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Journal articleWright MH, Clough B, Rackham MD, et al., 2013,
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach, Nature Chemistry, Vol: 6, Pages: 112-121, ISSN: 1755-4349
Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.
Journal articlePoulin B, Patzewitz E-M, Brady D, et al., 2013,
Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite, Biology Open, Vol: 2, Pages: 1160-1170, ISSN: 2046-6390
The phylum Apicomplexa comprises over 5000 intracellularprotozoan parasites, including Plasmodium and Toxoplasma,that are clinically important pathogens affecting humans andlivestock. Malaria parasites belonging to the genusPlasmodium possess a pellicle comprised of a plasmalemmaand inner membrane complex (IMC), which is implicated inparasite motility and invasion. Using live cell imaging andreverse genetics in the rodent malaria model P. berghei, welocalise two unique IMC sub-compartment proteins (ISPs)and examine their role in defining apical polarity duringzygote (ookinete) development. We show that these proteinslocalise to the anterior apical end of the parasite where IMCorganisation is initiated, and are expressed at alldevelopmental stages, especially those that are invasive.Both ISP proteins are N-myristoylated, phosphorylated andmembrane-bound. Gene disruption studies suggest that ISP1is likely essential for parasite development, whereas ISP3 isnot. However, an absence of ISP3 alters the apical localisationof ISP1 in all invasive stages including ookinetes andsporozoites, suggesting a coordinated function for theseproteins in the organisation of apical polarity in the parasite.
Journal articleAlibhai D, Kelly DJ, Warren S, et al., 2013,
Automated fluorescence lifetime imaging plate reader and its application to Forster resonant energy transfer readout of Gag protein aggregation, Journal of Biophotonics, Vol: 6, Pages: 398-408, ISSN: 1864-0648
Fluorescence lifetime measurements can provide quantitativereadouts of local fluorophore environment andcan be applied to biomolecular interactions via Fo¨ rsterresonant energy transfer (FRET). Fluorescence lifetimeimaging (FLIM) can therefore provide a high contentanalysis (HCA) modality to map protein-protein interactions(PPIs) with applications in drug discovery, systemsbiology and basic research. We present here an automatedmultiwell plate reader able to perform rapid unsupervisedoptically sectioned FLIM of fixed and livebiological samples and illustrate its potential to assayPPIs through application to Gag protein aggregationduring the HIV life cycle. We demonstrate both heteroFRETand homo-FRET readouts of protein aggregationand report the first quantitative evaluation of a FLIMHCA assay by generating dose response curves throughaddition of an inhibitor of Gag myristoylation. Z0 factorsexceeding 0.6 are realised for this FLIM FRET assay.Fluorescence lifetime plate map with representativeimages of high and low FRET cells and correspondingdose response plot.
Journal articleTate EW, Bell AS, Rackham MD, et al., 2013,
N- Myristoyltransferase as a potential drug target in malaria and leishmaniasis, Parasitology, Vol: 141, Pages: 37-49, ISSN: 1469-8161
Infections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.
Journal articleStorck EM, Serwa RA, Tate EW, 2013,
Chemical proteomics: a powerful tool for exploring protein lipidation, Biochemical Society Transactions, Vol: 41, Pages: 56-61, ISSN: 1470-8752
The study of post-translational modifications such as protein lipidation is a non-trivial challenge of the post-genomic era. In recent years the field of chemical proteomics has greatly advanced our ability to identify and quantify protein lipidation. In the present review, we give a brief overview of the tools available to study protein acylation, prenylation and cholesterylation, and their application in the identification and quantification of protein lipidation in health and disease.
Journal articleRackham MD, Brannigan JA, Moss DK, et al., 2013,
Discovery of Novel and Ligand-Efficient Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferase, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 56, Pages: 371-375, ISSN: 0022-2623
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Journal articleDouse CH, Green JL, Salgado PS, et al., 2012,
Regulation of the Plasmodium motor complex: phosphorylation of myosin A tail-interacting protein (MTIP) loosens its grip on MyoA., Journal of Biological Chemistry, Vol: 287, Pages: 36968-36977, ISSN: 1083-351X
Background: Recent phosphoproteome data reveal the extent of post-translational phosphorylation in selected apicomplexanparasites.Results: Binding site mutants that mimic the effect of MTIP phosphorylation in vivo severely decrease MyoA binding.Conclusion: Phosphorylation of selected binding site residues modulates the activity of the actomyosin motor.Significance: Study of Apicomplexa phosphosites can inform on the regulation of functions involved in pathogenesis.
Journal articleYu Z, Brannigan JA, Moss DK, et al., 2012,
Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery, Journal of Medicinal Chemistry, Vol: 55, Pages: 8879-8890, ISSN: 0022-2623
Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.
Journal articleThinon E, Mann D, Tate EW, 2012,
Targeting N-myristoyl transferase-1 in cancer using peptide microarrays, Journal of Peptide Science, Vol: 18, Pages: S75-S75, ISSN: 1099-1387
Conference paperKonitsiotis A, Chang S, Masumoto N, et al., 2012,
Hhat a Potential New Target in Treatment of Pancreatic Cancer, 22nd Biennial Congress of the European-Association-for-Cancer-Research, Publisher: ELSEVIER SCI LTD, Pages: S149-S149, ISSN: 0959-8049
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