A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

Abstract Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new ant...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jessica Knox, Nicolas Joly, Edmond M. Linossi, José A. Carmona-Negrón, Natalia Jura, Lionel Pintard, William Zuercher, Peter J. Roy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d0e282a9e8e24d77b3d9aefd33a45006
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d0e282a9e8e24d77b3d9aefd33a45006
record_format	dspace
spelling	oai:doaj.org-article:d0e282a9e8e24d77b3d9aefd33a450062021-12-02T17:39:19ZA survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics10.1038/s41598-021-88150-62045-2322https://doaj.org/article/d0e282a9e8e24d77b3d9aefd33a450062021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88150-6https://doaj.org/toc/2045-2322Abstract Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.Jessica KnoxNicolas JolyEdmond M. LinossiJosé A. Carmona-NegrónNatalia JuraLionel PintardWilliam ZuercherPeter J. RoyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jessica Knox Nicolas Joly Edmond M. Linossi José A. Carmona-Negrón Natalia Jura Lionel Pintard William Zuercher Peter J. Roy A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
description	Abstract Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.
format	article
author	Jessica Knox Nicolas Joly Edmond M. Linossi José A. Carmona-Negrón Natalia Jura Lionel Pintard William Zuercher Peter J. Roy
author_facet	Jessica Knox Nicolas Joly Edmond M. Linossi José A. Carmona-Negrón Natalia Jura Lionel Pintard William Zuercher Peter J. Roy
author_sort	Jessica Knox
title	A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
title_short	A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
title_full	A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
title_fullStr	A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
title_full_unstemmed	A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
title_sort	survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d0e282a9e8e24d77b3d9aefd33a45006
work_keys_str_mv	AT jessicaknox asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT nicolasjoly asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT edmondmlinossi asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT joseacarmonanegron asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT nataliajura asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT lionelpintard asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT williamzuercher asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT peterjroy asurveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT jessicaknox surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT nicolasjoly surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT edmondmlinossi surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT joseacarmonanegron surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT nataliajura surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT lionelpintard surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT williamzuercher surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics AT peterjroy surveyofthekinomepharmacopeiarevealsmultiplescaffoldsandtargetsforthedevelopmentofnovelanthelmintics
_version_	1718379849425354752

A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

Ejemplares similares