Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
File(s)
Author(s)
Mousnier, Aurélie
Bell, Andrew S
Swieboda, Dawid P
Morales-Sanfrutos, Julia
Pérez-Dorado, Inmaculada
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.
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.
Date Issued
2018-05-14
Date Acceptance
2018-03-01
Citation
Nature Chemistry, 2018, 10, pp.599-606
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
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
Identifier
https://www.nature.com/articles/s41557-018-0039-2
Grant Number
G0900278
105603/Z/14/Z
MRFAUK-2015-311
G1100238
n/a
Asthma UK Centre
087792/B/08/Z
CH11SJ
CH11SJ
20183
Subjects
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
Date Publish Online
2018-05-14