Hu Xin, Shrimp Jonathan H, Guo Hui, Xu Miao, Chen Catherine Z, Zhu Wei, Zakharov Alexey, Jain Sankalp, Shinn Paul, Simeonov Anton, Hall Matthew D, Shen Min
National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, United States.
bioRxiv. 2021 Mar 17:2020.12.28.424413. doi: 10.1101/2020.12.28.424413.
The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied a large-scale database screening for small molecule inhibitors against TMPRSS2. The hits were evaluated in the TMPRSS2 biochemical assay and the SARS-CoV-2 pseudotyped particle (PP) entry assay. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行促使研究人员将精力转向寻找抗病毒化合物和疫苗。在本研究中，我们聚焦于人类宿主细胞跨膜蛋白酶丝氨酸2（TMPRSS2），它通过切割刺突蛋白以启动膜融合，在病毒生命周期中发挥重要作用。TMPRSS2是一个有吸引力的靶点，在抗SARS和中东呼吸综合征（MERS）药物开发方面受到关注。从比较结构建模和结合模型分析入手，我们开发了一种基于药效团的有效方法，并应用大规模数据库筛选针对TMPRSS2的小分子抑制剂。通过TMPRSS2生化测定和SARS-CoV-2假型颗粒（PP）进入测定对筛选出的化合物进行评估。鉴定出了多种新型抑制剂，为进一步开发治疗新冠肺炎的候选药物提供了起点。
