基于逆转录酶结构和耐药突变的新型非核苷类逆转录酶抑制剂研究进展

Novel non-nucleoside reverse transcriptase inhibitors based on structure and mutations of reverse transcriptase:research advances

为了应对艾滋病治疗过程中严重的耐药性问题,开发新型抗耐药性非核苷类逆转录酶抑制剂(NNRTI)势在必行。本文通过分析2015~2018年文献报道的新型抗耐药性NNRTI的代表性实例,探讨了抗耐药性NNRTI与逆转录酶的结合模式,并讨论了药物化学策略在发现和优化新型抗HIV-1药物中的作用。本文指出基于逆转录酶晶体结构信息的药物化学策略是快速发现具有新结构的NNRTI的有效途径,前期构效关系研究能为后续的药物开发提供一定的支持。

With the rapid emergence of severe HIV-1 resistance during AIDS treatment,it is urgent to develop non-nucleoside reverse transcriptase inhibitors（NNRTI）with novel chemical phenotypes. This article reviews the representative examples of novel NNRTI with low nanomolar anti-HIV potency against wild-type and NNRTI-resistant viral strains reported in the literature from2015 to 2018,and discusses the binding patterns between compounds and reverse transcriptase,as well as medicinal chemistry strategies in the discovery and optimization of novel anti-HIV-1 agents. It also points out that the medicinal chemistry strategies based on the crystal structure information of reverse transcriptase are an effective way to find novel NNRTI quickly,and the preliminary structure-activity relationship study can provide some support for subsequent drug development.