Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

Wright, Megan H.; Clough, Barbara; Rackham, M.D.; Rangachari, K.; Brannigan, J.A.; Grainger, Munira; Moss, David K.; Bottrill, Andrew R.; Heal, William P.; Broncel, Malgorzata; Serwa, Remigiusz A.; Brady, Declan; Mann, David J.; Leatherbarrow, Robin J.; Tewari, Rita; Wilkinson, Anthony J.; Holder, Anthony A.; Tate, E.W.

doi:10.1038/nchem.1830

Cited by 201 publications

(356 citation statements)

References 52 publications

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“…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 ).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Affi Nity Purifi Cation Msmentioning

confidence: 99%

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

Soupène¹,

Kao²,

Cheng³

et al. 2016

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 99%

Section: Affi Nity Purifi Cation Msmentioning

confidence: 99%

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

Soupène¹,

Kao²,

Cheng³

et al. 2016

Journal of Lipid Research

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“…Functionalized lipidation probes have been used to prove the exploitation of host-cell-mediated prenylation for membrane targeting of Legionella effectors (Ivanov et al 2010). Probes for a number of additional lipid modifications have been published and used to study a variety of diseases such as malaria and cancer (Thinon et al 2014;Wright et al 2014;Tate et al 2015). These could be useful to determine if T4SS effectors exploit other lipid modifications as membrane anchors.…”

Section: Functionalized Substrate Analogues To Profile Ptmsmentioning

confidence: 99%

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

Mattheis

Tate

et al. 2015

Can. J. Microbiol.

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Abstract:The Gram-negative facultative intracellular pathogen Legionella pneumophila infects a wide range of different protozoa in the environment and also human alveolar macrophages upon inhalation of contaminated aerosols. Inside its hosts, it creates a defined and unique compartment, termed the Legionella-containing vacuole (LCV), for survival and replication. To establish the LCV, L. pneumophila uses its Dot/Icm type IV secretion system (T4SS) to translocate more than 300 effector proteins into the host cell. Although it has become apparent in the past years that these effectors subvert a multitude of cellular processes and allow Legionella to take control of host cell vesicle trafficking, transcription, and translation, the exact function of the vast majority of effectors still remains unknown. This is partly due to high functional redundancy among the effectors, which renders conventional genetic approaches to elucidate their role ineffective. Here, we review the current knowledge about Legionella T4SS effectors, highlight open questions, and discuss new methods that promise to facilitate the characterization of T4SS effector functions in the future.Key words: Legionella, type IV secretion system, effectors, Legionella-containing vacuole.Résumé : Le pathogène intracellulaire facultatif à Gram négatif Legionella pneumophila infecte une large gamme de différents protozoaires environnementaux de même que les macrophages alvéolaires humains des suites de l'inhalation d'aérosols contaminés. À l'intérieur de ses hôtes, il crée un compartiment précis et unique nommé vacuole contenant Legionella (« Legionella-containing vacuole », LCV) pour sa survie et sa multiplication. Afin d'établir une LCV, L. pneumophila utilise sont système de sécrétion de type IV (SST4) Dot/Icm, rendant possible la translocation de plus de 300 protéines effectrices dans la cellule hôte. Au cours des dernières années, on a établi que ces effecteurs subvertissent une multitude de processus cellulaires et permettent à Legionella de prendre le contrôle du trafic cellulaire, de la transcription et de la traduction. Or, la fonction exacte de la grande majorité des effecteurs est toujours inconnue. L'importante redondance fonctionnelle au sein des effecteurs explique en partie cette incertitude et invalide les approches génétiques conventionnelles adoptées pour élucider leur rôle. Dans le présent ouvrage, nous passons en revue les connaissances actuelles entourant les effecteurs SST4 de Legionella, faisons ressortir certaines interrogations, et abordons de nouvelles méthodes qui promettent de faciliter la caractérisation de la fonction des effecteurs SST4. [Traduit par la Rédaction] Mots-clés : Legionella, système de sécrétion de type IV, effecteurs, vacuole contenant Legionella.

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“…Based on ligand similarity beyond the sulfonamide functionality we decided to investigate N-myristoyltransferase. Further, it has recently been validated as a novel antimalarian drug target in Plasmodium vivax by Wright et al 21 In this work it was shown on a structural basis that aromatic sulfonamides are capable of inhibiting N-myristoyltransferase, and hence we chose the published co-crystal structure of enzymes and sulfonamide inhibitors as the basis for our in silico analysis (PDB 2YND). Induced fit docking of our series of sulfonamides to P. vivax N-myristoyltransferase yielded consistent binding modes, in contrast to static docking runs that often led to severely distorted ligand conformations.…”

Section: In Silico Mode-of-action Analysismentioning

confidence: 99%

Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials

et al. 2015

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Malaria parasites are currently gaining drug-resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical scaffolds, with superior antimalarial activity remain an important priority, for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium falciparum parasites in vitro. The screening results showed potent inhibitory activity of a number of novel sulphonamides against P. falciparum at low micromolar concentrations, in particular in late-stage parasite development. Based on computational studies we hypothesize N-myristoyltransferase as the target of the compounds developed here. Our results demonstrate the value of novel bepotastine-based sulphonamide compounds for targeting the asexual developmental stages of P. falciparum.

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Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

Abstract: Malaria is an infectious disease caused by parasites of the genus

Cited by 201 publications

References 52 publications

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

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

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials

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