5mu6
Human N-myristoyltransferase (NMT1) with Myristoyl-CoA and IMP-1088 inhibitor bound
Structural highlights
FunctionNMT1_HUMAN Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. Publication Abstract from PubMedRhinoviruses (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. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.,Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW Nat Chem. 2018 May 14. pii: 10.1038/s41557-018-0039-2. doi:, 10.1038/s41557-018-0039-2. PMID:29760414[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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