MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis

Abstract The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoi...

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Autores principales:	Rachel L. Edwards, Robert C. Brothers, Xu Wang, Maxim I. Maron, Peter D. Ziniel, Patricia S. Tsang, Thomas E. Kraft, Paul W. Hruz, Kim C. Williamson, Cynthia S. Dowd, Audrey R. Odom John
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/539d6d0aabfc46c68f5a489b64e29fac
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spelling	oai:doaj.org-article:539d6d0aabfc46c68f5a489b64e29fac2021-12-02T12:30:24ZMEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis10.1038/s41598-017-07159-y2045-2322https://doaj.org/article/539d6d0aabfc46c68f5a489b64e29fac2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07159-yhttps://doaj.org/toc/2045-2322Abstract The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.Rachel L. EdwardsRobert C. BrothersXu WangMaxim I. MaronPeter D. ZinielPatricia S. TsangThomas E. KraftPaul W. HruzKim C. WilliamsonCynthia S. DowdAudrey R. Odom JohnNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rachel L. Edwards Robert C. Brothers Xu Wang Maxim I. Maron Peter D. Ziniel Patricia S. Tsang Thomas E. Kraft Paul W. Hruz Kim C. Williamson Cynthia S. Dowd Audrey R. Odom John MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
description	Abstract The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.
format	article
author	Rachel L. Edwards Robert C. Brothers Xu Wang Maxim I. Maron Peter D. Ziniel Patricia S. Tsang Thomas E. Kraft Paul W. Hruz Kim C. Williamson Cynthia S. Dowd Audrey R. Odom John
author_facet	Rachel L. Edwards Robert C. Brothers Xu Wang Maxim I. Maron Peter D. Ziniel Patricia S. Tsang Thomas E. Kraft Paul W. Hruz Kim C. Williamson Cynthia S. Dowd Audrey R. Odom John
author_sort	Rachel L. Edwards
title	MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
title_short	MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
title_full	MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
title_fullStr	MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
title_full_unstemmed	MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
title_sort	mepicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/539d6d0aabfc46c68f5a489b64e29fac
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MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis

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