抗耐药性HIV非核苷类逆转录酶抑制剂的研究进展

Progress in next generation NNRTIs against drug-resistant HIV virus

从酶与抑制剂复合物的晶体结构入手,概述非核苷类逆转录酶抑制剂(NNRTIs)产生耐药性的机制、抗耐药性药物的结构特点以及新一代NNRTI类药物二芳基取代嘧啶(DAPY)类似物的设计和最新研究进展。指出抑制剂分子结构的柔韧性、与结合位点的作用方式和空间构象对抗突变活性起关键作用,将药物化学的基本原理与现代分子模拟技术相结合,开展多学科合作是研发新药的发展趋势和有效途径。

Based on the crystallographic complex structures of wild-type and mutated HIV-1 RT with NNRTIs, NNRTIs＇ drug-resistance mechanism and drug-design strategies for next generation NNRTIs are described in this review. Structural flexibility, positional adaptation and effectively binding conformation are useful drug-design features for reducing drug resistance. The discovery and development of diarypyrimidine （DAPY） analogues as next generation NNRTIs indicated a multidisciplinary coordination approach successful for novel anti-HIV drugs.