2. Academic Validation
  3. Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections

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

  • J Med Chem. 2015 Dec 24;58(24):9546-61. doi: 10.1021/acs.jmedchem.5b01064.
Suhui Yang 1,  Jyothi K R 2,  Sangbin Lim 2,  Tae Gyu Choi 2,  Jin-Hwan Kim 2,  Salima Akter 2,  Miran Jang 2,  Hyun-Jong Ahn 3,  Hee-Young Kim 4,  Marc P Windisch 4,  Daulat B Khadka 1,  Chao Zhao 1,  Yifeng Jin 1,  Insug Kang 2,  Joohun Ha 2,  Byung-Chul Oh 5,  Meehyein Kim 6,  Sung Soo Kim 2,  Won-Jea Cho 1
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
  • 2 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
  • 3 Department of Microbiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
  • 4 Applied Molecular Virology, Institute Pasteur Korea , Gyeonggi-do 463-400, Republic of Korea.
  • 5 Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science , Incheon 406-840, Republic of Korea.
  • 6 Virus Research and Testing Group, Korea Research Institute of Chemical Technology , Daejeon 305-600, Republic of Korea.
PMID: 26613291 DOI: 10.1021/acs.jmedchem.5b01064
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.

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