This is a proposal to develop newly discovered sulfamoylbenzamide derivatives as therapeutic agents for the treatment of chronic hepatitis B virus (HBV) infection. These molecules have been identified as inhibitors of HBV pregenomic (pg) RNA encapsidation, a critical step in the life cycle of HBV. PgRNA is the template for reverse transcriptional replication of HBV DNA, and its encapsidation into nucleocapsid with viral DNA polymerase is essential for the subsequent viral DNA synthesis. Distinct from the mechanism of the currently FDA-approved antiviral nucleos(t)ide analogues that inhibit HBV DNA polymerase, pgRNA assembly into nucleocapsids represents a novel therapeutic target and should complement the current antiviral medications. Through an extensive structure-activity-relationship (SAR) study of 591 sulfamoylbenzamide derivatives, we have already obtained compounds with sub-micromolar antiviral activity, with the best being DVR-23 (EC50 = 280 nM, EC90 = 860nM). In this Phase I project, we propose to further optimize the sulfonamide moiety of the current compounds to identify leads with superior antiviral, pharmacokinetic and toxicology profiles, and to test their antiviral efficacy in the HBV transgenic mouse model in vivo
Public Health Relevance: This is a proposal to develop newly discovered inhibitors of hepatitis B virus (HBV), referred to as sulfamoylbenzamide derivatives, into a drug for treatment of chronic hepatitis B. These compounds function by interfering with packaging of the template for viral DNA synthesis, pregenomic RNA, constituting a mechanism which is distinct from the currently FDA-approved anti-HBV medications. Hence, the drug may be of use by itself or in combination with current medications to achieve extended clinical benefits.
Public Health Relevance Statement: This is a proposal to develop newly discovered inhibitors of hepatitis B virus (HBV), referred to as sulfamoylbenzamide derivatives, into a drug for treatment of chronic hepatitis B. These compounds function by interfering with packaging of the template for viral DNA synthesis, pregenomic RNA, constituting a mechanism which is distinct from the currently FDA-approved anti-HBV medications. Hence, the drug may be of use by itself or in combination with current medications to achieve extended clinical benefits.
NIH Spending Category: Digestive Diseases; Genetics; HIV/AIDS; Hepatitis; Hepatitis - B; Infectious Diseases; Liver Disease
Project Terms: absorption; analog; Animal Model; anti-hepatitis B; Antiviral Agents; Back; Binding (Molecular Function); Biological Availability; Capsid; Chemicals; Chronic Hepatitis B; Clinical; Clinical Trials; Combined Modality Therapy; Complement; cytotoxicity; Data; design; Development; DNA biosynthesis; DNA-Directed DNA Polymerase; Dose; Drug Kinetics; Drug resistance; drug resistant virus; Duck Hepatitis B Virus; Excretory function; FDA approved; Frequencies (time pattern); Genome; Goals; Hepatitis B Virus; hepatitis B virus P protein; Hepatocyte; high throughput screening; Human; improved; In Vitro; in vivo; inhibitor/antagonist; Kinetics; Lead; Life Cycle Stages; Metabolism; Modeling; Modification; Molecular Target; mouse model; new therapeutic target; novel; Nucleocapsid; pgRNA; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; Polymerase; pre-clinical; Property; protein folding; Proteins; RNA; SCID Mice; Series; stable cell line; Structure-Activity Relationship; Sulfonamides; Testing; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Toxicity Tests; Toxicology; Transgenic Mice; Treatment Protocols; Viral; viral DNA; Virus Replication; Woodchuck Hepatitis B Virus; Work
