福韦酯)复方片剂的病毒抑制作用可与标准治疗方案(依法韦仑+恩曲他滨+富马酸替诺福韦酯)媲美,而其CNS和精神方面不良事件的发生率更低.这种四药合一的复方片剂(每日1次)为临床医师治疗初治及复治HIV感染提供了一种新选择.本文对埃替格韦的合成方法、药理学及临床研究等进行综述.
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HIV-1整合酶抑制剂的研究进展
HIV-1整合酶(integrase)是逆转录病毒复制所必需的酶,因而成为抗艾滋病(AIDS)药物设计的一个合理的靶点.本文综述了近几年的HIV-1整合酶及其抑制剂的发展现状,就如何将作用于整合酶靶点的先导化合物转变成有效的抗艾滋病药物进行了讨论.
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病毒学和免疫学随访经4-9年四种病毒抑制药包括整合酶抑制剂结合短程药物轮转AIDS治疗
AIM: To present the 4 to 9 years (median: 6 years)treatment follow up of 10 HIV1-AIDS patients, 9 at AIDS and 1 at A3 stages. METHODS: We have applied from 1992 to 1994, AZT combined with 2 integrase inhibitors,acriflavine and hydroxy-methyl-ellipticine. We could shift, in 1994, to combinations of 3 drugs including two more retrowanscfiptase inhibitors (RTI), ddI and ddC,and, after 1995, to combinations of 4 drugs including also two other RTI, d4T and 3TC, and 3 protease inhibitors (PI), indinavir, ritonavir, and saquinavir. In 1998, as cobalamine was shown by an in vitro test, to act as integrase inhibitor, vitamin B12 was added in cycles of various lengths. Every three weeks, not only the investigations were repeated, but the virostatics were changed. RESULTS: No grade 2 virostatics toxicity has been registered. The viral loads (VL) decreased according to exponential curves. Their initial parts obeyed first order kinetics. The second parts were and still are asymptotic. The first parts could be rectilinear or sinuous. The sinuosities were associated to cofactors present before treatment (chimerism, UV irradiation,hepatitis C or B and C, brain toxoplasmosis). The asymptotic parts, whose VL were below PCR detectable levels, presented discrete, reversible HIV1 rebounds,associated to other cofactors (such as herpes zoster,herpes 6, CMV, flat condyloma, and influenza).Among immunologic parameters, the monocyte and CTLnumbers increased and presented, during the rapidly decreasing part of VL curve, a significant inverse correlation with it. Neither CT4+ nor suppressor T-cell (STC) numbers presented such correlation. Near 100 %of CTL were CD28+ Later, vitamin B12 applications increased monocyte and CD28+ CTL numbers, and appeared to reinforce VL stabilization. CONCLU-SION: The combinations of inhibitors affecting 3retrovirus targets, retrotranscriptase, integrase, and protease have given to 10 out of 10 AIDS patients survivals varying today between 4 to 9 years, in excellent conditions. The UVA-pretreated patient is the only one presenting a not maximally reduced asymptotic VL, while his CD4 + and STC have been absent for 8 years. Other patient VL regressed exponentially to become asymptotic,below PCR detectable levels.
