Hepatitis C virus replication complex (Cyclophilin A-Non-structural protein 5A interaction) (CypA-NS5A)

The Hepatitis C virus (HCV) replication complex is a multi-protein assembly located on host cell membranes, where the interaction between the host protein Cyclophilin A (CypA) and the viral non-structural protein 5A (NS5A) is essential for viral genome replication (PubMed: 19153238). CypA, a peptidyl-prolyl cis-trans isomerase, acts as a molecular chaperone that binds to specific proline residues in Domain II of NS5A, facilitating the proper folding or assembly of the replication machinery (PubMed: 21994453). This interaction is critical for the formation of the "membranous web," the site of viral RNA synthesis, and its disruption leads to a potent inhibition of viral replication across multiple HCV genotypes (PubMed: 18515040). Because the target involves a conserved host factor, cyclophilin inhibitors like Alisporivir (Debio-025) and SCY-635 offer a high genetic barrier to viral resistance compared to direct-acting antivirals (DAAs). These drugs bind to the hydrophobic pocket of CypA, preventing its association with NS5A without inducing the immunosuppression typically associated with cyclosporine A (PubMed: 20638294). Clinical development of these inhibitors has focused on their pan-genotypic activity and their potential use in combination therapies for patients with chronic hepatitis C infection.

Other names

PPIA-NS5A interactionCyclophilin A-NS5A complexHCV replication complex host-viral interactionCypA-NS5A complex

Inhibition of host Cyclophilin A (CypA) peptidyl-prolyl isomerase activity, preventing its chaperone-like interaction with the viral NS5A protein, which disrupts the assembly and function of the HCV replication complex.