Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Chem ; 10(6): 599-606, 2018 06.
Article in English | MEDLINE | ID: mdl-29760414

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-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.


Subject(s)
Acyltransferases/antagonists & inhibitors , Antiviral Agents/pharmacology , Capsid/drug effects , Enzyme Inhibitors/pharmacology , Rhinovirus/drug effects , Virus Assembly/drug effects , Virus Replication/drug effects , Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , HeLa Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Rhinovirus/enzymology , Rhinovirus/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...