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

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• 作者：Ivana Mejdrová ; Dominika Chalupská ; Pavla Plačková ; Christin Müller ; Michal Šála ; Martin Klíma ; Adriana Baumlová ; Hubert Hřebabecký ; Eliška Procházková ; Milan Dejmek ; Dmytro Strunin ; Jan Weber ; Gary Lee ; Marika Matoušová ; Helena Mertlíková-Kaiserová ; John Ziebuhr ; Gabriel Birkus ; Evzen BouraRadim Nencka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：100-118
• 全文大小：979K
• ISSN：1520-4804

文摘

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.