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

Aurélie Mousnier, Andrew S. Bell, Dawid P. Swieboda, Julia Morales-Sanfrutos, Inmaculada Pérez-Dorado, James A. Brannigan, Joseph Newman, Markus Ritzefeld, Jennie A. Hutton, Anabel Guedán, Amin S. Asfor, Sean W. Robinson, Iva Hopkins-Navratilova, Anthony J. Wilkinson, Sebastian L. Johnston, Robin J. Leatherbarrow, Tobias J. Tuthill, Roberto Solari (Lead / Corresponding author), Edward W. Tate (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)599-606
Number of pages8
JournalNature Chemistry
Volume10
Issue number6
Early online date14 May 2018
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Chemical tools
  • Post-translational modifications
  • Small molecules
  • Target validation
  • Virology

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    Mousnier, A., Bell, A. S., Swieboda, D. P., Morales-Sanfrutos, J., Pérez-Dorado, I., Brannigan, J. A., Newman, J., Ritzefeld, M., Hutton, J. A., Guedán, A., Asfor, A. S., Robinson, S. W., Hopkins-Navratilova, I., Wilkinson, A. J., Johnston, S. L., Leatherbarrow, R. J., Tuthill, T. J., Solari, R., & Tate, E. W. (2018). Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. Nature Chemistry, 10(6), 599-606. https://doi.org/10.1038/s41557-018-0039-2