Enzymatic Preparation of 2 '-5 ',3 '-5 '-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations.
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22330%2F19%3A43920393" target="_blank" >RIV/60461373:22330/19:43920393 - isvavai.cz</a>
Alternative codes found
RIV/61388963:_____/19:00519161 RIV/00216208:11310/19:10404802
Result on the web
<a href="https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.9b01062" target="_blank" >https://pubs.acs.org/doi/pdf/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>
Alternative languages
Result language
angličtina
Original language name
Enzymatic Preparation of 2 '-5 ',3 '-5 '-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations.
Original language description
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-kappa B (I kappa B) kinase (IKK)/nuclear factor-kappa B (NF kappa B) 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.
Czech name
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Czech description
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Classification
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
Result continuities
Project
—
Continuities
S - Specificky vyzkum na vysokych skolach
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
—
Volume of the periodical
62
Issue of the periodical within the volume
23
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
10676-10690
UT code for WoS article
000503114200012
EID of the result in the Scopus database
2-s2.0-85076397575