Structure-Guided Identification of Resistance Breaking Antimalarial N-Myristoyltransferase Inhibitors

Schlott, Anja C.; Mayclin, Stephen; Reers, Alexandra R.; Coburn-Flynn, Olivia; Bell, Andrew S.; Green, Judith; Knuepfer, Ellen; Charter, David; Bonnert, Roger; Campo, Brice; Burrows, Jeremy; Lyons-Abbott, Sally; Staker, Bart L.; Chung, Chun-Wa; Myler, Peter J.; Fidock, David A.; Tate, Edward W.; Holder, Anthony A.

doi:10.1016/j.chembiol.2019.03.015

Title: Structure-Guided Identification of Resistance Breaking Antimalarial N-Myristoyltransferase Inhibitors

Journal Article · Thu May 09 00:00:00 EDT 2019 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2019.03.015· OSTI ID:1544855

^[1];

^[2];

^[3]; Coburn-Flynn, Olivia ^[4];

^[5];

^[6];

^[6]; Charter, David ^[7];

^[8];

^[8]; Lyons-Abbott, Sally ^[9];

^[3];

^[10];

^[11];

^[4];

^[5];

^[6]

Francis Crick Inst., London (United Kingdom); Imperial College, London (United Kingdom)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); UCB Pharma, Bainbridge Island, WA (United States)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Seattle Children’s Research Inst., Seattle, WA (United States)
Columbia Univ. Medical Center, New York, NY (United States)
Imperial College, London (United Kingdom)
Francis Crick Inst., London (United Kingdom)
GlaxoSmithKline, Stevenage, Hertfordshire (United Kingdom)
Medicines for Malaria Venture, Geneva (Switzerland)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Seattle Children’s Research Inst., Seattle, WA (United States); Novo Nordisk Research Center, Seattle, WA (United States)
GlaxoSmithKline, Stevenage, Hertfordshire (United Kingdom); GSK Medicines Research Centre, Stevenage (United Kingdom). Crick–GSK Biomedical LinkLabs
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States); Seattle Children’s Research Inst., Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)

The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Cancer Research UK; UK Medical Research Council; Wellcome Trust; Medicines for Malaria Venture; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); US Department of Health and Human Services (HHS)

Grant/Contract Number:: HHSN272201700059C; 1R21AI137815-01

OSTI ID:: 1544855

Journal Information:: Cell Chemical Biology, Vol. 26, Issue 7; ISSN 2451-9456

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 15 works

Citation information provided by
Web of Science

References (51)

PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
A molecular marker of artemisinin-resistant Plasmodium falciparum malaria Ariey, Frédéric; Witkowski, Benoit; Amaratunga, Chanaki Nature, Vol. 505, Issue 7481 https://doi.org/10.1038/nature12876	journal	December 2013
Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs Bell, Andrew S.; Mills, James E.; Williams, Gareth P. PLoS Neglected Tropical Diseases, Vol. 6, Issue 4 https://doi.org/10.1371/journal.pntd.0001625	journal	April 2012
N-Myristoyltransferase from Leishmania donovani: Structural and Functional Characterisation of a Potential Drug Target for Visceral Leishmaniasis Brannigan, James A.; Smith, Barbara A.; Yu, Zhiyong Journal of Molecular Biology, Vol. 396, Issue 4 https://doi.org/10.1016/j.jmb.2009.12.032	journal	March 2010
Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics Cowell, Annie N.; Istvan, Eva S.; Lukens, Amanda K. Science, Vol. 359, Issue 6372 https://doi.org/10.1126/science.aan4472	journal	January 2018
N -Myristoyltransferase Is a Cell Wall Target in Aspergillus fumigatus Fang, Wenxia; Robinson, David A.; Raimi, Olawale G. ACS Chemical Biology, Vol. 10, Issue 6 https://doi.org/10.1021/cb5008647	journal	February 2015
Using Genetic Methods To Define the Targets of Compounds with Antimalarial Activity: Miniperspectives Series on Phenotypic Screening for Antiinfective Targets Flannery, Erika L.; Fidock, David A.; Winzeler, Elizabeth A. Journal of Medicinal Chemistry, Vol. 56, Issue 20 https://doi.org/10.1021/jm400325j	journal	September 2013
N-myristoyltransferase inhibitors as new leads to treat sleeping sickness Frearson, Julie A.; Brand, Stephen; McElroy, Stuart P. Nature, Vol. 464, Issue 7289 https://doi.org/10.1038/nature08893	journal	April 2010
Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum Gerold, Peter; Schofield, Louis; Blackman, Michael J. Molecular and Biochemical Parasitology, Vol. 75, Issue 2 https://doi.org/10.1016/0166-6851(95)02518-9	journal	January 1996
Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system Ghorbal, Mehdi; Gorman, Molly; Macpherson, Cameron Ross Nature Biotechnology, Vol. 32, Issue 8 https://doi.org/10.1038/nbt.2925	journal	June 2014
A fluorescence-based assay for N-myristoyltransferase activity Goncalves, Victor; Brannigan, James A.; Thinon, Emmanuelle Analytical Biochemistry, Vol. 421, Issue 1 https://doi.org/10.1016/j.ab.2011.10.013	journal	February 2012
Discovery of Plasmodium vivax N -Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode Goncalves, Victor; Brannigan, James A.; Whalley, David Journal of Medicinal Chemistry, Vol. 55, Issue 7 https://doi.org/10.1021/jm300040p	journal	March 2012
Molecular Identification of a Malaria Merozoite Surface Sheddase Harris, Philippa K.; Yeoh, Sharon; Dluzewski, Anton R. PLoS Pathogens, Vol. 1, Issue 3 https://doi.org/10.1371/journal.ppat.0010029	journal	November 2005
Multifunctional protein labeling via enzymatic N-terminal tagging and elaboration by click chemistry Heal, William P.; Wright, Megan H.; Thinon, Emmanuelle Nature Protocols, Vol. 7, Issue 1 https://doi.org/10.1038/nprot.2011.425	journal	December 2011
Structure-Based Design of Potent and Selective Leishmania N -Myristoyltransferase Inhibitors Hutton, Jennie A.; Goncalves, Victor; Brannigan, James A. Journal of Medicinal Chemistry, Vol. 57, Issue 20 https://doi.org/10.1021/jm5011397	journal	October 2014
Generating conditional gene knockouts in Plasmodium – a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9 Knuepfer, Ellen; Napiorkowska, Marta; van Ooij, Christiaan Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-03984-3	journal	June 2017
In Vitro Resistance Profile of the Hepatitis C Virus NS3 Protease Inhibitor BI 201335 Lagacé, Lisette; White, Peter W.; Bousquet, Christiane Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 1 https://doi.org/10.1128/AAC.05166-11	journal	January 2012
UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes Lim, Michelle Yi-Xiu; LaMonte, Gregory; Lee, Marcus C. S. Nature Microbiology, Vol. 1, Issue 12 https://doi.org/10.1038/nmicrobiol.2016.166	journal	September 2016
Flexible guide-RNA design for CRISPR applications using Protospacer Workbench MacPherson, Cameron Ross; Scherf, Artur Nature Biotechnology, Vol. 33, Issue 8 https://doi.org/10.1038/nbt.3291	journal	June 2015
Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes Moon, R. W.; Hall, J.; Rangkuti, F. Proceedings of the National Academy of Sciences, Vol. 110, Issue 2 https://doi.org/10.1073/pnas.1216457110	journal	December 2012
Peptidomimetic inhibitors of N -myristoyltransferase from human malaria and leishmaniasis parasites Olaleye, Tayo O.; Brannigan, James A.; Roberts, Shirley M. Org. Biomol. Chem., Vol. 12, Issue 41 https://doi.org/10.1039/C4OB01669F	journal	January 2014
The Actinomyosin Motor Drives Malaria Parasite Red Blood Cell Invasion but Not Egress Perrin, Abigail J.; Collins, Christine R.; Russell, Matthew R. G. mBio, Vol. 9, Issue 4 https://doi.org/10.1128/mBio.00905-18	journal	September 2018
Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N -Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP) Rackham, Mark D.; Brannigan, James A.; Rangachari, Kaveri Journal of Medicinal Chemistry, Vol. 57, Issue 6 https://doi.org/10.1021/jm500066b	journal	March 2014
Discovery of high affinity inhibitors of Leishmania donovani N-myristoyltransferase Rackham, Mark D.; Yu, Zhiyong; Brannigan, James A. MedChemComm, Vol. 6, Issue 10 https://doi.org/10.1039/C5MD00241A	journal	January 2015
Dual acylation of the 45kDa gliding-associated protein (GAP45) in Plasmodium falciparum merozoites Rees-Channer, Roxanne R.; Martin, Stephen R.; Green, Judith L. Molecular and Biochemical Parasitology, Vol. 149, Issue 1 https://doi.org/10.1016/j.molbiopara.2006.04.008	journal	September 2006
Cloning of naturally occurring mixed infections of malaria parasites Rosario, V. Science, Vol. 212, Issue 4498 https://doi.org/10.1126/science.7015505	journal	May 1981
N -Myristoylation as a Drug Target in Malaria: Exploring the Role of N -Myristoyltransferase Substrates in the Inhibitor Mode of Action Schlott, Anja C.; Holder, Anthony A.; Tate, Edward W. ACS Infectious Diseases, Vol. 4, Issue 4 https://doi.org/10.1021/acsinfecdis.7b00203	journal	January 2018
The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase Slaughter, Alison; Jurado, Kellie A.; Deng, Nanjie Retrovirology, Vol. 11, Issue 1 https://doi.org/10.1186/s12977-014-0100-1	journal	November 2014
Two Nonrecombining Sympatric Forms of the Human Malaria Parasite Plasmodium ovale Occur Globally Sutherland, Colin J.; Tanomsing, Naowarat; Nolder, Debbie The Journal of Infectious Diseases, Vol. 201, Issue 10 https://doi.org/10.1086/652240	journal	May 2010
N- Myristoyltransferase as a potential drug target in malaria and leishmaniasis Tate, Edward W.; Bell, Andrew S.; Rackham, Mark D. Parasitology, Vol. 141, Issue 1 https://doi.org/10.1017/S0031182013000450	journal	April 2013
Development and Application of a Simple Plaque Assay for the Human Malaria Parasite Plasmodium falciparum Thomas, James A.; Collins, Christine R.; Das, Sujaan PLOS ONE, Vol. 11, Issue 6 https://doi.org/10.1371/journal.pone.0157873	journal	June 2016
Human Malaria Parasites in Continuous Culture Trager, William; Jensen, James B. Journal of Parasitology, Vol. 91, Issue 3 https://doi.org/10.1645/0022-3395(2005)091[0484:HMPICC]2.0.CO;2	journal	June 2005
Efficient CRISPR-Cas9–mediated genome editing in Plasmodium falciparum Wagner, Jeffrey C.; Platt, Randall J.; Goldfless, Stephen J. Nature Methods, Vol. 11, Issue 9 https://doi.org/10.1038/nmeth.3063	journal	August 2014
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach Wright, Megan H.; Clough, Barbara; Rackham, Mark D. Nature Chemistry, Vol. 6, Issue 2 https://doi.org/10.1038/nchem.1830	journal	December 2013
Global Profiling and Inhibition of Protein Lipidation in Vector and Host Stages of the Sleeping Sickness Parasite Trypanosoma brucei Wright, Megan H.; Paape, Daniel; Price, Helen P. ACS Infectious Diseases, Vol. 2, Issue 6 https://doi.org/10.1021/acsinfecdis.6b00034	journal	May 2016
Global Analysis of Protein N-Myristoylation and Exploration of N-Myristoyltransferase as a Drug Target in the Neglected Human Pathogen Leishmania donovani Wright, Megan H.; Paape, Daniel; Storck, Elisabeth M. Chemistry & Biology, Vol. 22, Issue 3 https://doi.org/10.1016/j.chembiol.2015.01.003	journal	March 2015
Subcellular Discharge of a Serine Protease Mediates Release of Invasive Malaria Parasites from Host Erythrocytes Yeoh, Sharon; O'Donnell, Rebecca A.; Koussis, Konstantinos Cell, Vol. 131, Issue 6 https://doi.org/10.1016/j.cell.2007.10.049	journal	December 2007
Design and Synthesis of Inhibitors of Plasmodium falciparumN -Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery Yu, Zhiyong; Brannigan, James A.; Moss, David K. Journal of Medicinal Chemistry, Vol. 55, Issue 20 https://doi.org/10.1021/jm301160h	journal	September 2012
Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase Yu, Zhiyong; Brannigan, James A.; Rangachari, Kaveri MedChemComm, Vol. 6, Issue 10 https://doi.org/10.1039/C5MD00242G	journal	January 2015
The Exoneme Helps Malaria Parasites to Break out of Blood Cells Janse, Chris J.; Waters, Andrew P. Cell, Vol. 131, Issue 6 https://doi.org/10.1016/j.cell.2007.11.026	journal	December 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Integration, scaling, space-group assignment and post-refinement Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 133-144 https://doi.org/10.1107/s0907444909047374	journal	January 2010
Presenting your structures: the CCP 4 mg molecular-graphics software McNicholas, S.; Potterton, E.; Wilson, K. S. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/s0907444911007281	journal	March 2011
High-throughput protein production and purification at the Seattle Structural Genomics Center for Infectious Disease Bryan, Cassie M.; Bhandari, Janhavi; Napuli, Alberto J. Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9 https://doi.org/10.1107/s1744309111018367	journal	August 2011
Diverse modes of binding in structures of Leishmania major N -myristoyltransferase with selective inhibitors Brannigan, James A.; Roberts, Shirley M.; Bell, Andrew S. IUCrJ, Vol. 1, Issue 4 https://doi.org/10.1107/s2052252514013001	journal	June 2014
MoRDa , an automatic molecular replacement pipeline Vagin, Alexey; Lebedev, Andrey Acta Crystallographica Section A Foundations and Advances, Vol. 71, Issue a1 https://doi.org/10.1107/s2053273315099672	journal	August 2015
Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development Green, Judith L.; Moon, Robert W.; Whalley, David Antimicrobial Agents and Chemotherapy, Vol. 60, Issue 3 https://doi.org/10.1128/aac.01748-15	journal	March 2016
Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening Smilkstein, Martin; Sriwilaijaroen, Nongluk; Kelly, Jane Xu Antimicrobial Agents and Chemotherapy, Vol. 48, Issue 5 https://doi.org/10.1128/aac.48.5.1803-1806.2004	journal	May 2004
Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor Wu, Yan; Gao, Feng; Qi, Jianxun Journal of Virology, Vol. 90, Issue 23 https://doi.org/10.1128/jvi.01703-16	journal	December 2016
Efficient Editing of Malaria Parasite Genome Using the CRISPR/Cas9 System Zhang, C.; Xiao, B.; Jiang, Y. mBio, Vol. 5, Issue 4, Article No. e01414-14 https://doi.org/10.1128/mbio.01414-14	journal	July 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

Similar Records

Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development

Journal Article · Mon Sep 18 00:00:00 EDT 2023 · ACS Infectious Diseases · OSTI ID:1544855

Fenwick, Michael K.; Reers, Alexandra R.; Liu, Yi; +11 more

Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Journal Article · Fri Apr 29 00:00:00 EDT 2016 · Journal of Medicinal Chemistry · OSTI ID:1544855

Kokkonda, Sreekanth; Deng, Xiaoyi; White, Karen L.; +23 more

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Journal Article · Wed Mar 20 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1544855

Baragaña, Beatriz; Forte, Barbara; Choi, Ryan; +74 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
antimalarial target
crystal structure
drug resistance development
genetic manipulation
malaria
myristoylation
N-myristoyl
transferase
Plasmodium
post-translational modification
protein lipidation

Title: Structure-Guided Identification of Resistance Breaking Antimalarial N-Myristoyltransferase Inhibitors

Citation Formats

References (51)

Similar Records

Related Subjects