biostudies-literatureMousnier ACancer Research UKMedical Research CouncilBiotechnology and Biological Sciences Research Council599-606https://www.ebi.ac.uk/biostudies/studies/S-EPMC6015761biostudies-literatureUnknown10(6)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-encoNature chemistryFragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.PMC6015761MC_PC_1410020183BBS/E/I/00007034G1000758G1100238G0900278Brannigan JAJohnston SLTuthill TJHopkins-Navratilova INewman JMousnier AAsfor ASSwieboda DPGuedan ALeatherbarrow RJSolari RTate EWBell ASHutton JAPerez-Dorado IMorales-Sanfrutos JWilkinson AJRitzefeld MRobinson SWfalseFragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.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-enco2018-01-01T00:00:00Z2018 Jun2026-05-04T07:50:49.737Z2019-03-27T00:07:03ZS-EPMC60157612976041410.1038/s41557-018-0039-2