Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4‑Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology

Phosphatidylinositol
4-kinase IIIβ (PI4KB) is indispensable for the replication of
various positive-sense single stranded RNA viruses, which hijack this
cellular enzyme to remodel intracellular membranes of infected cells
to set up the functional replication machinery. Therefore, the inhibition
of this PI4K isoform leads to the arrest of viral replication. Here,
we report on the synthesis of novel PI4KB inhibitors, which were rationally
designed based on two distinct structural types of inhibitors that
bind in the ATP binding side of PI4KB. These “hybrids”
not only excel in outstanding inhibitory activity but also show high
selectivity to PI4KB compared to other kinases. Thus, these compounds
exert selective nanomolar or even subnanomolar activity against PI4KB
as well as profound antiviral effect against hepatitis C virus, human
rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled
the exact position of the side chains and explains their extensive
contribution to the inhibitory activity.