Mejdrová Ivana, Chalupská Dominika, Kögler Martin, Šála Michal, Plačková Pavla, Baumlová Adriana, Hřebabecký Hubert, Procházková Eliška, Dejmek Milan, Guillon Rémi, Strunin Dmytro, Weber Jan, Lee Gary, Birkus Gabriel, Mertlíková-Kaiserová Helena, Boura Evzen, Nencka Radim
‡Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
J Med Chem. 2015 May 14;58(9):3767-93. doi: 10.1021/acs.jmedchem.5b00499. Epub 2015 May 4.
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.
磷脂酰肌醇4-激酶IIIβ是一种细胞脂质激酶，对多种RNA病毒的发病机制至关重要。这些病毒劫持该酶以改变细胞内膜的结构，并利用它们构建功能性复制机制。该酶的选择性抑制剂是潜在的广谱抗病毒药物，因为抑制该酶会导致PI4K IIIβ依赖性病毒的复制停滞。在此，我们报告了对PI4K IIIβ新型选择性抑制剂的详细研究，这些抑制剂对一组单链正义RNA病毒具有抗病毒活性。我们的晶体学数据表明，这些抑制剂占据了ATP分子腺嘌呤环的结合位点，从而阻止了磷酸化反应。
