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Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions.
mBio. 2021 03 30; 12(2)MBIO

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 μM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.

Authors+Show Affiliations

Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia t.haselhorst@griffith.edu.au m.jennings@griffith.edu.au.Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia t.haselhorst@griffith.edu.au m.jennings@griffith.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33785634

Citation

Day, Christopher J., et al. "Multidisciplinary Approaches Identify Compounds That Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions." MBio, vol. 12, no. 2, 2021.
Day CJ, Bailly B, Guillon P, et al. Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions. mBio. 2021;12(2).
Day, C. J., Bailly, B., Guillon, P., Dirr, L., Jen, F. E., Spillings, B. L., Mak, J., von Itzstein, M., Haselhorst, T., & Jennings, M. P. (2021). Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions. MBio, 12(2). https://doi.org/10.1128/mBio.03681-20
Day CJ, et al. Multidisciplinary Approaches Identify Compounds That Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions. mBio. 2021 03 30;12(2) PubMed PMID: 33785634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions. AU - Day,Christopher J, AU - Bailly,Benjamin, AU - Guillon,Patrice, AU - Dirr,Larissa, AU - Jen,Freda E-C, AU - Spillings,Belinda L, AU - Mak,Johnson, AU - von Itzstein,Mark, AU - Haselhorst,Thomas, AU - Jennings,Michael P, Y1 - 2021/03/30/ PY - 2021/3/31/entrez PY - 2021/4/1/pubmed PY - 2021/4/13/medline KW - ACE2 KW - SARS-CoV-2 KW - drug screening JF - mBio JO - mBio VL - 12 IS - 2 N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 μM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/33785634/Multidisciplinary_Approaches_Identify_Compounds_that_Bind_to_Human_ACE2_or_SARS_CoV_2_Spike_Protein_as_Candidates_to_Block_SARS_CoV_2_ACE2_Receptor_Interactions_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&amp;pmid=33785634 DB - PRIME DP - Unbound Medicine ER -