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.

Department of Chemistry of Natural Compounds Institute of Chemical Technology Prague Technická 5 Prague 166 28 Czech Republic

Gilead Sciences Inc 333 Lakeside Drive Foster City California 94404 United States

Institute of Medical Virology Justus Liebig University Giessen Schubertstrasse 81 D 35392 Giessen Germany

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Gilead Sciences and IOCB Research Centre Flemingovo nám 2 166 10 Prague 6 Czech Republic

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