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

被引：18

作者：

Vavrina, Zdenek ^{[1
,2
]}

Perlikova, Pavla ^{[1
,6
]}

Milisavljevic, Nemanja ^{[1
,3
]}

Chevrier, Florian ^{[1
]}

Smola, Miroslav ^{[1
]}

Smith, Joshua ^{[1
,4
]}

Dejmek, Milan ^{[1
]}

Havlicek, Vojtech ^{[1
,3
]}

Budesinsky, Milos ^{[1
]}

Liboska, Radek ^{[1
]}

Vanekova, Lenka ^{[1
,5
]}

Brynda, Jiri ^{[1
]}

Boura, Evzen ^{[1
]}

Rezacova, Pavlina ^{[1
]}

Hocek, Michal ^{[1
]}

Birkus, Gabriel ^{[1
]}

机构：

[1] Czech Acad Sci, Inst Organ Chem & Biochem, Prague 16610, Czech Republic

[2] Charles Univ Prague, Fac Sci, Dept Biochem, Prague 12800, Czech Republic

[3] Charles Univ Prague, Fac Sci, Dept Organ Chem, Prague 12800, Czech Republic

[4] Charles Univ Prague, Fac Med 1, Prague 12108, Czech Republic

[5] Charles Univ Prague, Fac Sci, Dept Cell Biol, Prague 12843, Czech Republic

[6] Univ Chem & Technol, Fac Chem Technol, Dept Organ Chem, Prague 16628, Czech Republic

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 20期

关键词：

GMP-AMP SYNTHASE; INTERFERON GENES; ADAPTER PROTEIN; ENZYMATIC-SYNTHESIS; DI-GMP; STIMULATOR; DNA; RIBONUCLEOSIDES; 2ND-MESSENGER; CHEMISTRY;

D O I：

10.1021/acs.jmedchem.2c01305

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 GMP-AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki-Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2'3'-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 pi-pi stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes.

引用

页码：14082 / 14103

页数：22

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