{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mousnier A"],"funding":["Cancer Research UK","Medical Research Council","Biotechnology and Biological Sciences Research Council"],"pagination":["599-606"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6015761"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(6)"],"pubmed_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-enco"],"journal":["Nature chemistry"],"pubmed_title":["Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus."],"pmcid":["PMC6015761"],"funding_grant_id":["MC_PC_14100","20183","BBS/E/I/00007034","G1000758","G1100238","G0900278"],"pubmed_authors":["Brannigan JA","Johnston SL","Tuthill TJ","Hopkins-Navratilova I","Newman J","Mousnier A","Asfor AS","Swieboda DP","Guedan A","Leatherbarrow RJ","Solari R","Tate EW","Bell AS","Hutton JA","Perez-Dorado I","Morales-Sanfrutos J","Wilkinson AJ","Ritzefeld M","Robinson SW"],"additional_accession":[]},"is_claimable":false,"name":"Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.","description":"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-enco","dates":{"release":"2018-01-01T00:00:00Z","publication":"2018 Jun","modification":"2026-05-04T07:50:49.737Z","creation":"2019-03-27T00:07:03Z"},"accession":"S-EPMC6015761","cross_references":{"pubmed":["29760414"],"doi":["10.1038/s41557-018-0039-2"]}}