Natural dehydrocostus lactone-based analogues as new structural PDPK1 allosteric activators against HBV
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Updated: Nov 6, 2026

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
Hang Sun1, Yu-Jing Mao1, Dan-Yang Zhu1
1Yunnan Key Laboratory of Cross-Border Infectious Disease Control and Prevention and Novel Drug Development (Under Construction), Center for Pharmaceutical Sciences, Faculty of Life Science and Technology, Kunming University of Science and Technology, Chenggong Campus, Kunming, 650500, China.
Abstract:
The limited efficacy of current anti-HBV therapies highlights an urgent need for novel agents with distinct mechanisms of action. Herein, a series of dehydrocostus lactone (DCL) derivatives were designed and synthesized. Several compounds were found to potently inhibit the secretions of HBsAg and HBeAg. Among them, the quinoxaline derivative 17i exhibited potent anti-HBV activity, accompanied by reduced cytotoxicity and improved pharmacokinetic properties. Its robust anti-HBV efficacy was further validated in a hydrodynamic-injection mouse model, with no observable hepatotoxicity. Mechanistic investigations revealed that 17i functions as an allosteric activator of PDPK1 (3-phosphoinositide dependent protein kinase 1). Unlike conventional kinase inhibitors, 17i binds to the allosteric hydrophobic pocket of PDPK1, inducing a unique phosphorylation-uncoupling effect on RPS6KB1 and subsequent autophagy suppression, thereby inhibiting HBV replication through a host-directed mechanism.
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