Potent sialic acid inhibitors that target influenza A virus hemagglutinin

Abstract Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of an...

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Autores principales:	Yu-Jen Chang, Cheng-Yun Yeh, Ju-Chien Cheng, Yu-Qi Huang, Kai-Cheng Hsu, Yu-Feng Lin, Chih-Hao Lu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/612921c1abcf4e3aab9f477b264a5b4c
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spelling	oai:doaj.org-article:612921c1abcf4e3aab9f477b264a5b4c2021-12-02T18:27:47ZPotent sialic acid inhibitors that target influenza A virus hemagglutinin10.1038/s41598-021-87845-02045-2322https://doaj.org/article/612921c1abcf4e3aab9f477b264a5b4c2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87845-0https://doaj.org/toc/2045-2322Abstract Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.Yu-Jen ChangCheng-Yun YehJu-Chien ChengYu-Qi HuangKai-Cheng HsuYu-Feng LinChih-Hao LuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yu-Jen Chang Cheng-Yun Yeh Ju-Chien Cheng Yu-Qi Huang Kai-Cheng Hsu Yu-Feng Lin Chih-Hao Lu Potent sialic acid inhibitors that target influenza A virus hemagglutinin
description	Abstract Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.
format	article
author	Yu-Jen Chang Cheng-Yun Yeh Ju-Chien Cheng Yu-Qi Huang Kai-Cheng Hsu Yu-Feng Lin Chih-Hao Lu
author_facet	Yu-Jen Chang Cheng-Yun Yeh Ju-Chien Cheng Yu-Qi Huang Kai-Cheng Hsu Yu-Feng Lin Chih-Hao Lu
author_sort	Yu-Jen Chang
title	Potent sialic acid inhibitors that target influenza A virus hemagglutinin
title_short	Potent sialic acid inhibitors that target influenza A virus hemagglutinin
title_full	Potent sialic acid inhibitors that target influenza A virus hemagglutinin
title_fullStr	Potent sialic acid inhibitors that target influenza A virus hemagglutinin
title_full_unstemmed	Potent sialic acid inhibitors that target influenza A virus hemagglutinin
title_sort	potent sialic acid inhibitors that target influenza a virus hemagglutinin
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/612921c1abcf4e3aab9f477b264a5b4c
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Potent sialic acid inhibitors that target influenza A virus hemagglutinin

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