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

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Title: Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
Authors: Mousnier, A
Bell, AS
Swieboda, DP
Morales-Sanfrutos, J
Pérez-Dorado, I
Brannigan, JA
Newman, J
Ritzefeld, M
Hutton, JA
Guedán, A
Asfor, AA
Robinson, SW
Hopkins-Navratilova, I
Wilkinson, AJ
Johnston, SL
Leatherbarrow, RJ
Tuthill, TJ
Solari, R
Tate, EW
Item Type: Journal Article
Abstract: Rhinoviruses 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 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. 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 co- translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, delivering low nanomolar antiviral activity against multiple rhinovirus 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.
Issue Date: 14-May-2018
Date of Acceptance: 1-Mar-2018
URI: http://hdl.handle.net/10044/1/58378
DOI: https://dx.doi.org/10.1038/s41557-018-0039-2
ISSN: 1755-4330
Publisher: Nature Publishing Group
Start Page: 599
End Page: 606
Journal / Book Title: Nature Chemistry
Volume: 10
Copyright Statement: © 2018 Springer Nature Limited. All rights reserved.
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
GlaxoSmithKline Services Unlimited
Wellcome Trust
Asthma UK
Asthma UK
Funder's Grant Number: 087792/B/08/Z
G0900278
G1100238
n/a
105603/Z/14/Z
MRFAUK-2015-311
Asthma UK Centre
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
CYSTIC-FIBROSIS
MYRISTOYLATION
PROTEOMICS
INFECTION
PREVENTS
ASTHMA
CELLS
03 Chemical Sciences
Organic Chemistry
Publication Status: Published
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
National Heart and Lung Institute
Faculty of Medicine
Faculty of Natural Sciences



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