@article{b03b2162bc184caa82b1ece6a9da7e47,
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}",
note = "Funding Information: We thank Ana Rodriguez at the Anti-Infectives Screening core at NYU School of Medicine for testing the in vivo efficacy of RCB-185. We also thank Sophie Alvarez at the Center for Biotechnology at the University of Nebraska-Lincoln for MEP metabolite analysis. This work is supported by the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital [MD-LI-2011-171 to A.R.O.J.], the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01AI086453 to C.S.D., R01AI103280 to A.R.O.J., R21AI123808 to A.R.O.J.], the March of Dimes [Basil O{\textquoteright}Connor Starter Scholar Research Award to A.R.O.J.]. R.L.E. is supported by NIH Infectious Disease Training Grant T32 AI007172-34. Funding Information: This work is supported by the Children's Discovery Institute of Washington University and St. Louis Children's Hospital [MD-LI-2011-171 to A.R.O.J.], the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01AI086453 to C.S.D., R01AI103280 to A.R.O.J., R21AI123808 to A.R.O.J.], the March of Dimes [Basil O'Connor Starter Scholar Research Award to A.R.O.J.]. R.L.E. is supported by NIH Infectious Disease Training Grant T32 AI007172-34. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41598-017-07159-y",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
number = "1",
}