Antimicrob Agents Chemother. 2019 Nov 11. pii: AAC.01701-19. doi: 10.1128/AAC.01701-19. [Epub ahead of print]
Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses in Vitro and in Humanized Mice.
Amblard F1, Boucle S1, Bassit L1, Cox B1, Sari O1, Tao S1, Chen Z1, Ozturk T1, Verma K1, Russell O1, Rat V2, de Rocquigny H2, Fiquet O3,4, Boussand M3,4, Di Santo J3,4, Strick-Marchand H3,4, Schinazi RF5.
Author information
1
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA.
2
Morphogenèse et Antigénicité du VIH et des Virus des Hépatites, Inserm - U1259 MAVIVH, Hôpital Bretonneau, 10 boulevard Tonnellé - BP 3223 37032 Tours Cedex 1, France.
3
Innate Immunity Unit, Institut Pasteur, 75724 Paris, France.
4
Inserm U1223, 75724 Paris, France.
5
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA [email protected].
Abstract
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.