Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
Applied Molecular Virology Laboratory, Discovery Biology Division, Institut Pasteur Korea, Sampyung-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Virology. 2022 May;570:9-17. doi: 10.1016/j.virol.2022.02.006. Epub 2022 Mar 10.
The repurposing of marketed drugs for new indications is an elegant strategy to quickly and cost-efficiently address unmet medical needs. The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been shown to be a valid drug target. We performed structure-based virtual screening to assess the off-label utilization of existing drugs as novel HCV inhibitors. The virtual screen showed that tigecycline could potentially dock with high affinity to the palm site of the HCV RdRp. In vitro validation showed that tigecycline had therapeutic indexes (CC/EC) greater than 13 and 6.5 against infectious HCV and subgenomic HCV replicons, respectively. Furthermore, tigecycline displayed synergistic activity with sofosbuvir and daclatasvir against HCV. In silico screening identified tigecycline as a putative inhibitor of HCV RdRp, which was validated in vitro and demonstrated synergistic effects in combination with first-line anti-HCV therapies.
重新利用已上市药物的新适应证是一种快速、经济高效地满足未满足医疗需求的优雅策略。丙型肝炎病毒（HCV）RNA 依赖性 RNA 聚合酶（RdRp）已被证明是一个有效的药物靶点。我们进行了基于结构的虚拟筛选，以评估现有药物作为新型 HCV 抑制剂的潜在用途。虚拟筛选表明替加环素可能与 HCV RdRp 的手掌部位以高亲和力结合。体外验证表明，替加环素对感染性 HCV 和亚基因组 HCV 复制子的治疗指数（CC/EC）分别大于 13 和 6.5。此外，替加环素与索非布韦和达卡他韦联合使用对 HCV 显示协同作用。基于计算机的筛选确定替加环素是 HCV RdRp 的潜在抑制剂，在体外得到验证，并与一线抗 HCV 治疗联合显示协同作用。
