2. Academic Validation
  3. Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors

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

  • Cell Chem Biol. 2019 Jul 18;26(7):991-1000.e7. doi: 10.1016/j.chembiol.2019.03.015.
Anja C Schlott 1,  Stephen Mayclin 2,  Alexandra R Reers 3,  Olivia Coburn-Flynn 4,  Andrew S Bell 5,  Judith Green 6,  Ellen Knuepfer 6,  David Charter 7,  Roger Bonnert 8,  Brice Campo 8,  Jeremy Burrows 8,  Sally Lyons-Abbott 3,  Bart L Staker 3,  Chun-Wa Chung 9,  Peter J Myler 10,  David A Fidock 11,  Edward W Tate 12,  Anthony A Holder 13
Affiliations

Affiliations

  • 1 Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Molecular Sciences Research Hub, Imperial College, White City Campus Wood Lane, London W12 0BZ, UK. Electronic address: [email protected].
  • 2 Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA; UCB Pharma, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
  • 3 Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, USA.
  • 4 Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032, USA.
  • 5 Molecular Sciences Research Hub, Imperial College, White City Campus Wood Lane, London W12 0BZ, UK.
  • 6 Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 7 Structural and Biophysical Sciences, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
  • 8 Medicines for Malaria Venture, Route de Pré-Bois 20, Post Box 1826, 1215 Geneva 15, Switzerland.
  • 9 Structural and Biophysical Sciences, GlaxoSmithKline, Stevenage, Hertfordshire, UK; Crick-GSK Biomedical LinkLabs, GSK Medicines Research Centre, Stevenage, UK.
  • 10 Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, USA; Department of Biomedical Informatics & Medical Education, University of Washington, Seattle, USA; Department of Global Health, University of Washington, Seattle, USA.
  • 11 Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 12 Molecular Sciences Research Hub, Imperial College, White City Campus Wood Lane, London W12 0BZ, UK. Electronic address: [email protected].
  • 13 Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: [email protected].
PMID: 31080074 DOI: 10.1016/j.chembiol.2019.03.015
Abstract

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.

Keywords

N-myristoyltransferase; Plasmodium; antimalarial target; crystal structure; drug resistance development; genetic manipulation; malaria; myristoylation; post-translational modification; protein lipidation.

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