Počet záznamů: 1
Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists
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SYSNO ASEP 0563157 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists Tvůrce(i) Vavřina, Zdeněk (UOCHB-X) ORCID
Perlíková, Pavla (UOCHB-X) RID, ORCID
Milisavljevič, Nemanja (UOCHB-X)
Chevrier, Florian (UOCHB-X)
Smola, Miroslav (UOCHB-X) ORCID
Smith, Joshua (UOCHB-X)
Dejmek, Milan (UOCHB-X) RID, ORCID
Havlíček, Vojtěch (UOCHB-X)
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Liboska, Radek (UOCHB-X) RID, ORCID
Vaneková, Lenka (UOCHB-X) ORCID
Brynda, Jiří (UOCHB-X) RID, ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Řezáčová, Pavlína (UOCHB-X) RID, ORCID
Hocek, Michal (UOCHB-X) RID, ORCID
Birkuš, Gabriel (UOCHB-X) ORCIDZdroj.dok. Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 65, č. 20 (2022), s. 14082-14103Poč.str. 22 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova GMP-AMP synthase ; interferon genes ; adapter protein Obor OECD Biochemistry and molecular biology CEP LX22NPO5102 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000875645400001 EID SCOPUS 85139868029 DOI 10.1021/acs.jmedchem.2c01305 Anotace Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMPAMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by SuzukiMiyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 23-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed ππ stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes. 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 2023 Elektronická adresa https://doi.org/10.1021/acs.jmedchem.2c01305
Počet záznamů: 1