Division of Genetics, Department of Pediatrics, Center for Drug Discovery Innovation, Program in Immunology, Institute for Genomic Medicine, 9500 Gilman Drive MC 0762, La Jolla, California 92093, United States.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
J Med Chem. 2022 Feb 24;65(4):2866-2879. doi: 10.1021/acs.jmedchem.1c00566. Epub 2021 Sep 27.
The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (M). FRET-based screening against recombinant SARS-CoV-2 M identified six compounds that inhibit proteolysis with nanomolar IC values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 M can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit M competitively. Lead E24 inhibited viral replication with a nanomolar EC value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of M inhibition that should facilitate the design of future COVID-19 treatments.
一种新型冠状病毒（严重急性呼吸综合征冠状病毒 2，SARS-CoV-2）的出现引发了一场紧迫的公共卫生危机。由于缺乏可用的靶向治疗药物，COVID-19 患者的治疗选择仍然有限。我们采用药物化学和合理药物设计策略，鉴定出一类以 2-苯基-1,2-苯并硒唑-3-酮为靶点的化合物，可靶向 SARS-CoV-2 主蛋白酶（M）。基于荧光共振能量转移（FRET）的重组 SARS-CoV-2 M 筛选鉴定出 6 种具有纳摩尔 IC 值的抑制蛋白酶活性的化合物。预孵育稀释实验和分子对接确定，SARS-CoV-2 M 的抑制作用可以通过共价或非共价机制发生，先导化合物 E04 被确定为竞争性抑制剂。先导化合物 E24 在感染 SARS-CoV-2 的 Vero E6 细胞中以纳摩尔 EC 值（844 nM）抑制病毒复制，并进一步证实其能在人肺上皮细胞和人诱导多能干细胞衍生的 3D 肺类器官中抑制 SARS-CoV-2 复制。总之，这些研究提供了一个 M 抑制的结构框架和机制，应有助于设计未来的 COVID-19 治疗方法。
