Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase III?.

ABSTRACT: Type III phosphatidylinositol 4-kinase (PI4KIII?) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIII?. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIII? inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIII? bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIII? inhibitors, which may play significant roles as antiviral therapeutics.

SUBMITTER: Rutaganira FU 

PROVIDER: S-EPMC5289284 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature