TY - JOUR
T1 - Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
AU - Mousnier, Aurelie
AU - Bell, Andrew S.
AU - Swieboda, Dawid P.
AU - Morales-Sanfrutos, Julia
AU - Pérez-Dorado, Inmaculada
AU - Brannigan, James A.
AU - Newman, Joseph
AU - Ritzefeld, Markus
AU - Hutton, Jennie A.
AU - Guedán, Anabel
AU - Asfor, Amin S.
AU - Robinson, Sean W.
AU - Hopkins-Navratilova, Iva
AU - Wilkinson, Anthony J.
AU - Johnston, Sebastian L.
AU - Leatherbarrow, Robin J.
AU - Tuthill, Tobias J.
AU - Solari, Roberto
AU - Tate, Edward W.
PY - 2018/5/14
Y1 - 2018/5/14
N2 - 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.
AB - 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.
U2 - 10.1038/s41557-018-0039-2
DO - 10.1038/s41557-018-0039-2
M3 - Article
SN - 1755-4330
VL - 10
SP - 599
EP - 606
JO - Nature chemistry
JF - Nature chemistry
IS - 6
ER -