By the same authors

From the same journal

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

Research output: Contribution to journalArticle

Author(s)

  • 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
  • Edward W. Tate

Department/unit(s)

Publication details

JournalNature Chemistry
DateAccepted/In press - 1 Mar 2018
DateE-pub ahead of print - 14 May 2018
DatePublished (current) - 1 Jun 2018
Issue number6
Volume10
Number of pages8
Pages (from-to)599-606
Early online date14/05/18
Original languageEnglish

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.

Bibliographical note

© 2018 Macmillan Publishers Limited, part of Springer Nature. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

Discover related content

Find related publications, people, projects, datasets and more using interactive charts.

View graph of relations