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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00474385" target="_blank" >RIV/61388963:_____/17:00474385 - isvavai.cz</a>
Alternative codes found
RIV/60461373:22330/17:43913342
Result on the web
<a href="http://dx.doi.org/10.1021/acs.jmedchem.6b01465" target="_blank" >http://dx.doi.org/10.1021/acs.jmedchem.6b01465</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.6b01465" target="_blank" >10.1021/acs.jmedchem.6b01465</a>

Result language
angličtina
Original language name
Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase III beta (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology
Original language description
Phosphatidylinositol 4-kinase III beta (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.
Czech name
—
Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/GA15-09310S" target="_blank" >GA15-09310S: Rational design of phosphatidylinositol 4-kinase IIalpha inhibitors as tools for chemical biology and potential therapeutics</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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