Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

Abstract	Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3'-5' and 2'-5' phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2'3'-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound 8d (KD = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (KD = 0.543 μM). Cellular assays confirmed that 8d could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. 8d also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings provide guidelines for the design and structural optimization of CDNs as STING agonists.
Authors	Xin Xie, Junyi Liu, Xiaowei Wang
Journal	Molecules (Basel, Switzerland) (Molecules) Vol. 25 Issue 22 (Nov 12 2020) ISSN: 1420-3049 [Electronic] Switzerland
PMID	33198423 (Publication Type: Journal Article)
Chemical References	Cytokines Membrane Proteins Nucleotides, Cyclic STING1 protein, human cyclic guanosine monophosphate-adenosine monophosphate
Topics	Binding Sites Catalysis Cytokines (metabolism) Humans Immunotherapy Kinetics Membrane Proteins (agonists) Molecular Docking Simulation Molecular Structure Nucleotides, Cyclic (chemical synthesis, chemistry) Protein Binding Signal Transduction Surface Plasmon Resonance

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