<i>N</i>‐Myristoyltransferase: a Prospective Drug Target for Protozoan Parasites

Bowyer, Paul W.; Tate, Edward W.; Leatherbarrow, Robin J.; Holder, Anthony A.; Smith, Deborah F.; Brown, Katherine A.

doi:10.1002/cmdc.200700301

Cited by 60 publications

(67 citation statements)

References 82 publications

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“…Several parasitic protozoa also possess NMTs essential for their survival in the host [113]. NMT enzymes have been characterised in L. major [32] (which causes leishmaniasis), T. brucei (responsible for African sleeping sickness) [32] and P. falciparum (the parasite causing most cases of malaria in humans) [25].…”

Section: Nmt In Infectious Diseasementioning

confidence: 99%

“…NMT enzymes have been characterised in L. major [32] (which causes leishmaniasis), T. brucei (responsible for African sleeping sickness) [32] and P. falciparum (the parasite causing most cases of malaria in humans) [25]. Several studies have sought to identify selective inhibitors of the NMTs in these organisms [26,113,114]. Another potential target for NMT inhibitors is HIV-1 infection.…”

Section: Nmt In Infectious Diseasementioning

confidence: 99%

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Protein myristoylation in health and disease

et al. 2009

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N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.Keywords Post-translational modification . Drug design . Myristoylation . Lipidation . Chemical proteomics Post-translational modification and myristoylationThe proteome is a larger and more dynamic entity than the genome, a result of both increased sequence diversity at the mRNA level due to alternative splicing of genes, and increased chemical and functional complexity at the protein level due to post-translational modification (PTM). This explains to some extent why larger genomes do not necessarily translate into more complex organisms. Posttranslational modification allows the incorporation of chemistries and new molecular functions that cannot be directly encoded by the gene sequence. Myristoylation is the attachment of a 14-carbon saturated fatty acid, myristate, to the N-terminal glycine of a subset of eukaryotic proteins [8,16,17]. Although often referred to as a PTM, it usually occurs co-translationally [18], when fewer than 100 residues have been polymerised by the

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Section: Nmt In Infectious Diseasementioning

confidence: 99%

Section: Nmt In Infectious Diseasementioning

confidence: 99%

Protein myristoylation in health and disease

et al. 2009

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“…7 A number of potential substrates were tested, with Homo sapiens pp60 src (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) (GSNKSKPKDASQRRR-NH 2 ) being chosen as the most suitable substrate for the PvNMT assay, with apparent K m (K m app ) of 5.71 ± 0.6 μM in assay conditions. The compound collection was sourced by Medical Research Council Technology, largely from commercial suppliers.…”

Section: Screeningmentioning

confidence: 99%

“…3 NMT has been found to be essential in eukaryotes and the sequence variation between parasite and host NMTs should permit the development of selective inhibitors. [4][5][6] Therefore, targeting Nmyristoylation in P. vivax might constitute an attractive strategy for the treatment of vivax malaria. However, in order to validate this approach, inhibitors of P. vivax NMT (PvNMT) must first be identified.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Plasmodium vivaxN-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

et al. 2012

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N-myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.

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“…The benzo [b]furan ring system in particular is an important scaffold for drug development. [1] Several 2-substituted benzofurans have shown antifungal [2] and antiplasmodial [3] as well as antioxidant, anti-HIV, anticancer and estrogenic activities. [4] Several retrosynthetic disconnections to commercially available starting materials for the synthesis of benzo [b]furans are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

2‐Substituted Benzo[b]furans from (E)‐1,2‐Dichlorovinyl Ethers and Organoboron Reagents: Scope and Mechanistic Investigations into the One‐Pot Suzuki Coupling/Direct Arylation

Geary

Hultin

2010

Eur J Org Chem

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Abstract2‐Substituted benzo[b]furans can easily be assembled from simple phenols, boronic acids or other organoboron reagents, and trichloroethylene. The overall process requires only two synthetic steps, with the key step being a one‐pot sequential Suzuki cross‐coupling/direct arylation reaction. The method tolerates many useful functional groups and does not require the installation of any other activating functionality. The modular nature of the process permits the rapid synthesis of many analogues using essentially the same chemistry, of particular value in drug development. Results of kinetic isotope effect studies and investigations into the regioselectivity of the process indicate that the direct arylation step most likely does not involve an electrophilic palladation. The most likely mechanism lies somewhere on the continuum between a C–H bond metathesis and an assisted palladation or concerted metallation‐deprotonation pathway.

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N‐Myristoyltransferase: a Prospective Drug Target for Protozoan Parasites

Cited by 60 publications

References 82 publications

Protein myristoylation in health and disease

Protein myristoylation in health and disease

Discovery of Plasmodium vivaxN-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

2‐Substituted Benzo[b]furans from (E)‐1,2‐Dichlorovinyl Ethers and Organoboron Reagents: Scope and Mechanistic Investigations into the One‐Pot Suzuki Coupling/Direct Arylation

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