Latham Catherine F, La Jennifer, Tinetti Ricky N, Chalmers David K, Tachedjian Gilda
Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia.
Curr Top Med Chem. 2016;16(10):1135-53. doi: 10.2174/1568026615666150901114329.
Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.
人类免疫缺陷病毒（HIV）仍然是一个全球性的健康问题。虽然联合抗逆转录病毒疗法已成功控制患者体内的病毒，但HIV可能会对用于治疗的药物产生耐药性，使现有药物的效果降低，并限制治疗选择。寻找治疗HIV新药物的工作正在进行中，尽管传统的药物设计方法通常侧重于针对已知的结合位点，以抑制诸如逆转录酶和整合酶等既定的药物靶点。这些方法往往倾向于在临床上已经使用的同一类药物中产生更多的抑制剂。抗逆转录病毒药物种类缺乏多样性可能导致治疗选择有限，因为在仅用某一类中的一种药物治疗的患者中，可能会出现对整个药物类别的交叉耐药性。寻找新型HIV-1药物的一种新方法是基于片段的药物发现（FBDD），这是一种经过验证的药物发现策略，基于使用主要通过生物物理测定法筛选的较小的低分子量分子（<300 Da）文库。FBDD不仅旨在寻找新型药物支架，还旨在探测靶蛋白以找到新的、通常是变构的抑制性结合位点。几种基于片段的策略已成功为HIV-1的两个已证实的药物靶点——逆转录酶和整合酶，鉴定出新型抑制位点或支架。虽然任何基于FBDD生成的HIV-1药物尚未进入临床，但最近针对这两个特征明确的HIV-1靶点的FBDD计划为抗逆转录病毒药物发现和寻找新型HIV-1药物类别注入了新的活力。
