Xu Zhen, Zou Yunting, Gao Xi, Niu Miao-Miao, Li Jindong, Xue Lu, Jiang Su
Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2022 Oct 19;13:1041331. doi: 10.3389/fphar.2022.1041331. eCollection 2022.
The receptor-binding domain (RBD) and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) play a crucial role in the entry and replication of viral particles, and co-targeting both of them could be an attractive approach for the treatment of SARS-CoV-2 infection by setting up a "double lock" in the viral lifecycle. However, few dual RBD/Mpro-targeting agents have been reported. Here, four novel RBD/Mpro dual-targeting peptides, termed as MRs 1-4, were discovered by an integrated virtual screening scheme combining molecular docking-based screening and molecular dynamics simulation. All of them possessed nanomolar binding affinities to both RBD and Mpro ranging from 14.4 to 39.2 nM and 22.5-40.4 nM, respectively. Further pseudovirus infection assay revealed that the four selected peptides showed >50% inhibition against SARS-CoV-2 pseudovirus at a concentration of 5 µM without significant cytotoxicity to host cells. This study leads to the identification of a class of dual RBD/Mpro-targeting agents, which may be developed as potential and effective SARS-CoV-2 therapeutics.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的受体结合域（RBD）和主要蛋白酶（Mpro）在病毒颗粒的进入和复制中起着关键作用，通过在病毒生命周期中设置“双锁”，共同靶向这两者可能是治疗SARS-CoV-2感染的一种有吸引力的方法。然而，很少有报道双RBD/Mpro靶向剂。在此，通过结合基于分子对接的筛选和分子动力学模拟的综合虚拟筛选方案，发现了四种新型的RBD/Mpro双靶向肽，称为MRs 1-4。它们对RBD和Mpro的结合亲和力均为纳摩尔级，分别为14.4至39.2 nM和22.5至40.4 nM。进一步的假病毒感染试验表明，四种选定的肽在5 μM浓度下对SARS-CoV-2假病毒的抑制率>50%，且对宿主细胞无明显细胞毒性。本研究鉴定出一类双RBD/Mpro靶向剂，可开发为潜在有效的SARS-CoV-2治疗药物。
