“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency
Based on our proposed "pseudosubstrate envelope" concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, <b>IC-1k</b>, exhibited an EC<sub>50</sub> of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, <b>IC-1k</b> emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that <b>IC-1k</b> targeted HIV-1 CA within the chemical space of the "pseudosubstrate envelope". Further mechanistic studies revealed a dual-stage inhibition profile: <b>IC-1k</b> disrupted early-stage capsid-host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for <b>IC-1k</b> (<i>T</i><sub>1/2</sub> = 91.3 min) compared to PF74 (<i>T</i><sub>1/2</sub> = 0.7 min), alongside a favorable safety profile. Overall, <b>IC-1k</b> presents a promising lead compound for further optimization.
Authors
- Zhijiao Zhang
- Christophe Pannecouque (ORCID: https://orcid.org/0000-0002-1254-4473)
- Alexej Dick (ORCID: https://orcid.org/0000-0003-0580-1897)
- Yang Zhou (ORCID: https://orcid.org/0000-0002-1548-973X)
- Xiangyi Jiang (ORCID: https://orcid.org/0000-0001-6224-2513)
- Xinyong Liu (ORCID: https://orcid.org/0000-0002-7302-2214)
- Shenghua Gao (ORCID: https://orcid.org/0000-0001-9853-3793)
- N.A. Foley
- David C. Goldstone (ORCID: https://orcid.org/0000-0003-0069-9408)
- Peng Zhan (ORCID: https://orcid.org/0000-0002-9675-6026)
- Laura Walsham (ORCID: https://orcid.org/0009-0005-0503-6090)
- Shujing Xu (ORCID: https://orcid.org/0000-0002-7168-613X)
- Lin Sun (ORCID: https://orcid.org/0000-0002-8395-5886)
- Kai Tang (ORCID: https://orcid.org/0000-0002-9770-9459)
- Dazhou Shi
- Xiaoyu Shi (ORCID: https://orcid.org/0000-0003-3856-594X)
- Shuo Wang (ORCID: https://orcid.org/0009-0008-6060-6019)
Institutions
- Shandong University (CN)
- University of Auckland (NZ)
- Rega Institute for Medical Research (BE)
- Drexel University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01544
- Citations
- 7
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.72
Funders
- Wallace H. Coulter Foundation
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke