Hepatitis B virus X protein–Cyclophilin A protein–protein interface (HBx–CypA PPI)

The Hepatitis B virus X protein (HBx)–Cyclophilin A (CypA) protein–protein interface is a critical regulatory node in the life cycle of the Hepatitis B virus (HBV) (Gallay & Lin, 2013). HBx is a multifunctional viral protein essential for viral replication and the development of HBV-related liver diseases, including hepatocellular carcinoma (Bouchard & Schneider, 2004). Cyclophilin A, a host peptidyl-prolyl cis-trans isomerase, acts as a molecular chaperone for HBx, facilitating its proper folding and stability (Phillips et al., 2015). Drugs like Rencofilstat (CRV431) target this interface by binding to the active site of CypA, thereby preventing its association with HBx (Foster et al., 2022). This inhibition results in reduced HBV DNA levels and decreased production of viral antigens in experimental models. Beyond its antiviral effects, targeting this interface has shown potential in reducing liver fibrosis and inflammation, making it a promising therapeutic strategy for chronic hepatitis B and non-alcoholic steatohepatitis (Hepion Pharmaceuticals, 2023). Unlike earlier cyclophilin inhibitors like cyclosporine A, modern candidates like Rencofilstat are designed to be non-immunosuppressive by avoiding calcineurin binding. The disruption of this specific protein-protein interaction represents a novel approach to treating chronic liver disease by addressing both viral and host factors.

Other names

HBx-CypA interactionHBx-PPIA complexHBx-Cyclophilin A complexHepatitis B virus X protein-Peptidyl-prolyl cis-trans isomerase A interaction

Rencofilstat (CRV431) is a pan-cyclophilin inhibitor that binds to the hydrophobic pocket of Cyclophilin A (CypA), sterically hindering its interaction with the Hepatitis B virus X protein (HBx). This disruption prevents the chaperone-mediated stabilization and proper folding of HBx, which is essential for the HBV life cycle, thereby reducing viral replication and the expression of pro-inflammatory and pro-fibrotic genes (Gallay & Lin, 2013; Foster et al., 2022).