Targeted Degradation of Capsid by Host-Hijacking PROTAC Overcomes Drug Resistance

  • J Med Chem. 2026 Jul 23;69(14):16878-16895. doi: 10.1021/acs.jmedchem.6c00553.
Mei Wang  1 ,  Zeyu Peng  2 ,  Yang Zhou  1 ,  Yuexi Ma  2 ,  Jiacheng Gui  3 ,  Shujing Xu  1 ,  Xiangyi Jiang  1 ,  Tianyu Tang  2 ,  Xinyong Liu  1 ,  Christophe Pannecouque  4 ,  Lu Xue  3 ,  Xiaoli Xiong  3 ,  Kai Tang  1  5 ,  Guochao Wei  2  6 ,  Peng Zhan  1
Affiliations
  • 1. Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Shandong Basic Science Special Academic Zone (Pharmacy), School of Pharmaceutical Sciences, Shandong University, 250012 Jinan, Shandong, PR China.
  • 2. Department of Microbiology and Infectious Disease Center, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory for Research and Translation of Immunological and Molecular Diagnostic Technologies for Major Viral Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, 100191 Beijing, PR China.
  • 3. State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510005 Guangzhou, PR China.
  • 4. Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven B-3000, Belgium.
  • 5. School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, PR China.
  • 6. Peking University Health Science Center (Taizhou) Pharmaceutical and Health Industry Innovation Center, Taizhou 225300 Jiangsu, PR China.
PMID: 42438214 DOI: 10.1021/acs.jmedchem.6c00553
Abstract

The escalating prevalence of HIV-1 drug-resistant variants and the toxicity limitations of conventional antiretroviral therapies necessitate therapeutic strategies with novel mechanisms of action. This study focuses on HIV-1 capsid (CA), an essential replication-related viral protein. We developed CA-targeted proteolysis-targeting chimera (PROTAC) degraders by conjugating PF74-derived CA ligand IIA-4 with VHL E3 Ligase ligand. Among these, VHL-3 exhibited potent anti-HIV-1 activity in MT-4 cells (EC50 = 3.0 ± 1.5 nM), a 300-fold improvement over PF74. Mechanistic studies confirmed VHL-3 dose- and time-dependently reduced CA levels in HEK293T cells (early stage, DC50 = 812 nM; late stage, DC50 = 252 nM) via a proteasome-driven pathway. Notably, it effectively degraded clinically relevant CA-resistant mutants (N74D, K70R). This work pioneers the development of CA-targeted degraders, providing a framework for next-generation anti-HIV therapies with high potency and resistance barriers.

Products