0563157 - ÚOCHB 2023 RIV US eng J - Článek v odborném periodiku
Vavřina, Zdeněk - Perlíková, Pavla - Milisavljevič, Nemanja - Chevrier, Florian - Smola, Miroslav - Smith, Joshua - Dejmek, Milan - Havlíček, Vojtěch - Buděšínský, Miloš - Liboska, Radek - Vaneková, Lenka - Brynda, Jiří - Bouřa, Evžen - Řezáčová, Pavlína - Hocek, Michal - Birkuš, Gabriel
Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists.
Journal of Medicinal Chemistry. Roč. 65, č. 20 (2022), s. 14082-14103. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA MŠMT LX22NPO5102; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: GMP-AMP synthase * interferon genes * adapter protein
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 7.3, rok: 2022 ; AIS: 1.587, rok: 2022
Způsob publikování: Open access
Web výsledku:
https://doi.org/10.1021/acs.jmedchem.2c01305DOI: https://doi.org/10.1021/acs.jmedchem.2c01305

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.
Trvalý link: https://hdl.handle.net/11104/0335201
Vědecká data: PDB, PDB, PDB