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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: 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: Medical Research Council (MRC)
Wellcome Trust
Asthma UK
Medical Research Council (MRC)
GlaxoSmithKline Services Unlimited
Asthma UK
Wellcome Trust
Asthma UK
Asthma UK
Cancer Research UK
Funder's Grant Number: G0900278
105603/Z/14/Z
MRFAUK-2015-311
G1100238
n/a
Asthma UK Centre
087792/B/08/Z
CH11SJ
CH11SJ
20183
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
CYSTIC-FIBROSIS
MYRISTOYLATION
PROTEOMICS
INFECTION
PREVENTS
ASTHMA
CELLS
Acyltransferases
Antiviral Agents
Capsid
Enzyme Inhibitors
HeLa Cells
Humans
Inhibitory Concentration 50
Molecular Structure
Rhinovirus
Virus Assembly
Virus Replication
Hela Cells
Humans
Rhinovirus
Capsid
Acyltransferases
Enzyme Inhibitors
Antiviral Agents
Inhibitory Concentration 50
Virus Replication
Virus Assembly
Molecular Structure
Organic Chemistry
03 Chemical Sciences
Publication Status: Published
Online Publication Date: 2018-05-14
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
National Heart and Lung Institute
Faculty of Medicine
Faculty of Natural Sciences