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}
}
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 -