The National Institute for Allergy and Infectious Diseases has awarded a SBIR Phase I grant (R43AI104086A) to Enantigen Therapeutics, Inc. and the Natural Products Discovery Institute to study new technologies for addressing viral hepatitis infection. The goal of this program is to identify natural products that inhibit the formation, maintenance or expression of Hepatitis B Virus (HBV) covalently closed circular DNA (cccDNA), the persistent form of HBV infection that is essential for the virus life cycle. Despite being essential, cccDNA has not been the target of high throughput screening (HTS), largely because of practical limitations.
In response to this need, Enantigen is using a cell culture system in which the production of a reporter molecule, HBV “e antigen” (HBeAg), is monitored. Induction of HBV genome transcription and replication results in the establishment of cccDNA and concomitant HBeAg production. In preliminary studies, screening of 2,000 natural product extracts resulted in the identification of two small molecules that would be predicted to affect cccDNA gene expression.
During Phase I of this research program, the new cccDNA assay methodology will be applied to additional portions of the NPDI extract collection (>100,000 samples). Active extracts will be deconvoluted by bioassay guided fractionation to pure molecules, whose structures will be determined by high field nuclear magnetic resonance and mass spectrometry. At the conclusion of this Phase I grant, the most “druggable” lead(s) will be selected for optimization in Phase II.