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

DOI: 10.1038/s41557-018-0039-2 DOI Help

Authors: Aurélie Mousnier (Imperial College London; Queen’s University Belfast) , Andrew S. Bell (Imperial College London) , Dawid P. Swieboda (Imperial College London) , Julia Morales-sanfrutos (Imperial College London) , Inmaculada Perez-dorado (Imperial College London) , James A. Brannigan (University of York) , Joseph Newman (The Pirbright Institute) , Markus Ritzefeld (Imperial College London) , Jennie A. Hutton (Imperial College London) , Anabel Guedán (Imperial College London) , Amin S. Asfor (The Pirbright Institute) , Sean W. Robinson (Kinetic Discovery Limited) , Iva Hopkins-navratilova (Kinetic Discovery Limited) , Anthony J. Wilkinson (University of York) , Sebastian L. Johnston (Imperial College London) , Robin J. Leatherbarrow (Imperial College London) , Tobias J. Tuthill (The Pirbright Institute) , Roberto Solari (Imperial College London) , Edward W. Tate (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemistry , VOL 10 , PAGES 599 - 606

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 12579 , 7864 , 9948

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.

Journal Keywords: Chemical tools; Post-translational modifications; Small molecules; Target validation; Virology

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography