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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&apos;-5&apos;,3&apos;-5&apos;-cyclic dinucleotides (2&apos;3&apos;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&apos;-triphosphate (NTP) analogues and use them to prepare 33 2&apos;3&apos;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

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • 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