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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 24, 2015
• 年：2015
• 卷：58
• 期：24
• 页码：9546-9561
• 全文大小：890K
• ISSN：1520-4804

文摘

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 <b>5b> through virtual screening, the lead compound <b>25b> was developed using molecular modeling-based design and systematic exploration of the structure–activity relationship. The lead <b>25b> lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, <b>25b> 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.