Exploring the HIV-1 Reverse Transcriptase p51/p66 Interface: Structure-Based Design and Optimization of Novel 2,4,6-Trisubstituted Pyrimidines as Potent NNRTIs with Improved Resistance Profiles.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-17 DOI:10.1021/acs.jmedchem.5c01695

Xiangkai Ji,Xiangyi Jiang,Zhen Gao,Heng Gao,Xing Huang,Fabao Zhao,Erik De Clercq,Zhao Wang,Christophe Pannecouque,Dongwei Kang,Peng Zhan,Xinyong Liu

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引用次数: 0

Abstract

The emerging challenge of HIV-1 drug resistance urgently demands the development of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, we designed and synthesized two series of novel 2,4,6-trisubstituted pyrimidines that target a previously insufficiently explored binding site at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT). After iterative structural optimization, 15k turned out to exhibit potent antiviral activity to wild-type and mutant HIV-1 strains, with EC50 values ranging from 0.0046 to 0.033 μM and relatively low cytotoxicity (CC50 = 26.64 μM). Molecular modeling revealed that 15k adopts a unique "Y-shaped" conformation within the NNRTI-binding pocket (NNIBP), forming novel hydrogen bonds with E138 and K101 at the p51-p66 interface─a key factor contributing to its potent resistance profile. Moreover, 15k exhibits favorable in vivo metabolic (T1/2 = 2.12 h) and safety profiles. In summary, newly discovered 15k represents a promising anti-HIV-1 drug candidate for further development.

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探索HIV-1逆转录酶p51/p66界面：基于结构的新型2,4,6-三取代嘧啶的设计和优化，作为具有改善抗性谱的有效NNRTIs。

新出现的HIV-1耐药挑战迫切需要开发下一代HIV-1非核苷逆转录酶抑制剂（NNRTIs）。在此，我们设计并合成了两个新的2,4,6-三取代嘧啶系列，它们靶向HIV-1逆转录酶（RT） p66和p51亚基之间的一个先前未充分探索的结合位点。经过反复的结构优化，15k对野生型和突变型HIV-1株具有较强的抗病毒活性，EC50值在0.0046 ~ 0.033 μM之间，CC50值为26.64 μM，细胞毒性较低。分子模型显示，15k在nnrti结合口袋（NNIBP）内采用独特的“y形”构象，在p51-p66界面与E138和K101形成新的氢键，这是促成其强抗性谱的关键因素。此外，15k具有良好的体内代谢（T1/2 = 2.12 h）和安全性。总之，新发现的15k代表了一种有希望进一步开发的抗hiv -1候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.