This is a phase I proposal to determine the feasibility of developing newly discovered fluorinated sulfamoylbenzamide (FSBA) 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, which 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 nucleocapsid represents a novel therapeutic target and the FSBA compounds should thus complement the current antiviral medications. Through an extensive structure-activity-relationship (SAR) study, we have now obtained FSBA compounds with nanomolar antiviral activity. In this Phase I project, we propose to advance lead FSBA compounds with the most favorable ADME, safety and pharmacokinetics (PK) profiles for antiviral efficacy study in the HBV transgenic mouse model in vivo. Having confirmed the in vivo antiviral efficacy in the transgenic mice model, we will further evaluate the safety profile and antiviral efficacy of the lead FSBAs in HBV infected human chimeric uPA-SCID mice model in Phase II study. At the end of Phase II, we will advance one lead candidate for extensive IND enabling studies, and prepare a case for human clinical trial.

Public Health Relevance

This is a proposal to develop the newly discovered inhibitors of hepatitis B virus (HBV), fluorinated sulfamoylbenzamide derivatives, into a drug for treatment of chronic hepatitis B. The drug candidate functions through interfering with incorporation of pregenomic RNA, the template for viral DNA synthesis, into nucleocapsids, which is a distinct target 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. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI104066-01
Application #
8454218
Study Section
Special Emphasis Panel (ZRG1-IDM-U (10))
Program Officer
Koshy, Rajen
Project Start
2013-01-18
Project End
2014-06-30
Budget Start
2013-01-18
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$294,674
Indirect Cost
Name
Enantigen Therapeutics, Inc.
Department
Type
DUNS #
828761697
City
Doylestown
State
PA
Country
United States
Zip Code
18902