Synthese Of CGAMP And Screning For Chemical Regulators Of CGAS-STING Signaling Pathway

cGAMP,a newly discovered second messenger,is involved in the function of innate immune response mediated by the cGAS-STING pathway in response to immunogenic DNA,which plays an important role in cancer,pathogen infection and autoimmune diseases.The immune response can be achieved by adjusting the level of cGAMP in a certain extent.Improving the level of cGAMP can be achieved by introduction of exogenous cGAMP and pathway activator,but decreasing the level of cGAMP only be achieved by antagonism,eventually reducing the downstream cytokine response.Therefore,the syntheses of cGAMP and the discovery of regulatory compounds in the cGAS-STING pathway are important in the immunology and health care.It may provide a new strategy for the treatment of cancer and autoimmune diseases.The biological synthesis of cGAMP is straightforward,while the yield is very low.However the chemical synthesis is complicated with considerable yield and the purification is the problem in the scale-up.In vivo,cGAMP synthase cGAS is an important cytoplasm DNA sensor,which plays a major role in antiviral immunity.This thesis carried on the syntheses of cGAMP by the biological and chemical synthetic methods and we verified its activity in cells.In order to find the regulator of cGAMP,we screened the compounds from two different sources.One was a series of small molecular compounds prepared by the method of chemical synthesis;the other source came from natural compounds.We identified several natural active compounds through the screening system based on THP1-Lucia-ISG cell.In summary,after three years of study and practice,the experiment results are showed as below:(1)cGAMP could be obtained by biological method and chemical synthesis,which was estimated by activity experiment;(2)In screening of the regulators in cGAS-STING pathway,we found that resveratrol,dihydroartemisinin and fucoxanthin salt showed much stronger down regulation.