More than 350 million people globally are infected with chronic hepatitis B virus (HBV), and the virus causes up to 1 million deaths per year, including from complications of hepatocellular carcinoma or cirrhosis.  While there are some small molecule therapeutics on the market for HBV, very few patients have complete viral clearance, and many suffer from adverse side effects.  Furthermore, drug resistant viral strains are emerging.  Covalently closed circular DNA (cccDNA) from hepatitis B virus is integral to viral infection, with the underlying cause of chronic disease attributed to the intracellular persistence of the cccDNA of the viral genome that is stable in the nuclei of infected hepatocytes.  Directly inhibiting cccDNA formation and maintenance is an attractive therapeutic strategy that has not been explored.

Researchers in Drexel University’s Department of Microbiology & Immunology and the Baruch S. Blumberg Institute have confirmed that disubstituted sulfonamides (DSS) are inhibitors of cccDNA production with low µM effective concentrations in vitro.  An in-house small molecule library of drug-like compounds was screened in a cell-based cccDNA assay, and further mechanistic studies were conducted on the lead sulfonamide compounds, CCC-0975 and CCC-0346.  Work is ongoing to improve the potency of the hit compounds before translating the compounds into animal models.