Journal
NATURE CHEMISTRY
Volume 10, Issue 6, Pages 599-606Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41557-018-0039-2
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Funding
- Medical Research Council (MRC) of the UK [G0900278, MC-PC-14100]
- EPSRC [EP/F500416/1]
- Cancer Research UK [C29637/A20183]
- MRC Asthma UK Centre in Allergic Mechanisms of Asthma [G1000758]
- Imperial Innovations
- MRF/Asthma UK [MRFAUK-2015-311]
- Asthma UK [CH11SJ]
- Biotechnology and Biological Research Council of the UK
- BBSRC [BBS/E/I/00007034] Funding Source: UKRI
- MRC [G1100238, G0900278] Funding Source: UKRI
- Asthma UK [CH11SJ] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/I/00007034] Funding Source: researchfish
- Cancer Research UK [20183] Funding Source: researchfish
- Medical Research Council [G0900278, G1100238] Funding Source: researchfish
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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.
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