title: 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.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
authors.forename: Suhui
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Jyothi
authors.initials: J
authors.lastname: K R
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Sangbin
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Salima
authors.initials: S
authors.lastname: Akter
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Miran
authors.initials: M
authors.lastname: Jang
authors.affiliation: Department of Microbiology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Ahn
authors.affiliation: Applied Molecular Virology, Institute Pasteur Korea , Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Applied Molecular Virology, Institute Pasteur Korea , Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Windisch
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
authors.forename: Daulat B
authors.initials: DB
authors.lastname: Khadka
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science , Incheon 406-840, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.affiliation: Virus Research and Testing Group, Korea Research Institute of Chemical Technology , Daejeon 305-600, Republic of Korea.
authors.forename: Meehyein
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul 130-701, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University , Gwangju 500-757, Republic of Korea.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D007165:Immunosuppression Therapy; D007210:Indoleacetic Acids / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D011485:Protein Binding; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007210:Indoleacetic Acids; C000607190:N-cyclohexyl-2-((2-1H-indol-3-ylacetyl)-(4-isopropylphenyl)amino)-2-(3,4,5-trimethoxyphenyl)acetamide; D021984:Cyclophilin A; D005998:Glycine