2. Academic Validation
  3. Synthesis and biological evaluation of all possible inosine-mixed cyclic dinucleotides that activate different hSTING variants

Synthesis and biological evaluation of all possible inosine-mixed cyclic dinucleotides that activate different hSTING variants

  • Bioorg Med Chem. 2021 Jan 1;29:115899. doi: 10.1016/j.bmc.2020.115899.
Zhenghua Wang 1,  Cancan Zhao 2,  Chuanlin Wang 1,  Hang Zhang 1,  Dejun Ma 1,  Qiangzhe Zhang 2,  Xin Wen 1,  Luyuan Li 3,  Zhen Xi 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-organic Chemistry, Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
  • 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China. Electronic address: liluyuan@nankai.edu.cn.
  • 4 State Key Laboratory of Elemento-organic Chemistry, Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China; National Pesticide Engineering Research Centre (Tianjin), China. Electronic address: zhenxi@nankai.edu.cn.
PMID: 33285409 DOI: 10.1016/j.bmc.2020.115899
Abstract

Cyclic dinucleotides (CDNs) could activate stimulator of interferon genes (STING) protein to produce type I interferon and other pro-inflammation cytokines in mammalian cells. To explore new types of potentially efficient STING activators targeting all five major hSTING variants (WT, R232H, HAQ, AQ and R293Q), we here reported the synthesis of a total of 19 inosine-containing CDNs based on the combinations of hypoxanthine with four natural bases (A, G, C and U) and three phosphodiester linkage backbones (3'-3', 2'-3', 2'-2'). The IFN-β induction results showed that all of the 2'-3' and 2'-2' CDNs linked by inosine and purine nucleosides favored the stacking interaction with Y167 and R238 residues of hSTING protein, and several CDNs constructed by hypoxanthine and pyrimidine like c[I(2',5')U(2',5')] could also activate all five hSTING variants. The molecular dynamic simulation and the isothermal titration calorimetric (ITC) assay further demonstrated the potential of cAIMP isomers with 2'-5' phosphate to form the hydrogen binding with R232 and R238 residues of hSTING in an entropically driven manner compared to cGAMP isomers. It would be promising to exploit novel inosine-mixed CDNs as activators of hSTING variants in immune therapy.

Keywords

Cyclic dinucleotides; Inosine; Interferon-β; STING.

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