Imperial College London
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Prof Ed Tate

Faculty of Natural Sciences, Department of Chemistry

GSK Chair in Chemical Biology
 
 
 
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Contact

 

+44 (0)20 7594 3752e.tate Website CV

 
 
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Assistant

 

Ms Agnes Lee +44 (0)20 7594 9852

 
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Location

 

301BMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Mousnier:2018:10.1038/s41557-018-0039-2,
author = {Mousnier, A and Bell, AS and Swieboda, DP and Morales-Sanfrutos, J and Pérez-Dorado, I and Brannigan, JA and Newman, J and Ritzefeld, M and Hutton, JA and Guedán, A and Asfor, AA and Robinson, SW and Hopkins-Navratilova, I and Wilkinson, AJ and Johnston, SL and Leatherbarrow, RJ and Tuthill, TJ and Solari, R and Tate, EW},
doi = {10.1038/s41557-018-0039-2},
journal = {Nature Chemistry},
pages = {599--606},
title = {Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus},
url = {http://dx.doi.org/10.1038/s41557-018-0039-2},
volume = {10},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Mousnier,A
AU  - Bell,AS
AU  - Swieboda,DP
AU  - Morales-Sanfrutos,J
AU  - Pérez-Dorado,I
AU  - Brannigan,JA
AU  - Newman,J
AU  - Ritzefeld,M
AU  - Hutton,JA
AU  - Guedán,A
AU  - Asfor,AA
AU  - Robinson,SW
AU  - Hopkins-Navratilova,I
AU  - Wilkinson,AJ
AU  - Johnston,SL
AU  - Leatherbarrow,RJ
AU  - Tuthill,TJ
AU  - Solari,R
AU  - Tate,EW
DO  - 10.1038/s41557-018-0039-2
EP  - 606
PY  - 2018///
SN  - 1755-4330
SP  - 599
TI  - Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
T2  - Nature Chemistry
UR  - http://dx.doi.org/10.1038/s41557-018-0039-2
UR  - https://www.nature.com/articles/s41557-018-0039-2
UR  - http://hdl.handle.net/10044/1/58378
VL  - 10
ER  -
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