2-amino-N-(2,6-dichloropyridin-3-yl)acetamide derivatives as a novel class of HBV capsid assembly inhibitor.

Capsid structure is crucial for the maturation and maintenance of the stable hepatitis B virion. Therefore, chemicals that inhibit capsid assembly might potentially act as potent antiviral compounds. However, only a few chemicals are known to block the capsid assembly process and further viral proliferation. In this study, we present a novel family of capsid assembly inhibitors that act against hepatitis B virus (HBV). Based on X-ray crystallographic data of the HBV core protein (Cp), we built dimer and hexamer structural models to be used in library searches. Several chemicals in the 2-amino-N-(2,6-dichloropyridin-3-yl)acetamide family were predicted to have high affinity for the groove structure in Cp. Using in vitro assembly and the HepG2.2.15 cell culture test, we verified that these chemicals demonstrated inhibitory effects on capsid assembly. Furthermore, we investigated the combinatorial effects of these assembly inhibitor chemicals with lamivudine and revealed that, in combination, they have synergistic inhibitory effects on decreasing viral concentration. We propose that these inhibitors could be utilized as an effective combination treatment against HBV infection.