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

Lin Wang; Yan Wu; Sheng Yao; Huan Ge; Ya Zhu; Kun Chen; Wen-Zhang Chen; Yi Zhang; Wei Zhu; Hong-Yang Wang; Yu Guo; Pei-Xiang Ma; Peng-Xuan Ren; Xiang-Lei Zhang; Hui-Qiong Li; Mohammad A Ali; Wen-Qing Xu; Hua-Liang Jiang; Lei-Ke Zhang; Li-Li Zhu; Yang Ye; Wei-Juan Shang; Fang Bai

doi:10.1038/s41401-021-00735-z

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

Acta Pharmacol Sin. 2022 Apr;43(4):788-796. doi: 10.1038/s41401-021-00735-z. Epub 2021 Aug 4.

Authors

Lin Wang^#^{1

2}, Yan Wu^#³, Sheng Yao^#^{4

5}, Huan Ge^#⁶, Ya Zhu⁷, Kun Chen⁷, Wen-Zhang Chen¹, Yi Zhang¹, Wei Zhu¹, Hong-Yang Wang², Yu Guo⁸, Pei-Xiang Ma¹, Peng-Xuan Ren^{1

2}, Xiang-Lei Zhang^{1

2}, Hui-Qiong Li^{1

2}, Mohammad A Ali⁹, Wen-Qing Xu², Hua-Liang Jiang^{1

7}, Lei-Ke Zhang¹⁰, Li-Li Zhu^{11

12}, Yang Ye^{13

14}, Wei-Juan Shang¹⁵, Fang Bai^{16

17}

Affiliations

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.
¹⁰ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430064, China. zhangleike@wh.iov.cn.
¹¹ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. zhulfl@ecust.edu.cn.
¹² 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. zhulfl@ecust.edu.cn.
¹³ Department of Natural Products Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yye@mail.shcnc.ac.cn.
¹⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yye@mail.shcnc.ac.cn.
¹⁵ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430064, China. Shangweijuan@wh.iov.cn.
¹⁶ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. baifang@shanghaitech.edu.cn.
¹⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. baifang@shanghaitech.edu.cn.

^# Contributed equally.

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 K_D) of 0.0947 µM and anti-virus IC₅₀ of 85.75 µM.

Keywords: SARS-CoV-2; natural products; protein-protein interaction modulators; spike protein; virtual screening.

MeSH terms

COVID-19 Drug Treatment*
Humans
Protein Binding
SARS-CoV-2
Spike Glycoprotein, Coronavirus*

Substances

Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2