Zhuang Chunlin, Pannecouque Christophe, De Clercq Erik, Chen Fener
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
Acta Pharm Sin B. 2020 Jun;10(6):961-978. doi: 10.1016/j.apsb.2019.11.010. Epub 2019 Nov 21.
Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.
人类免疫缺陷病毒（HIV）是获得性免疫缺陷综合征（AIDS）的主要感染源，非核苷类逆转录酶抑制剂（NNRTIs）是HIV治疗的基石。在过去20年里，我们的药物化学团队在开发几种不同的新型NNRTIs方面取得了巨大进展，包括1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶（HEPT）、硫代二氢烷氧基苄基氧嘧啶（-DABO）、二芳基三嗪（DATA）、二芳基嘧啶（DAPY）类似物及其杂化衍生物。综合运用现代药物研发策略，包括基于结构的药物设计、基于片段的优化、骨架/片段跳跃、分子/片段杂交和生物电子等排体，促使我们开发出了几种高效的类似物以供进一步评估。在本文中，我们回顾了过去二十年中使用上述优化策略开发NNRTIs的过程，包括它们的构效关系、分子建模以及与HIV-1逆转录酶（RT）的结合模式。同时也讨论了设计方面的未来方向和前景以及相关挑战。
