Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein
Lin Wang1,2,
Yan Wu3,
Sheng Yao4,5,
Huan Ge6,
Ya Zhu7,
Kun Chen7,
Wen-zhang Chen1,
Yi Zhang1,
Wei Zhu1,
Hong-yang Wang2,
Yu Guo8,
Pei-xiang Ma1,
Peng-xuan Ren1,2,
Xiang-lei Zhang1,2,
Hui-qiong Li1,2,
Mohammad A. Ali9,
Wen-qing Xu2,
Hua-liang Jiang1,7,
Lei-ke Zhang3,
Li-li Zhu2,6,
Yang Ye4,5,
Wei-juan Shang3,
Fang Bai1,2
1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430064, China
4 Department of Natural Products Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
6 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
7 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
8 College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
9 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
Correspondence to: Lei-ke Zhang: zhangleike@wh.iov.cn, Li-li Zhu: zhulfl@ecust.edu.cn, Yang Ye: yye@mail.shcnc.ac.cn, Wei-juan Shang: Shangweijuan@wh.iov.cn, Fang Bai: baifang@shanghaitech.edu.cn,
DOI: 10.1038/s41401-021-00735-z
Received: 15 March 2021
Accepted: 29 June 2021
Advance online: 4 August 2021
Abstract
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 KD) of 0.0947 μM and anti-virus IC50 of 85.75 μM.
Keywords:
SARS-CoV-2; natural products; virtual screening; spike protein; protein-protein interaction modulators
