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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
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SYSNO ASEP 0519161 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations Author(s) Novotná, Barbora (UOCHB-X) ORCID
Vaneková, Lenka (UOCHB-X) ORCID
Zavřel, Martin (UOCHB-X) ORCID
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Dejmek, Milan (UOCHB-X) RID, ORCID
Smola, Miroslav (UOCHB-X) ORCID
Gutten, Ondrej (UOCHB-X) RID, ORCID
Tehrani, Zahra Aliakbar (UOCHB-X) ORCID
Pimková Polidarová, Markéta (UOCHB-X) ORCID
Brázdová, Andrea (UOCHB-X) ORCID
Liboska, Radek (UOCHB-X) RID, ORCID
Štěpánek, Ivan (UOCHB-X)
Vavřina, Zdeněk (UOCHB-X) ORCID
Jandušík, Tomáš (UOCHB-X) ORCID
Nencka, Radim (UOCHB-X) RID, ORCID
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Brynda, Jiří (UOCHB-X) RID, ORCID
Páv, Ondřej (UOCHB-X) RID, ORCID
Birkuš, Gabriel (UOCHB-X) ORCIDSource Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 62, č. 23 (2019), s. 10676-10690Number of pages 15 s. Language eng - English Country US - United States Keywords cyclic GMP-AMP ; cytosolic DNA sensor ; di-GMP Subject RIV CC - Organic Chemistry OECD category Organic chemistry R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA20-08772S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000503114200012 EID SCOPUS 85076397575 DOI 10.1021/acs.jmedchem.9b01062 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2020 Electronic address https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01062
Number of the records: 1