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.

• Authors: Tayo O Olaleye, James A Brannigan, Shirley M Roberts, Robin J Leatherbarrow, Anthony J Wilkinson, Edward W Tate
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 12 Issue 41 Pg. 8132-7 (Nov 07 2014) ISSN: 1477-0539 [Electronic] England
• PMID: 25230674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Enzyme Inhibitors
• Peptidomimetics
• Acyltransferases
• glycylpeptide N-tetradecanoyltransferase

Topics

• Acyltransferases (antagonists & inhibitors, metabolism)
• Antifungal Agents (chemical synthesis, chemistry, pharmacology)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Leishmania (drug effects, enzymology)
• Models, Molecular
• Molecular Structure
• Parasitic Sensitivity Tests
• Peptidomimetics (chemical synthesis, chemistry, pharmacology)
• Plasmodium (drug effects, enzymology)
• Structure-Activity Relationship