MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis

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

doi:10.1038/s41598-017-07159-y

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.

Highlights

Despite intense efforts in drug development and aggressive vector control programs, malaria remains a formidable challenge to public health
deoxyxylulose phosphate reductoisomerase (Dxr) catalyzes the reductive isomerization of 1-deoxy-D-xylulose 5-phosphate (DXP) to 2-C-methyl-D-erythritol 3-phosphate (MEP), using a divalent cation (Mg2+, Mn2+, or Co2+) and NADPH as a cofactor[12]
Data indicate that FSM directly inhibits the P. falciparum Dxr enzyme with a half-maximal inhibitory concentration (IC50) of 21–160 nM, and FSM is active against asexual P. falciparum[21]

Summary

Introduction

Despite intense efforts in drug development and aggressive vector control programs, malaria remains a formidable challenge to public health. Dxr is druggable, contains a high flux-control coefficient, and is one of only seven antimalarial targets that have been clinically validated[9, 12, 14, 15] These data demonstrate the essentiality of the Dxr enzyme and its value as a therapeutic target to combat P. falciparum malaria. A substantial proportion of patients treated with FSM, in either monotherapy or in combination, suffer from recrudescent infections, likely due to suboptimal drug characteristics[24, 28] Despite these shortcomings, FSM partnered with piperaquine has been evaluated in Phase II clinical trials as a non-artemisinin-based combination therapy to treat acute P. falciparum malaria[29, 30]

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Results

Conclusion