Abstract
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.
Highlights
The leishmaniases are diseases caused by more than 20 different Leishmania parasite species (Burza et al 2018; Sasidharan and Saudagar 2021)
According to the World Health Organization, more than 1 billion people live in areas where leishmaniasis is endemic, and it is estimated there are 30,000 and 1 million new cases, respectively, of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) annually occurring mainly in South America, East Africa, the Middle East and the Indian subcontinent
The promastigote form of the parasite which is injected into the skin is taken up by macrophages, or other mononuclear phagocytes, where it becomes enclosed in a phagosome that fuses with lysosomes to form a parasitophorous vesicle (PV)
Summary
The leishmaniases are diseases caused by more than 20 different Leishmania parasite species (Burza et al 2018; Sasidharan and Saudagar 2021). Miltefosine is a repurposed anti-cancer drug and an alkyl phosphocholine which can be orally administered for treatment of VL, though it is expensive. It too suffers from side effects, and significantly, it has been identified as a teratogen which limits its suitability. It has a long half-life in the body giving rise to concerns that resistance will emerge as the parasites are exposed to sub-lethal concentrations of the drug. It plays a key role in catalysis, acting as a base to deprotonate the α-amino
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