2. Academic Validation
  3. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

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

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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