Abstract
The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-Myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT).
Highlights
N-Myristoyltransferase (NMT, EC 2.3.1.97) catalyses the transfer of the fatty acid chain C14:0 from myristoyl coenzyme A (MyrCoA) to the N-terminal glycine residue of substrate proteins.[1]
We reported in 2012 the discovery of a Plasmodium vivax NMT (PvNMT) inhibitor based on a quinoline scaffold.[21]
Crystal structure of lead compound 1 in complex with Plasmodium vivax NMT First, compound 1 was co-crystallized with PvNMT and S-(2oxo)pentadecyl-coenzyme A, a non-hydrolysable myristoyl-coenzyme A analogue (Fig. 2),[26] and the structure of the resulting ternary complex was solved by X-ray crystallography
Summary
N-Myristoyltransferase (NMT, EC 2.3.1.97) catalyses the transfer of the fatty acid chain C14:0 from myristoyl coenzyme A (MyrCoA) to the N-terminal glycine residue of substrate proteins.[1] This co- and post-translational modification is ubiquitous in eukaryotic organisms and plays a central role in a variety of cellular processes such as the addressing and reversible anchoring of proteins to membranes.[2,3] The N-terminal myristate chain can participate in the stabilization of the tertiary structure of proteins and form part of recognition elements that establish protein–protein interactions.[4,5] Due to the essential functions of myristoylation, the modulation of NMT activity has emerged as an attractive strategy in the treatment of various pathologies. The first reported NMT inhibitors were obtained through rational design strategies, by mimicking the structure of peptide substrates,[14,15] or by designing non-hydrolysable MyrCoA analogues.[16,17] NMT has been validated as a pharmacological target in fungal infections,[6] in a range of parasitic diseases caused by Trypanosoma,[7] Leishmania[8] and Plasmodium[9,10,11] protozoa and filarial nematodes,[12] and as a potential target for the treatment of cancer.[13]
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