<i>N</i>‐Myristoyltransferase as a Target for Drug Discovery in Malaria

Brannigan, J.A.; Wilkinson, Anthony J.

doi:10.1002/9783527694082.ch12

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“…The role of myristoylation in diverse regulatory functions suggests that NMT is an essential enzyme in Leishmania and therefore a rational target for the development of new therapeutics targeting leishmaniasis. Supporting this notion, NMT has been shown to be essential in the protozoan parasites, T. brucei , T. cruzi and P. falciparum , using both genetic and chemical methods (Brannigan and Wilkinson 2016 ; Frearson et al 2010 ; Herrera et al 2016 ; Schlott et al 2018 ; Wright et al 2014 ).…”

Section: N-myristoyltransferase and Protein Myristoylation In Leishmaniamentioning

confidence: 99%

Drug discovery in leishmaniasis using protein lipidation as a target

Brannigan

Wilkinson

2021

Biophys Rev

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The leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.

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