The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design

Abstract Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first st...

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Autores principales:	Larissa Dirr, Ibrahim M. El-Deeb, Leonard M. G. Chavas, Patrice Guillon, Mark von Itzstein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab9653c079f4487ab0d1b377bba12a09
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spelling	oai:doaj.org-article:ab9653c079f4487ab0d1b377bba12a092021-12-02T15:18:54ZThe impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design10.1038/s41598-017-04656-y2045-2322https://doaj.org/article/ab9653c079f4487ab0d1b377bba12a092017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04656-yhttps://doaj.org/toc/2045-2322Abstract Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid’s C-4 substituent’s size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein.Larissa DirrIbrahim M. El-DeebLeonard M. G. ChavasPatrice GuillonMark von ItzsteinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Larissa Dirr Ibrahim M. El-Deeb Leonard M. G. Chavas Patrice Guillon Mark von Itzstein The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
description	Abstract Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid’s C-4 substituent’s size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein.
format	article
author	Larissa Dirr Ibrahim M. El-Deeb Leonard M. G. Chavas Patrice Guillon Mark von Itzstein
author_facet	Larissa Dirr Ibrahim M. El-Deeb Leonard M. G. Chavas Patrice Guillon Mark von Itzstein
author_sort	Larissa Dirr
title	The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
title_short	The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
title_full	The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
title_fullStr	The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
title_full_unstemmed	The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
title_sort	impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ab9653c079f4487ab0d1b377bba12a09
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The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design

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