"Pseudosubstrate Envelope"/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency

  • J Med Chem. 2024 Oct 17. doi: 10.1021/acs.jmedchem.4c01544.
Shujing Xu  1 ,  Shuo Wang  1 ,  Yang Zhou  1 ,  Nicholas Foley  2 ,  Lin Sun  1 ,  Laura Walsham  3 ,  Kai Tang  1 ,  Dazhou Shi  1 ,  Xiaoyu Shi  1 ,  Zhijiao Zhang  1 ,  Xiangyi Jiang  1 ,  Shenghua Gao  1 ,  Xinyong Liu  1 ,  Christophe Pannecouque  4 ,  David C Goldstone  3 ,  Alexej Dick  2 ,  Peng Zhan  1
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, PR China.
  • 2. Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
  • 3. School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand.
  • 4. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium.
PMID: 39418501 DOI: 10.1021/acs.jmedchem.4c01544
Abstract

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, IC-1k, exhibited an EC50 of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, IC-1k 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 IC-1k targeted HIV-1 CA within the chemical space of the "pseudosubstrate envelope". Further mechanistic studies revealed a dual-stage inhibition profile: IC-1k 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 IC-1k (T1/2 = 91.3 min) compared to PF74 (T1/2 = 0.7 min), alongside a favorable safety profile. Overall, IC-1k presents a promising lead compound for further optimization.

Products