Development of sulfamoylbenzamide-based capsid assembly modulators for hepatitis B virus capsid assembly.

Hepatitis B virus (HBV) is a leading cause of chronic hepatitis and remains a significant global public health concern due to the lack of effective treatments. HBV replicates through reverse transcription within the viral capsid, making capsid assembly a promising antiviral target. However, no approved therapies currently target this process. In our previous study, we optimized the structure-activity relationship (SAR) of NVR 3-778 by modifying the A and B rings, leading to the identification of KR-26556 and Compound 3. In this study, we further synthesized derivatives to modify the C ring, resulting in the discovery of KR019 and KR026. These compounds exhibited over 170-fold higher selectivity than the reference compound while demonstrating potent antiviral activity in HBV-replicating cells. Mechanistic studies revealed that KR019 binds to the hydrophobic pocket at the core protein dimer-dimer interface, misdirecting capsid assembly into genome-free capsids and thereby inhibiting viral replication. Additionally, pharmacokinetic profiling confirmed favorable stability and safety. These findings highlight the strong antiviral potential of KR019 and KR026 and provide a foundation for further in vivo investigation.