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.

• Authors: Suhui Yang, Jyothi K R, Sangbin Lim, Tae Gyu Choi, Jin-Hwan Kim, Salima Akter, Miran Jang, Hyun-Jong Ahn, Hee-Young Kim, Marc P Windisch, Daulat B Khadka, Chao Zhao, Yifeng Jin, Insug Kang, Joohun Ha, Byung-Chul Oh, Meehyein Kim, Sung Soo Kim, Won-Jea Cho
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 24 Pg. 9546-61 (Dec 24 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26613291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Indoleacetic Acids
• N-cyclohexyl-2-((2-1H-indol-3-ylacetyl)-(4-isopropylphenyl)amino)-2-(3,4,5-trimethoxyphenyl)acetamide
• Cyclophilin A
• Glycine

Topics

• Animals
• Antiviral Agents (chemistry, pharmacology, toxicity)
• Cell Line, Tumor
• Cyclophilin A (antagonists & inhibitors)
• Drug Synergism
• Glycine (analogs & derivatives, chemistry, pharmacology, toxicity)
• Hepacivirus (drug effects, physiology)
• Hepatitis C (drug therapy, immunology, virology)
• Humans
• Immunosuppression Therapy
• Indoleacetic Acids (chemistry, pharmacology, toxicity)
• Mice, Inbred NOD
• Mice, SCID
• Models, Molecular
• Protein Binding
• Replicon (drug effects)
• Structure-Activity Relationship
• Virus Replication (drug effects)