HIV-1 蛋白酶：耐药性的结构视角。

Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA; E-Mail:

Viruses. 2009 Dec;1(3):1110-36. doi: 10.3390/v1031110. Epub 2009 Dec 3.

Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV.

抗 HIV-1 蛋白酶的抗病毒抑制剂是基于结构的药物设计的显著成功范例，极大地改善了艾滋病的治疗方法。对耐药蛋白酶变异体的结构和活性分析揭示了耐药的新分子机制，并指导了针对耐药变异体的紧密结合抑制剂的设计。大量的结构揭示了与耐药性相关的不同分子机制：突变改变了蛋白酶与抑制剂或底物的相互作用；突变改变了二聚体稳定性；以及远距离突变将变化传递到活性位点。这些见解将为针对耐药 HIV 株的新型抗病毒抑制剂的持续设计提供信息。