110
IRUS TotalDownloads
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
File | Description | Size | Format | |
---|---|---|---|---|
![]() | Accepted version | 4.7 MB | Adobe PDF | View/Open |
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 |