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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-06

AUTHORS

Aurélie Mousnier, Andrew S. Bell, Dawid P. Swieboda, Julia Morales-Sanfrutos, Inmaculada Pérez-Dorado, James A. Brannigan, Joseph Newman, Markus Ritzefeld, Jennie A. Hutton, Anabel Guedán, Amin S. Asfor, Sean W. Robinson, Iva Hopkins-Navratilova, Anthony J. Wilkinson, Sebastian L. Johnston, Robin J. Leatherbarrow, Tobias J. Tuthill, Roberto Solari, Edward W. Tate

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. More... »

PAGES

599-606

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41557-018-0039-2

DOI

http://dx.doi.org/10.1038/s41557-018-0039-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103971114

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29760414


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Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41557-018-0039-2'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41557-018-0039-2'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41557-018-0039-2'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41557-018-0039-2'


 

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311 School of Life Sciences, University of Dundee, Dundee, UK
312 rdf:type schema:Organization
 




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