Discovery and structure activity relationship of glyoxamide derivatives as anti-hepatitis B virus agents

• Authors: Franck Amblard, Emory University; Sebastien Boucle, Emory University; Leda Bassit, Emory University; Zhe Chen, Emory University; Ozkan Sari, Emory University; Bryan Cox, Emory University; Kiran Verma, Emory University; Tugba Ozturk, Emory University; Olivia Ollinger-Russell, Emory University; Raymond Schinazi, Emory University
• Journal Title: Bioorganic & Medicinal Chemistry
• Volume: Volume 31
• Publisher: Pergamon-Elsevier Science Ltd. | 2021-01-06, Pages 115952-115952
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bmc.2020.115952
• Subjects: Chemistry, Biochemistry; Health Sciences, Pharmacology; Health Sciences, Human Development; Chemistry, Organic
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physical Sciences; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic; Pharmacology & Pharmacy; Chemistry; Capsid; Hepatitis B virus; Antiviral; cccDNA; HBV

Abstract

Chronic hepatitis B viral infection is a significant health problem world-wide, and currently available antiviral agents suppress HBV infections, but rarely cure this disease. It is presumed that antiviral agents that target the viral nuclear reservoir of transcriptionally active cccDNA may eliminate HBV infection. Through a series of chemical optimization, we identified a new series of glyoxamide derivatives affecting HBV nucleocapsid formation and cccDNA maintenance at low nanomolar levels. Among all the compounds synthesized, GLP-26 displays a major effect on HBV DNA, HBeAg secretion and cccDNA amplification. In addition, GLP-26 shows a promising pre-clinical profile and long-term effect on viral loads in a humanized mouse model.