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Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites.

ABSTRACT: N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex.

SUBMITTER: Olaleye TO

PROVIDER: S-EPMC4224572 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites.

Olaleye Tayo O TO Brannigan James A JA Roberts Shirley M SM Leatherbarrow Robin J RJ Wilkinson Anthony J AJ Tate Edward W EW

Organic & biomolecular chemistry 20140918 41

N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evid ...[more]

PMID: 25230674

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