Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step

Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute re...

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Autores principales:	Shiu-Wan Chan, Talha Shafi, Robert C. Ford
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	COVID-19 SARS-CoV-2 anti-viral screening pseudovirus spike protein virus entry Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f2dd9d95e53d41e08c051f48bd9646ae
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spelling	oai:doaj.org-article:f2dd9d95e53d41e08c051f48bd9646ae2021-11-25T19:14:25ZKite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step10.3390/v131123061999-4915https://doaj.org/article/f2dd9d95e53d41e08c051f48bd9646ae2021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2306https://doaj.org/toc/1999-4915Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC<sub>50</sub> values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.Shiu-Wan ChanTalha ShafiRobert C. FordMDPI AGarticleCOVID-19SARS-CoV-2anti-viral screeningpseudovirusspike proteinvirus entryMicrobiologyQR1-502ENViruses, Vol 13, Iss 2306, p 2306 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 SARS-CoV-2 anti-viral screening pseudovirus spike protein virus entry Microbiology QR1-502
spellingShingle	COVID-19 SARS-CoV-2 anti-viral screening pseudovirus spike protein virus entry Microbiology QR1-502 Shiu-Wan Chan Talha Shafi Robert C. Ford Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
description	Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC<sub>50</sub> values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.
format	article
author	Shiu-Wan Chan Talha Shafi Robert C. Ford
author_facet	Shiu-Wan Chan Talha Shafi Robert C. Ford
author_sort	Shiu-Wan Chan
title	Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
title_short	Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
title_full	Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
title_fullStr	Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
title_full_unstemmed	Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step
title_sort	kite-shaped molecules block sars-cov-2 cell entry at a post-attachment step
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f2dd9d95e53d41e08c051f48bd9646ae
work_keys_str_mv	AT shiuwanchan kiteshapedmoleculesblocksarscov2cellentryatapostattachmentstep AT talhashafi kiteshapedmoleculesblocksarscov2cellentryatapostattachmentstep AT robertcford kiteshapedmoleculesblocksarscov2cellentryatapostattachmentstep
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Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step

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