Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections

Hepatitis
C virus (HCV) is a major cause of end-stage liver disease.
Direct-acting antivirals (DAAs), including inhibitors of nonstructural
proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key
components of anti-HCV treatment, but these are associated with increased
drug resistance and toxicity. Thus, the development of host-targeted
antiviral agents, such as cyclophilin A inhibitors, is an alternative
approach for more effective, selective, and safer treatment. Starting
with the discovery of a bis-amide derivative 5 through
virtual screening, the lead compound 25 was developed
using molecular modeling-based design and systematic exploration of
the structure–activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective
and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV
replication, restored host immune responses without acute toxicity
in vitro and in vivo, and exhibited a high
synergistic effect in combination with other drugs. These findings
suggest that the bis-amides have significant potential to extend the
arsenal of HCV therapeutics.