Highly Selective Phosphatidylinositol 4-Kinase IIIβ Inhibitors and Structural Insight into Their Mode of Action

Abstract

Phosphatidylinositol 4-kinase IIIβ is a cellular lipid kinase pivotal to pathogenesis of various RNA viruses. These viruses hijack the enzyme in order to modify the structure of intracellular membranes and use them for the construction of functional replication machinery. Selective inhibitors of this enzyme are potential broad-spectrum antiviral agents, as inhibition of this enzyme results in the arrest of replication of PI4K IIIβ-dependent viruses. Herein, we report a detailed study of novel selective inhibitors of PI4K IIIβ, which exert antiviral activity against a panel of single-stranded positive-sense RNA viruses. Our crystallographic data show that the inhibitors occupy the binding site for the adenine ring of the ATP molecule and therefore prevent the phosphorylation reaction.

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

“…Enviroxime itself was also proven to inhibit PI4K class III enzymes although with rather low selectivity [89]. Recently, we have prepared compounds based on T-00127-HEV1 with excellent selectivity for PI4K IIIβ (three orders of magnitude difference in IC 50 values comparing PI4K IIIβ and PI4K IIIα) [148] and our structural analysis revealed that the inhibitors occupy the binding site for the ATP adenine ring [148].…”

Phosphatidylinositol 4-Kinase Enzymes: Functional Roles and Potential for Drug Target

“…The activity of PI4KIIα can be determined by measuring ADP generation using an ADP-Glo kinase kit (Promega, USA) as previously described [17]. Briefly, 1 μg protein in a kinase buffer containing 20 mM Tris, pH 7.5, 150 mM NaCl, 0.2% Triton X-100 (or 0.1% Anzergent), 1 mM EDTA and 20 mM MgCl 2 was used in this assay.…”

Isothiazolo[4,3-b]pyridines as inhibitors of cyclin G associated kinase: synthesis, structure–activity relationship studies and antiviral activity

“…Small molecule inhibitors of these enzymes have been synthesized and found to be endowed with potent activity against HCV. 15-16 Alpha-glucosidase I is another example of a host factor essential for HCV infection. Alpha-glucosidase I inhibitors, such as celgosivir, have been shown to inhibit replication of HCV as well as Dengue virus.…”