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Ko, C. ; Zhou, X.* ; Bester, R. ; Park, S.* ; Park, J.* ; Blossey, C. ; Plank, V. ; Hofmann, S. ; Nassal, M.* ; Schreiner, S. ; Gao, L.* ; Protzer, U.

A new role of class A hepatitis B virus capsid assembly modulators in core protein dynamics and covalently closed circular DNA replenishment.

Cell. Mol. Gast. Hept. 20:101860 (2026)
Publ. Version/Full Text Research data DOI PMC
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Background & Aims Current treatments of chronic hepatitis B are rarely curative. Capsid assembly modulators target capsid formation by the hepatitis B virus core protein. Class A capsid assembly modulators induce abnormal core protein assembly, but how they affect core protein dynamics and inhibit hepatitis B virus replication is only partially understood. Methods Human liver chimeric mice and hepatitis B virus–susceptible cells were infected to monitor dynamic changes and the fate of core protein and assembled capsids. We analyzed hepatitis B virus and protein dynamics over 4 weeks under treatment of the class A capsid assembly modulator molecule HAP_R01. Results We found an altered nuclear-cytoplasmic distribution of hepatitis B virus core protein upon treatment with HAP_R01. This effect was confirmed in primary human hepatocytes and in hepatitis B virus–infected liver-humanized mice. Mechanism-of-action studies in hepatitis B virus–permissive cells demonstrated that HAP_R01 primarily targets newly synthesized core protein and affects capsid assembly, core protein localization, and solubility in a dose- and time-dependent manner. At 50 nM, HAP_R01 promoted assembly of hepatitis B virus genome-free capsids and nuclear accumulation of core protein. At ≥500 nM, HAP_R01 treatment reduced soluble core protein and capsid levels, but markedly increased insoluble core protein levels, resulting in an overall intracellular accumulation of core protein. Insoluble nuclear agglomerations of core protein were deposited in promyelocytic leukemia nuclear bodies. Treating infected cells for 31 days significantly reduced an established covalently closed circular DNA pool and secreted hepatitis B surface antigen and hepatitis B e antigen levels, by inhibiting covalently closed circular DNA replenishment. Conclusions As an exemplary class A capsid assembly modulator, HAP_R01 inhibits hepatitis B virus genome replication by perturbing capsid assembly and by inducing insoluble core protein accumulation in the nucleus that affects replenishment of the covalently closed circular DNA pool.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Capsid ; Capsid Assembly Modulators ; Core Protein ; Hepatitis B Virus
ISSN (print) / ISBN 2352-345X
e-ISSN 2352-345X
Journal Cellular and Molecular Gastroenterology and Hepatology
Quellenangaben Volume: 20, Issue: 11, Pages: , Article Number: 101860 Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Institute(s) Institute of Virology (VIRO)