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

Abstract

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.

Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

“…Targeting CypA via inhibiting agents with no cytotoxicity in vitro and in vivo, potent anti-viral activity and having high binding affinity for CypA are required for viral infection therapies. The advantage of targeting host factors for viral therapies is the higher genetic barrier to the emergence of viral escape mutants (Yang et al, 2015). Inlast, the findings discussed here would provide a base in understading CypA role in viral infection and development of novel anti-viral agents.…”

“…In the last few decades, substantial studies have focused on the development of CypA inhibitors since CypA is associated with the regulation of disease and viral infections (Sokolskaja et al, 2010;Yang et al, 2015). The development of host CypA inhibitors has been regarded as an alternative approach for viral infection because it is selective, effective and safe (Yang et al, 2015).…”

“…The development of host CypA inhibitors has been regarded as an alternative approach for viral infection because it is selective, effective and safe (Yang et al, 2015). For example, in HepG2215, HepaRG and HuH-7 cells, alisporivir decreases the intracellular HBV DNA level probably by breaking its contact with CypA.…”

“…A recent study demonstrated that lead 25, a bis-amide derivative 5, can bind with CypA and has a potent anti-HCV activity. Unlike cyclosporin A, the lead compound 25 successfully inhibits the viral replication, can restore host immune responses without acute toxicity in vitro and in vivo, and exhibits a high synergistic effect in combination with other drugs (Yang et al, 2015).…”

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

“…Filibuvir / VX-222 -Nonnucleoside inhibitors filibuvir (PF-00868554) and VX-222 (VCH-222) bind to the thumb II allosteric pocket of NS5B and prevent HCV subgenomic replicon (Yi et al, 2012). The EC 50 values of filibuvir and VX-222 achieved up to 70 nM and 5 nM, respectively (Yi et al, 2012). Moreover, NS5B substitutions M423T and I482L could affect the antiviral activity of filibuvir and VX-222 (Yi et al, 2012).…”