Discovery of Novel Inhibitor against SARS-CoV-2 Infection

戴立德Li-Te Tai1, 葉呈筠2,鄭如茜3,陸志豪4,5,*

1Industrial Development Graduate Program of College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

2The Ph.D. Program of Biotechnology and Biomedical industry, China Medical University, Taichung, Taiwan

3College of Medicine, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan

4Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

5Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. The angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry. Consequently, different therapeutic approaches associated with spike protein and ACE2 interaction show high-level feasibility for inhibiting virus infection. We selected the receptor-binding domain (RBD) of spike protein as the target protein for structure-based virtual screening. Two bioinformatics tools, iGEMDOCK and SiMMap, were determined to preliminarily screen potential compounds blocking the binding of ACE2 and RBD spike protein. Among 208,023 compounds from United States National Cancer Institute (NCI) database, 10 candidates were selected for further biological activity assay. In bioassay validation, SARS-CoV2 pseudotyped virus with reporter gene was applied to screen effective compounds in ACE2 stable-expressed cells. Eventually, NSC121365, NSC660827, and NSC660825 indicated significant antiviral activity against SARS-Cov-2 in BHK-hACE2 cells with the estimated EC50 at 9.3 μM, 7.8 μM and 6.8 μM, respectively. Thus, our virtual screening has successfully discovered 3 lead compounds binding to RBD of the spike protein and was capable of attenuating virus infection.