Advancing HBV antivirals that suppress viral replication and HBsAg production

About This Grant

Summary Chronic Hepatitis B Virus (HBV) is pandemic. About 300M people have chronic HBV and each year about 800,000 will die from its effects: liver failure, cirrhosis, and hepatocellular carcinoma. Biomarkers for chronic HBV include serum expression of virus and the HBV surface protein, HBsAg. Notably, patients with chronic HBV do not mount an immune response to HBsAg. Expression of high levels of HBsAg appear to tolerize the immune system; an immune response to HBsAg is indicative of virus clearance. There is no cure for chronic HBV, thus a treatment that would enable an immune response could be part of a functional cure. A functional cure, a finite treatment that eliminates expression of virus and HBsAg, would save lives and prevent further propagation of HBV. The basis of chronic HBV is a stable episome encoding the viral genome, the so-called covalently closed circular DNA (cccDNA). cccDNA is decorated with nucleosomes and resembles chromatin except it is also associated with two viral proteins HBc and HBx. HBc is best known for its role as HBV’s self- assembling capsid protein. Yet, HBc from inoculum is persistently associated with cccDNA and it recruits epigenetic factors to cccDNA. HBc may also affect regulation of host proteins, including those of the innate immune system. Door Pharmaceuticals has developed a strategy for isolating molecules that bind to the dimeric form of HBc, not the 120-dimer capsid. Door has found that a large fraction of these molecules show the antiviral effect of suppressing expression of viral proteins and virus. By suppressing expression of HBsAg, it is likely that immune system tolerance for HBsAg will be broken. By acting through HBc, we obtain specificity and decrease the possibility of off-target effects. What is needed is a molecule that has efficacy in relevant cells and pharmacological properties suitable clinical testing. The goal of this study is to select specific molecules to advance to Investigational New Drug (IND) status by examining their activity in primary human hepatocytes and in combination with other established HBV therapies. Molecules with promise will be modified with a focused medicinal chemistry campaign.