抗HIV药物小分子CCR5拮抗剂的研究进展

The Research of Anti-HIV Drugs Small Molecular CCR5 Antagonist

高活性逆转录治疗方法抗病毒作用强,为欧美发达国家治疗艾滋病的常规方法。然而,这种方法并不能清除整合在CD4+T淋巴细胞中的HIV-1的DNA,对中晚期感染者效果不明显,长期服用产生耐药性、毒副作用以及费用昂贵,使其治疗艾滋病越来越受到限制。属于G蛋白偶联受体家族趋化因子受体5(CCR5)的发现为开发新型抗病毒药物找到了方向。CCR5是HIV-1进入巨噬细胞过程中发挥重要作用的一个辅助受体,是抗艾滋病药物作用的重要靶点之一。目前,已有许多活性强、选择性高的小分子CCR5拮抗剂进入了临床试验阶段。本文对近年来文献报道的小分子CCR5拮抗剂进行综述。

Highly active antiretroviral therapy with reverse transcriptase and protease inhibitors greatly reduced morbidity and mortality in HIV-1-infected individuals. However, the current anti-retroviral treatment showed many disadvantages. To improve the convenience of anti-HIV therapy, to reduce its toxicity, and to enhance its activity against both wild-type and resistant viral strains were needed. These problems emphasized the need to develop new anti-HIV-1 drugs targeting different steps in the viral rep lication cycle. HIV-1 entry into target cells was a multistep process involving the interaction of viral envelope proteins with cell surface receptors. Binding to CD4 was followed by engagement of specific che mokine receptors （CCRS）, and triggering molecular rearrangements in the envelope transmembrane subunit that results in membrane fusion. The CCR5 belongs to the protein superfamily of G protein-coupled receptors. When HIV-1 entered macrophage cells, CCR5 played an important role in the process as an auxiliary receptor. In addition to the CD4 receptor, it opened new therapeutic possibilities. Currently, a lot of strong, highly selective active CCR5 antagoniss have been found, part of which entersd the clinical trial stage. The small molecular CCR5 auxiliary receptor antagonist reports in recent years were reviewed.