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.  There is a need to develop a low toxicity, effective therapy for HBV that targets a different aspect of the viral life cycle than the viral polymerase inhibitors that currently exist.

Researchers in Drexel University’s Department of Microbiology & Immunology and the Baruch S. Blumberg Institute have designed, synthesized, and evaluated novel triazolo-pyrimidine inhibitors of hepatitis B virus surface antigen cellular secretion.  There is a high level of HBV surface antigen in the blood of infected patients, and this antigenemia suppresses the innate immune response to the virus.  Inhibiting surface antigen secretion would allow for a new therapeutic route and could be combined with existing nucleoside drugs to treat HBV infection.

Activity has been demonstrated against drug-resistant HBV variants.  The triazolo-pyrimidine compounds were determined to be specific inhibitors of HBV envelope secretion, rather than viral genomic replication that is targeted by existing HBV small molecule drugs.  The compounds were optimized for potency and displayed desirable pharmacokinetics profiles, including low toxicity, in rats.