Ribaudo Giovanni, Yun Xiaoyun, Ongaro Alberto, Oselladore Erika, Ng Jerome P L, Haynes Richard K, Law Betty Yuen Kwan, Memo Maurizio, Wong Vincent Kam Wai, Coghi Paolo, Gianoncelli Alessandra
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Chem Biol Drug Des. 2023 Apr;101(4):809-818. doi: 10.1111/cbdd.14187. Epub 2022 Dec 14.
The development of inhibitors that target the papain-like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causing coronavirus disease 2019 (COVID-19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS-CoV-2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a μM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.
靶向木瓜样蛋白酶（PLpro）的抑制剂的开发有可能对抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的传播，SARS-CoV-2是引起2019冠状病毒病（COVID-19）的病原体。基于对其若干下游效应的考虑，干扰PLpro既可以恢复病毒施加的免疫抑制，又可以抑制病毒复制。通过采用重新利用策略，本研究评估了抗疟药物作为PLpro抑制剂的潜力，以及它们用于治疗SARS-CoV-2感染的可能性。利用计算工具进行结构分析、分子对接和分子动力学模拟，以筛选针对PLpro的抗疟药物，并通过体外实验验证了计算机模拟数据。虚拟筛选突出显示阿莫地喹和亚甲蓝是最佳候选药物，体外实验结果补充了这些发现，表明阿莫地喹是一种微摩尔级的PLpro去泛素化酶抑制剂。本研究结果表明，这里采用的计算流程可以正确识别活性化合物。因此，所突出显示的抗疟药物代表了通过结构优化开发新型PLpro抑制剂的起点。
