Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00519161" target="_blank" >RIV/61388963:_____/19:00519161 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00216208:11310/19:10404802 RIV/60461373:22330/19:43920393
Výsledek na webu
<a href="https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01062" target="_blank" >https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01062</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.9b01062" target="_blank" >10.1021/acs.jmedchem.9b01062</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
Popis výsledku v původním jazyce
Cyclic dinucleotides are second messengers in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB (IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling cascades. In this work, we describe an enzymatic preparation of 2′-5′,3′-5′-cyclic dinucleotides (2′3′CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse, and chicken. We profile substrate specificity of these enzymes by employing a small library of nucleotide-5′-triphosphate (NTP) analogues and use them to prepare 33 2′3′CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokine and chemokine induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure-activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.
Název v anglickém jazyce
Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
Popis výsledku anglicky
Cyclic dinucleotides are second messengers in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB (IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling cascades. In this work, we describe an enzymatic preparation of 2′-5′,3′-5′-cyclic dinucleotides (2′3′CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse, and chicken. We profile substrate specificity of these enzymes by employing a small library of nucleotide-5′-triphosphate (NTP) analogues and use them to prepare 33 2′3′CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokine and chemokine induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure-activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.
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
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2019
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
62
Číslo periodika v rámci svazku
23
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
15
Strana od-do
10676-10690
Kód UT WoS článku
000503114200012
EID výsledku v databázi Scopus
2-s2.0-85076397575