Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses in Vitro and in Humanized Mice (original) (raw)

Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently-closed circular DNA (cccDNA) – the viral minichromosome – in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment. Our group identified GLP-26, a novel glyoxamide derivative that alters HBV nucleocapsid assembly and prevents viral DNA replication. GLP-26 exhibited single-digit nanomolar anti-HBV activity and inhibition of HBeAg secretion, and reduced cccDNA amplification in addition to a promising pre-clinical profile. Strikingly, long term combination treatment with entecavir in a humanized mouse model induced decrease in viral loads and viral antigens that was sustained for up to 12 weeks after treatment cessation.