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dc.contributor.authorDay, CJ
dc.contributor.authorBailly, B
dc.contributor.authorGuillon, P
dc.contributor.authorDirr, L
dc.contributor.authorJen, FEC
dc.contributor.authorSpillings, BL
dc.contributor.authorMak, J
dc.contributor.authorvon Itzstein, M
dc.contributor.authorHaselhorst, T
dc.contributor.authorJennings, MP
dc.date.accessioned2021-04-07T23:58:34Z
dc.date.available2021-04-07T23:58:34Z
dc.date.issued2021
dc.identifier.issn2161-2129en_US
dc.identifier.doi10.1128/mBio.03681-20en_US
dc.identifier.urihttp://hdl.handle.net/10072/403623
dc.description.abstractSevere 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 sur-face 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 K (equilibrium dissociation constant) <3μM 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 angio-tensin 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.en_US
dc.description.sponsorshipDepartment of Tourism, Innovation and Sport (DTIS)en_US
dc.description.sponsorshipMr Zen Wei Peu (Individual)en_US
dc.languageengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofpagefrome03681-20en_US
dc.relation.ispartofissue2en_US
dc.relation.ispartofjournalmBioen_US
dc.relation.ispartofvolume12en_US
dc.subject.fieldofresearchMicrobiologyen_US
dc.subject.fieldofresearchcode0605en_US
dc.subject.keywordsACE2en_US
dc.subject.keywordsSARS-CoV-2en_US
dc.subject.keywordsdrug screeningen_US
dc.titleMultidisciplinary approaches identify compounds that bind to human ace2 or sars-cov-2 spike protein as candidates to block sars-cov-2–ace2 receptor interactionsen_US
dc.typeJournal articleen_US
dcterms.bibliographicCitationDay, CJ; Bailly, B; Guillon, P; Dirr, L; Jen, FEC; Spillings, BL; Mak, J; von Itzstein, M; Haselhorst, T; Jennings, MP, 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), pp. e03681-20en_US
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-04-07T22:21:26Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2021 Day et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
gro.hasfulltextFull Text
gro.griffith.authorJen, Freda E.
gro.griffith.authorBailly, Benjamin
gro.griffith.authorJennings, Michael P.
gro.griffith.authorde Villiers, Belinda
gro.griffith.authorHaselhorst, Thomas E.
gro.griffith.authorMak, Johnson
gro.griffith.authorvon Itzstein, Mark


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