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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2017-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-07159-y |
| _version_ | 1818981957720080384 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T17:39:35Z |
| format | Article |
| id | doaj.art-539d6d0aabfc46c68f5a489b64e29fac |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T17:39:35Z |
| publishDate | 2017-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-539d6d0aabfc46c68f5a489b64e29fac2022-12-21T19:31:09ZengNature PortfolioScientific Reports2045-23222017-08-017111110.1038/s41598-017-07159-yMEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesisRachel L. Edwards0Robert C. Brothers1Xu Wang2Maxim I. Maron3Peter D. Ziniel4Patricia S. Tsang5Thomas E. Kraft6Paul W. Hruz7Kim C. Williamson8Cynthia S. Dowd9Audrey R. Odom John10Department of Pediatrics, Washington University School of MedicineDepartment of Chemistry, George Washington UniversityDepartment of Chemistry, George Washington UniversityDepartment of Biology, Loyola University ChicagoUniformed Services University of the Health SciencesTuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIAID, NIHDepartment of Pediatrics, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicineDepartment of Biology, Loyola University ChicagoDepartment of Chemistry, George Washington UniversityDepartment of Pediatrics, Washington University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-017-07159-y |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis |
| title_sort | mepicides potent antimalarial prodrugs targeting isoprenoid biosynthesis |
| url | https://doi.org/10.1038/s41598-017-07159-y |
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