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.
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Acknowledgements
We greatly thank Dr. Guo from Nan Kai University and the National Protein Center of China for providing protein samples. This work was supported by the Science and Technology Commission of Shanghai Municipality grants (Grant IDs: 20431900102, 20431900100, 20430780300, 21920102003 and 2043190012); the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (Grant ID: 2018ZX09711002); National Natural Science Foundation of China (No. 21920102003); Shanghai Science and Technology Development Funds (Grant ID: 20QA1406400); the Youth Innovation Promotion Association CAS (grants 2018367 to LKZ); as well as the startup package from ShanghaiTech University.
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FB, LKZ, YY, WJS, LLZ, and HLJ designed research; LW, PXR, HQL, MAA, and FB performed calculations and analyzed data; SY and YY prepared compound samples; YG and PXM prepared protein samples; WZC and and WZ performed Mass Spectrometry experiments and analyzed the results; YZ performed Bio-Layer Interferometry analysis and analyzed data; HG, HYW, KC, XLZ, YZ, WQX, and LLZ performed Surface Plasmon Resonance and analyzed data; YW, LKZ, and WJS performed anti-viral activity assay and analyzed data. The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.
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Wang, L., Wu, Y., Yao, S. et al. Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein. Acta Pharmacol Sin 43, 788–796 (2022). https://doi.org/10.1038/s41401-021-00735-z
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DOI: https://doi.org/10.1038/s41401-021-00735-z
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