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Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries.
Molecules. 2021 May 27; 26(11)M

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC[®]1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.

Authors+Show Affiliations

Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Pharmacology, Israel Institute for Biological, Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.Department of Biotechnology, Israel Institute for Biological Chemical and Environmental Sciences, Ness Ziona 7410001, Israel.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34072087

Citation

David, Alon Ben, et al. "Identification of SARS-CoV-2 Receptor Binding Inhibitors By in Vitro Screening of Drug Libraries." Molecules (Basel, Switzerland), vol. 26, no. 11, 2021.
David AB, Diamant E, Dor E, et al. Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries. Molecules. 2021;26(11).
David, A. B., Diamant, E., Dor, E., Barnea, A., Natan, N., Levin, L., Chapman, S., Mimran, L. C., Epstein, E., Zichel, R., & Torgeman, A. (2021). Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries. Molecules (Basel, Switzerland), 26(11). https://doi.org/10.3390/molecules26113213
David AB, et al. Identification of SARS-CoV-2 Receptor Binding Inhibitors By in Vitro Screening of Drug Libraries. Molecules. 2021 May 27;26(11) PubMed PMID: 34072087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries. AU - David,Alon Ben, AU - Diamant,Eran, AU - Dor,Eyal, AU - Barnea,Ada, AU - Natan,Niva, AU - Levin,Lilach, AU - Chapman,Shira, AU - Mimran,Lilach Cherry, AU - Epstein,Eyal, AU - Zichel,Ran, AU - Torgeman,Amram, Y1 - 2021/05/27/ PY - 2021/05/02/received PY - 2021/05/20/revised PY - 2021/05/24/accepted PY - 2021/6/2/entrez PY - 2021/6/3/pubmed PY - 2021/6/9/medline KW - COVID-19 KW - SARS-CoV-2 KW - angiotensin-converting enzyme 2 (ACE2), high-throughput screening KW - drug repurposing KW - receptor binding domain (RBD) KW - small molecule inhibitors (SMIs) KW - spike protein JF - Molecules (Basel, Switzerland) JO - Molecules VL - 26 IS - 11 N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC[®]1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/34072087/Identification_of_SARS_CoV_2_Receptor_Binding_Inhibitors_by_In_Vitro_Screening_of_Drug_Libraries_ DB - PRIME DP - Unbound Medicine ER -