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

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

doi:10.1038/nchem.1830

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

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

Biosciences

Research output: Contribution to journal › Article › peer-review

165 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	112-121
Number of pages	10
Journal	Nature Chemistry
Volume	6
Issue number	2
DOIs	https://doi.org/10.1038/nchem.1830
Publication status	Published - Feb 2014

Bibliographical note

Funding Information:
The authors thank the staff at the Diamond Light Source (Harwell, UK) for assistance with crystallography, and S. Roberts for crystal handling. The authors also thank L. Haigh for assistance with mass spectrometry and P. Bowyer and members of the Tate group for critical reading of the manuscript. The authors thank P. Wyatt for helpful discussions. This work was supported by grants from the Institute of Chemical Biology (Imperial College London), the UK Engineering and Physical Sciences Research Council (Studentship awards and Doctoral Prize Fellowship awards to M.H.W. and M.D.R., grants EP/F500416/1 and EP/K039946/1), the UK Medical Research Council (grants G0900278, MR/K011782/1 and U117532067), European Commission FP7 (2007–2013) (grant 242095), the German Research Foundation (DFG, grant BR 4387/1-1) and the UK Biotechnology and Biological Sciences Research Council (grant BB/D02014X/1).

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wright, M. H., Clough, B., Rackham, M. D., Rangachari, K., Brannigan, J. A., Grainger, M., Moss, D. K., Bottrill, A. R., Heal, W. P., Broncel, M., Serwa, R. A., Brady, D., Mann, D. J., Leatherbarrow, R. J., Tewari, R., Wilkinson, A. J., Holder, A. A., & Tate, E. W. (2014). Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach. Nature Chemistry, 6(2), 112-121. https://doi.org/10.1038/nchem.1830

@article{f31b9895dc774af282bc1a7d55ae89c3,

title = "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 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.",

author = "Wright, {Megan H.} and Barbara Clough and Rackham, {Mark D.} and Kaveri Rangachari and Brannigan, {James A.} and Munira Grainger and Moss, {David K.} and Bottrill, {Andrew R.} and Heal, {William P.} and Malgorzata Broncel and Serwa, {Remigiusz A.} and Declan Brady and Mann, {David J.} and Leatherbarrow, {Robin J.} and Rita Tewari and Wilkinson, {Anthony J.} and Holder, {Anthony A.} and Tate, {Edward W.}",

note = "Funding Information: The authors thank the staff at the Diamond Light Source (Harwell, UK) for assistance with crystallography, and S. Roberts for crystal handling. The authors also thank L. Haigh for assistance with mass spectrometry and P. Bowyer and members of the Tate group for critical reading of the manuscript. The authors thank P. Wyatt for helpful discussions. This work was supported by grants from the Institute of Chemical Biology (Imperial College London), the UK Engineering and Physical Sciences Research Council (Studentship awards and Doctoral Prize Fellowship awards to M.H.W. and M.D.R., grants EP/F500416/1 and EP/K039946/1), the UK Medical Research Council (grants G0900278, MR/K011782/1 and U117532067), European Commission FP7 (2007–2013) (grant 242095), the German Research Foundation (DFG, grant BR 4387/1-1) and the UK Biotechnology and Biological Sciences Research Council (grant BB/D02014X/1).",

year = "2014",

month = feb,

doi = "10.1038/nchem.1830",

language = "English",

volume = "6",

pages = "112--121",

journal = "Nature Chemistry",

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Wright, MH, Clough, B, Rackham, MD, Rangachari, K, Brannigan, JA, Grainger, M, Moss, DK, Bottrill, AR, Heal, WP, Broncel, M, Serwa, RA, Brady, D, Mann, DJ, Leatherbarrow, RJ, Tewari, R, Wilkinson, AJ, Holder, AA & Tate, EW 2014, 'Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach', Nature Chemistry, vol. 6, no. 2, pp. 112-121. https://doi.org/10.1038/nchem.1830

TY - JOUR

T1 - Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

AU - Wright, Megan H.

AU - Clough, Barbara

AU - Rackham, Mark D.

AU - Rangachari, Kaveri

AU - Brannigan, James A.

AU - Grainger, Munira

AU - Moss, David K.

AU - Bottrill, Andrew R.

AU - Heal, William P.

AU - Broncel, Malgorzata

AU - Serwa, Remigiusz A.

AU - Brady, Declan

AU - Mann, David J.

AU - Leatherbarrow, Robin J.

AU - Tewari, Rita

AU - Wilkinson, Anthony J.

AU - Holder, Anthony A.

AU - Tate, Edward W.

N1 - Funding Information: The authors thank the staff at the Diamond Light Source (Harwell, UK) for assistance with crystallography, and S. Roberts for crystal handling. The authors also thank L. Haigh for assistance with mass spectrometry and P. Bowyer and members of the Tate group for critical reading of the manuscript. The authors thank P. Wyatt for helpful discussions. This work was supported by grants from the Institute of Chemical Biology (Imperial College London), the UK Engineering and Physical Sciences Research Council (Studentship awards and Doctoral Prize Fellowship awards to M.H.W. and M.D.R., grants EP/F500416/1 and EP/K039946/1), the UK Medical Research Council (grants G0900278, MR/K011782/1 and U117532067), European Commission FP7 (2007–2013) (grant 242095), the German Research Foundation (DFG, grant BR 4387/1-1) and the UK Biotechnology and Biological Sciences Research Council (grant BB/D02014X/1).

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

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U2 - 10.1038/nchem.1830

DO - 10.1038/nchem.1830

M3 - Article

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AN - SCOPUS:84892956192

SN - 1755-4330

VL - 6

SP - 112

EP - 121

JO - Nature Chemistry

JF - Nature Chemistry

IS - 2

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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