N-Myristoyltransferase as a potential drug target in malaria and leishmaniasis

Abstract

SUMMARY 12 13Infections caused by protozoan parasites are among the most widespread and intractable transmissible 14 diseases affecting the developing world, with malaria and leishmaniasis being most costly in terms of 15 morbidity and mortality. Although new drugs are urgently required against both diseases in the face of 16 ever-rising resistance to frontline therapies, very few candidates passing through development 17 pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and 18 under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-19 terminally lipidates a wide range of specific target proteins through post-translational modification, as 20 a potential drug target in malaria and the leishmaniases. We discuss the limitations of current 21 knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress 22 towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. 23Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in 24 protozoan parasites, and the generation of potential development candidates based on the output of 25 our recently-reported high-throughput screens. 26 INTRODUCTION 27Malaria 28 Malaria is a disease caused by infection of a human host with protozoan parasites of the genus 29Plasmodium, and is a devastating global health issue with approximately 200 million cases and 30 1 million deaths in 2010 alone (Murray et al. 2012). The complex life cycle of malaria parasites 31 spreads across two hosts and five host tissues whilst undergoing at least ten distinct morphological 32 transitions (Sturm et al. 2006; Mackinnon and Marsh 2010). Replication of parasites and subsequent 33 rupture of erythrocytes in the intra-erythrocytic stages are responsible for the clinical symptoms of 34 malaria, and the majority of drugs target these asexual (human-host) stages of the life cycle. Some 35 species of malaria, most notably Plasmodium vivax, can exist in a latent liver hypnozoite form that 36 can cause relapse even after clearance of bloodstream parasites (Derbyshire et al. 2012; Rodrigues et 37 al. 2012). Of the five relevant species of human parasite, the vast majority of deaths occur from P. 38 falciparum infections, which is the typical cause of severe malaria (Claessens et al. 2012). This has 39 led to the majority of drug discovery efforts focussing on P. falciparum, typically at the expense of 40 other species. Although the demand for new P. falciparum drugs is in no doubt, P. vivax is 41 responsible for the majority of worldwide malaria endemicity (Price et al. 2009; WHO 2011). 42However, difficulties culturing the parasite (Udomsangpetch et al. 2007) For the latter half of the 20 th century, antimalarial drug discovery was a success story for natural 47 product-inspired therapies, by far the most widely used of which are chloroquine (Loeb et al. 1946) 48 and artemisinin (Miller and Su 2011). 49Chlo...

Inhibition of N‐myristoyltransferase1 affects dengue virus replication

“…Previous NMT1 studies have focused on cancer development, diagnostic biomarkers, and chemotherapeutic targets (Selvakumar et al., ; Shrivastav, Varma, Saxena, DeCoteau, & Sharma, ; Thinon, Morales‐Sanfrutos, Mann, & Tate, ). Several studies have investigated the biology and pathogenesis of NMT from malaria and leishmania within its potential as a novel drug target by exploiting the inhibition effect observed when NMT expression is disrupted (Banerjee, Arora, & Murty, ; Bell et al., ; Brannigan et al., ; Tate, Bell, Rackham, & Wright, ). Furthermore, recognition of NMT as a cell wall target of Aspergillus fumigatus infection has also identified NMT as a potential therapeutic drug target (Fang et al., ; Valiante, Macheleidt, Foge, & Brakhage, ), and NMT has been identified as a novel antifungal target of Candida albicans (Sikorski et al., ; Wiegand et al., ).…”

Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

“…Because binding of the peptides does not affect acyl-CoA binding to the N-terminal motif ( 33,53,54 ), compounds that can recognize the C-terminal binding domain of the NMT proteins of invading pathogens seem to be good candidates to specifi cally disrupt myristoylation without impacting acylation of the proteins of the host (28)(29)(30)(31)(32)(34)(35)(36). As examples, the development of Plasmodium falciparum in erythroid cells is blocked by several chemicals inhibiting the P. falciparum NMT enzyme (35)(36)(37)55 ). The inhibition of myristoylation of the HIV Gag protein prevents its membrane association and blocks viral budding ( 56 ).…”

“…Although amide linkage of the myristate to the glycine residue appears irreversible, a structural conformational property of some acyl-proteins, called the myristoylswitch, can remove the aliphatic tail from the lipid bilayer and dissociate the proteins from their membrane-bound location ( 25,27 ). The acyl-transferase activity of the NMT enzymes is specifi c toward myristoyl-CoA (C 14 -CoA) and is essential for the intracellular development of pathogens (28)(29)(30)(31)(32)(33)(34)(35)(36). Chemicals inhibiting myristoylation of proteins are potent drugs against parasitic protozoa and fungi.…”

Recent Advances in The Discovery of N‐Myristoyltransferase Inhibitors

“…A large number of NMT inhibitors have been reported so far. [74] Finally, anticancer NMT inhibitors possess cytotoxicity against cancer cells. However, NMT's role as a target for antiparasitic agents is still emerging, and investigations into NMT as a target for anticancer therapies is still in its infancy.…”