MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

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

doi:10.1038/s41598-017-07159-y

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English
Article number	8400
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-07159-y
State	Published - Dec 1 2017

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title = "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 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.",

author = "Edwards, {Rachel L.} and Brothers, {Robert C.} and Xu Wang and Maron, {Maxim I.} and Ziniel, {Peter D.} and Tsang, {Patricia S.} and Kraft, {Thomas E.} and Hruz, {Paul W.} and Williamson, {Kim C.} and Dowd, {Cynthia S.} and John, {Audrey R.Odom}",

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MEPicides : Potent antimalarial prodrugs targeting isoprenoid biosynthesis. / Edwards, Rachel L.; Brothers, Robert C.; Wang, Xu; Maron, Maxim I.; Ziniel, Peter D.; Tsang, Patricia S.; Kraft, Thomas E.; Hruz, Paul W.; Williamson, Kim C.; Dowd, Cynthia S.; John, Audrey R.Odom.

In: Scientific reports, Vol. 7, No. 1, 8400, 01.12.2017.

Research output: Contribution to journal › Article › peer-review

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AU - Brothers, Robert C.

AU - Wang, Xu

AU - Maron, Maxim I.

AU - Ziniel, Peter D.

AU - Tsang, Patricia S.

AU - Kraft, Thomas E.

AU - Hruz, Paul W.

AU - Williamson, Kim C.

AU - Dowd, Cynthia S.

AU - John, Audrey R.Odom

PY - 2017/12/1

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N2 - 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.

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