Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent

Abstract Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand‐binding sites in tubulin makes this protein an attractive target for anti‐parasite drug discovery. However, despite remarkable successes as anti‐cancer agents, the rati...

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Autores principales:	Natacha Gaillard, Ashwani Sharma, Izra Abbaali, Tianyang Liu, Fiona Shilliday, Alexander D Cook, Valentin Ehrhard, Mamata Bangera, Anthony J Roberts, Carolyn A Moores, Naomi Morrissette, Michel O Steinmetz
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	anti‐parasite microtubules rational structure‐based drug design species‐specific tubulin inhibitor Medicine (General) R5-920 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/c0f9fdde1699413aa5e8e00497b1e055
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spelling	oai:doaj.org-article:c0f9fdde1699413aa5e8e00497b1e0552021-11-08T09:27:45ZInhibiting parasite proliferation using a rationally designed anti‐tubulin agent1757-46841757-467610.15252/emmm.202013818https://doaj.org/article/c0f9fdde1699413aa5e8e00497b1e0552021-11-01T00:00:00Zhttps://doi.org/10.15252/emmm.202013818https://doaj.org/toc/1757-4676https://doaj.org/toc/1757-4684Abstract Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand‐binding sites in tubulin makes this protein an attractive target for anti‐parasite drug discovery. However, despite remarkable successes as anti‐cancer agents, the rational development of protozoan parasite‐specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug‐binding sites. Based on this information, we rationally designed the parasite‐specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species‐specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much‐needed, novel parasite inhibitors.Natacha GaillardAshwani SharmaIzra AbbaaliTianyang LiuFiona ShillidayAlexander D CookValentin EhrhardMamata BangeraAnthony J RobertsCarolyn A MooresNaomi MorrissetteMichel O SteinmetzWileyarticleanti‐parasitemicrotubulesrational structure‐based drug designspecies‐specific tubulin inhibitorMedicine (General)R5-920GeneticsQH426-470ENEMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	anti‐parasite microtubules rational structure‐based drug design species‐specific tubulin inhibitor Medicine (General) R5-920 Genetics QH426-470
spellingShingle	anti‐parasite microtubules rational structure‐based drug design species‐specific tubulin inhibitor Medicine (General) R5-920 Genetics QH426-470 Natacha Gaillard Ashwani Sharma Izra Abbaali Tianyang Liu Fiona Shilliday Alexander D Cook Valentin Ehrhard Mamata Bangera Anthony J Roberts Carolyn A Moores Naomi Morrissette Michel O Steinmetz Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
description	Abstract Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand‐binding sites in tubulin makes this protein an attractive target for anti‐parasite drug discovery. However, despite remarkable successes as anti‐cancer agents, the rational development of protozoan parasite‐specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug‐binding sites. Based on this information, we rationally designed the parasite‐specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species‐specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much‐needed, novel parasite inhibitors.
format	article
author	Natacha Gaillard Ashwani Sharma Izra Abbaali Tianyang Liu Fiona Shilliday Alexander D Cook Valentin Ehrhard Mamata Bangera Anthony J Roberts Carolyn A Moores Naomi Morrissette Michel O Steinmetz
author_facet	Natacha Gaillard Ashwani Sharma Izra Abbaali Tianyang Liu Fiona Shilliday Alexander D Cook Valentin Ehrhard Mamata Bangera Anthony J Roberts Carolyn A Moores Naomi Morrissette Michel O Steinmetz
author_sort	Natacha Gaillard
title	Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
title_short	Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
title_full	Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
title_fullStr	Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
title_full_unstemmed	Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
title_sort	inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/c0f9fdde1699413aa5e8e00497b1e055
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Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent

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