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

  • J Med Chem. 2025 Oct 9;68(19):20519-20535. doi: 10.1021/acs.jmedchem.5c01695.
Xiangkai Ji  1 ,  Xiangyi Jiang  1 ,  Zhen Gao  1 ,  Heng Gao  1 ,  Xing Huang  1 ,  Fabao Zhao  1 ,  Erik De Clercq  2 ,  Zhao Wang  1  3 ,  Christophe Pannecouque  2 ,  Dongwei Kang  1  3 ,  Peng Zhan  1  3 ,  Xinyong Liu  1  3
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, China.
  • 2. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium.
  • 3. China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan 250012, China.
PMID: 40960051 DOI: 10.1021/acs.jmedchem.5c01695
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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