摘要
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.Structureeactivity relationship(SAR)analysis identified compound HyT-S7,featuring an adamantyl group,exhibiting potent inhibitory activity(EC_(50)= 0.46 mmol/L,HepAD38 cells)and degradation ability(DC_(50) = 3.020.54 mmol/L)in a doseand time-dependent manner.Mechanistic studies demonstrated that the autophagyelysosome 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.
基金
the Key Research and Development Program,Ministry of Science and Technology of the People’s Republic of China(2023YFC2606500)
Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)
Drug Innovation Major Project(2018ZX09101003-003-003,China)
CAMS Innovation Fund for Medical Sciences(CAMS-2021-I2M-1-030,China)
National Natural Science Foundation of China(81803592)and Shandong Laboratory Program(SYS202205,China).
