Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

0563157 - ÚOCHB 2023 RIV US eng J - Journal Article
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
R&D Projects: GA MŠMT LX22NPO5102; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : GMP-AMP synthase * interferon genes * adapter protein
OECD category: Biochemistry and molecular biology
Impact factor: 7.3, year: 2022
Method of publishing: Open access
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.
Permanent Link: https://hdl.handle.net/11104/0335201


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