Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.

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

SUBMITTER: Mousnier A 

PROVIDER: S-EPMC6015761 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature