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
Identifikátory výsledku
Kód výsledku v 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>
Nalezeny alternativní kódy
RIV/60461373:22330/17:43913342
Výsledek na webu
<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>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
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
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
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
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10401 - Organic chemistry
Návaznosti výsledku
Projekt
<a href="/cs/project/GA15-09310S" target="_blank" >GA15-09310S: Racionální design inhibitorů fosfatidylinositol 4-kinasy IIalfa jako nástrojů pro chemickou biologii a potenciální terapeutika</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2017
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
—
Svazek periodika
60
Číslo periodika v rámci svazku
1
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
19
Strana od-do
100-118
Kód UT WoS článku
000392035100006
EID výsledku v databázi Scopus
2-s2.0-85018504368