Discovery and mechanism verification of first-in-class hydrophobic tagging-based degraders of HBV core protein.
10.1016/j.apsb.2025.02.033
- Author:
Shujing XU
1
;
Ya WANG
2
;
Dazhou SHI
1
;
Shuo WANG
1
;
Lijun QIAO
2
;
Ge YANG
2
;
Yang ZHOU
1
;
Xinyong LIU
1
;
Shuo WU
3
;
Yuhuan LI
3
;
Peng ZHAN
1
Author Information
1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
3. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology for Microbial Drugs, CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
Autophagy–lysosome pathway;
Core protein;
Degrader;
Drug design;
Drug resistance;
Hepatitis B virus;
Hydrophobic tagging;
Mechanism verification
- From:
Acta Pharmaceutica Sinica B
2025;15(4):2170-2196
- CountryChina
- Language:English
-
Abstract:
Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC50 = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC50 = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.
