Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ

Type
III phosphatidylinositol 4-kinase (PI4KIIIβ) 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 PI4KIIIβ.
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)
PI4KIIIβ inhibitors. These compounds showed antiviral activity
against hepatitis C virus. The co-crystal structure of PI4KIIIβ
bound to one of the most potent compounds reveals the molecular basis
of specificity. This work will be vital in the design of novel PI4KIIIβ
inhibitors, which may play significant roles as antiviral therapeutics.