N-Myristoyltransferases as antileishmanial targets: a piggyback approach with benzoheterocyclic analogues

Leishmaniasis is one of the neglected diseases that remain in need for pharmacological alternatives. In this context, N-Myristoyltransferases (NMT) arise as interesting targets to explore since they are involved in the co/post-translational processing of peptides which are responsible for host cell invasion. Studies that consider these enzymes as targets point out the potential of benzoheterocyclic compounds as inhibitors of Candida albicans's N-myristoyltransferase. Here we applied a combination of comparative binding site analysis and molecular docking studies based on a Piggyback approach in the search for new Leishmania major NMT ligands. Our results revealed that NMT enzymes from both pathogens present enough structural similarity to allow extrapolation of the knowledge available from C. albicans studies to develop new L. major NMT inhibitors. Molecular docking studies with benzoheterocyclic analogues indicate the potential of benzothiazole derivatives as L. major NMT ligands, giving rise to a completely new class of chemical compounds to be explored in the development of antileishmanial drugs.

Regulation of N-Myristoyltransferase by the Calpain and Caspase Systems.

N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. In higher eukaryotes, two isoforms of NMT have been identified (NMT1 and NMT2) which share about 76% amino acid sequence identity in humans. Protein-protein interactions of NMTs reveal that m-calpain interacts with NMT1 whereas caspase-3 interacts with NMT2. These findings reveal differential interactions of both isoforms of NMT with various signaling molecules. This minireview provides an overview of the regulation of N-myristoyltransferase by calpain and caspase systems.