Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Wang, Lin; Wu, Yan; Yao, Sheng; Ge, Huan; Zhu, Ya; Chen, Kun; Chen, Wen-zhang; Zhang, Yi; Zhu, Wei; Wang, Hong-yang; Guo, Yu; Ma, Pei-xiang; Ren, Peng-xuan; Zhang, Xiang-lei; Li, Hui-qiong; Ali, Mohammad A.; Xu, Wen-qing; Jiang, Hua-liang; Zhang, Lei-ke; Zhu, Li-li; Ye, Yang; Shang, Wei-juan; Bai, Fang

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant K(D)) of 0.0947 µM and anti-virus IC(50) of 85.75 µM.