N-Myristoyltransferase inhibition as a tool for antileishmanial drug discovery: Use in high-throughput, de novo, and piggyback strategies for drug development

Leishmaniasis is a disease caused by the Leishmania genus of protozoan parasites, and spread by the phlebotomine genus of sandfly. The disease is caused by at least 20 different species of Leishmania parasites, and manifests itself in three forms: cutaneous, mucocutaneous, and most severely, visceral leishmaniasis. Current chemotherapeutic treatments for leishmaniasis are limited by parasite resistance to existing drugs, highly toxic side effects, and high cost of treatment. As a neglected tropical disease, there has been relatively little research toward new drugs, despite a large need, comprising 1.3m new cases and 20,000-50,000 deaths annually. Fortunately, although there is a wide variety in species causing the disease, visceral leishmaniasis is largely caused by a single species of parasite, Leishmania donovani, greatly simplifying the search for drugs against the most dangerous form of the disease. The whole genome of the species has been sequenced, and many crystal structures of key proteins have been elucidated. Specifically, N-myristoyltransferase (NMT) has emerged as a promising enzyme for target-based antileishmanial drug development, with a wide array of tools available for any level of drug discovery: in silico modeling and docking, enzyme specific assays for protozoan and human isoforms, high throughput in vitro assays against both the parasite itself and infected host cells, and animal models of the disease. However, with L. donovani NMT as a newer target, research has yet to utilize all of these individual elements synergistically with themselves, or with related studies in different parasite species. Combined analysis of these methods can yield a more efficient search for antileishmanials, regardless of screening type