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

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.丙型肝炎病毒（Hepatitis C virus, HCV）是引发终末期肝病的主要病原体。直接抗病毒药物（Direct-acting antivirals, DAAs）涵盖非结构蛋白（NS3/4A蛋白酶、NS5A及NS5B聚合酶）抑制剂，是抗HCV治疗的核心组成部分，但此类药物易诱发耐药性与毒性反应。因此，开发宿主靶向抗病毒药物（如亲环素A抑制剂（cyclophilin A inhibitors）），成为实现更高效、高选择性且更安全的抗HCV治疗方案的可行替代途径。研究团队通过虚拟筛选发现双酰胺衍生物5，并以此为起点，采用基于分子建模的设计方法与系统的构效关系（structure–activity relationship）探索，开发出先导化合物25。先导化合物25无细胞毒性（cytotoxicity），具备强效抗HCV活性，且对亲环素A（CypA）表现出高选择性结合亲和力。与环孢素A（cyclosporin A）不同，先导化合物25无免疫抑制作用（immunosuppressive effects），可在体外与体内（in vitro and in vivo）模型中有效抑制HCV复制、恢复宿主免疫应答（host immune responses）且未引发急性毒性（acute toxicity），同时与其他药物联合使用时展现出显著的协同效应（synergistic effect）。上述研究结果表明，双酰胺类化合物具备拓展HCV治疗药物库的巨大潜力。