SAR study of bisamides as cyclophilin a inhibitors for the development of host-targeting therapy for hepatitis C virus infection |
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| Affiliation: | 1. College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea;2. Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea;3. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea;1. Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA;2. Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA;3. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD 21205, USA;4. Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA;1. Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, People’s Republic of China;2. Sichuan Institute for Food and Drug Control, Chengdu 611731, People’s Republic of China;3. Department of Chemistry, School of Science, Beijing Technology and Business University, Beijing 100048, People’s Republic of China;1. Pharmaceutical Department, 251 General Air Force Hospital, 11525 Athens, Greece;2. Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece;3. Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece;4. Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China;2. Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada |
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| Abstract: | The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment. |
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| Keywords: | Hepatitis C Virus Cyclophilin A inhibitor Cyclosporine A Ugi reaction Molecular docking |
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