ArticleCellular and molecular gastroenterology and hepatology2026
A New Role of Class A Hepatitis B Virus Capsid Assembly Modulators in Core Protein Dynamics and Covalently Closed Circular DNA Replenishment.
Article in Cellular and molecular gastroenterology and hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND &
aimsCurrent 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.
methodsHuman 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.
resultsWe 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.
conclusionsAs 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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