Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

  • Nat Chem. 2018 Jun;10(6):599-606. doi: 10.1038/s41557-018-0039-2.
Aurélie Mousnier  1  2 ,  Andrew S Bell  3 ,  Dawid P Swieboda  1 ,  Julia Morales-Sanfrutos  3 ,  Inmaculada Pérez-Dorado  3  4 ,  James A Brannigan  5 ,  Joseph Newman  6 ,  Markus Ritzefeld  3 ,  Jennie A Hutton  3 ,  Anabel Guedán  1 ,  Amin S Asfor  6 ,  Sean W Robinson  7 ,  Iva Hopkins-Navratilova  7  8 ,  Anthony J Wilkinson  5 ,  Sebastian L Johnston  1 ,  Robin J Leatherbarrow  3  9 ,  Tobias J Tuthill  6 ,  Roberto Solari  10 ,  Edward W Tate  11
Affiliations
  • 1. National Heart & Lung Institute, Imperial College London, London, UK.
  • 2. Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
  • 3. Department of Chemistry, Imperial College London, London, UK.
  • 4. Department of Life Sciences, Imperial College London, London, UK.
  • 5. Structural Biology Laboratory, Department of Chemistry, University of York, York, UK.
  • 6. The Pirbright Institute, Woking, UK.
  • 7. Kinetic Discovery Limited, Dundee, UK.
  • 8. School of Life Sciences, University of Dundee, Dundee, UK.
  • 9. Liverpool John Moores University, Liverpool, UK.
  • 10. National Heart & Lung Institute, Imperial College London, London, UK. [email protected].
  • 11. Department of Chemistry, Imperial College London, London, UK. [email protected].
PMID: 29760414 DOI: 10.1038/s41557-018-0039-2
Abstract

Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar Antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

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