Structure-Based Design of Potent and Selective <i>Leishmania</i> <i>N</i>-Myristoyltransferase Inhibitors

Hutton, J.A.; Gonçalves, Victor; Brannigan, J.A.; Paape, Daniel; Wright, Megan H.; Waugh, T.; Roberts, S.M.; Bell, Andrew S.; Wilkinson, Anthony J.; Smith, Deborah F.; Leatherbarrow, Robin J.; Tate, Edward W.

doi:10.1021/jm5011397

Cited by 56 publications

(62 citation statements)

References 39 publications

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“…All binding modes of the described compounds differ from the binding modeso ft he previously described pyrazole sulfonamide compounds ( Figures 4B and 7B), or an umber of structures of Leishmania NMT with various ligands that were published subsequent to the work reported herein. [15,16] This enabled us to explore new vectors andi nteractions when attemptingt oo ptimise the affinitieso ft he hit compounds.…”

Section: Discussionmentioning

confidence: 99%

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

et al. 2015

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The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.

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Section: Discussionmentioning

confidence: 99%

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

et al. 2015

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“…Although the myristoyl-CoA binding site is highly conserved between human and pathogen NMTs, the peptide binding sites are quite different. By taking advantage of these differences, NMT has been targeted in Candida albicans, Trypanosoma brucei, and Leishmania major , organisms that cause fungal infections, African sleeping sickness, and leishmaniasis, respectively[144–146]. …”

Section: Fatty Acyl Transferases As Targets In Human Diseasesmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

237

235

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Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

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“…While this enzyme is ubiquitous in eukaryotes, including human isoforms, it has been validated as a target for cancer, as well as fungal, malarial, and viral infections . Furthermore, this enzyme has been found to be essential for kinetoplastid survival, including T. brucei in culture and in mouse models . While not completely resolved, over 60 proteins are believed to be substrates of TbNMT including ADP‐ribosylation factor‐1 (ARF‐1) and ADP‐ribosylation factor‐like (ARL‐1) protein, both of which are essential for bloodstream viability of T. brucei .…”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

Cited by 56 publications

References 39 publications

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

Fatty acylation of proteins: The long and the short of it

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

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