Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

Novotná, Barbora; Vaneková, Lenka; Zavřel, Martin; Buděšínský, Miloš; Dejmek, Milan; Smola, Miroslav; Gutten, Ondrej; Tehrani, Zahra Aliakbar; Pimková Polidarová, Markéta; Brázdová, Andrea; Liboska, Radek; Štěpánek, Ivan; Vavřina, Zdeněk; Jandušík, Tomáš; Nencka, Radim; Rulíšek, Lubomír; Bouřa, Evžen; Brynda, Jiří; Páv, Ondřej; Birkuš, Gabriel

doi:https://dx.doi.org/10.1021/acs.jmedchem.9b01062

Počet záznamů: 1

Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

1.

SYSNO ASEP	0519161
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Enzymatic Preparation of 2′–5′,3′–5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations
Tvůrce(i)	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)_ORCID
Zdroj.dok.	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 62, č. 23 (2019), s. 10676-10690
Poč.str.	15 s.
Jazyk dok.	eng - angličtina
Země vyd.	US - Spojené státy americké
Klíč. slova	cyclic GMP-AMP ; cytosolic DNA sensor ; di-GMP
Vědní obor RIV	CC - Organická chemie
Obor OECD	Organic chemistry
CEP	EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
	GA20-08772S GA ČR - Grantová agentura ČR
Způsob publikování	Omezený přístup
Institucionální podpora	UOCHB-X - RVO:61388963
UT WOS	000503114200012
EID SCOPUS	85076397575
DOI	10.1021/acs.jmedchem.9b01062
Anotace	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.
Pracoviště	Ústav organické chemie a biochemie
Kontakt	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418
Rok sběru	2020
Elektronická adresa	https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01062

Počet záznamů: 1