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

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]; ^[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)

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)

OSTI ID:: 1544855

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

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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

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