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

    Research output: Contribution to journalArticle

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    • Aurelie 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
    • Edward W. Tate

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    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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    Original languageEnglish
    Number of pages8
    Pages (from-to)599-606
    JournalNature chemistry
    Journal publication date14 May 2018
    Issue number6
    Volume10
    DOIs
    StatePublished - 14 May 2018

    ID: 150009602