Synthesis Of Agonists Based On Innate Immune CGAS-cGAMP-STING Pathway

Cancer as human has yet to conquer malignant diseases,the low survival rate and high fatality rate is threatening human health,with cancer situation increasingly serious nowadays,the tradition such as surgery,radiation therapy,chemotherapy treatments,have gradually cannot meet the demand of current anticancer,some malignant tumor and metastatic cancer is still an incurable disease.After more than a century of stagnation since Coley's discovery of Coley's Toxins in 1893,immunotherapy has gained renewed interest with the recent success of some clinical trials.cGAS·STING signaling pathways as an important part of the innate immune system,its function is to detect the DNA of the cytoplasm,and triggered a series of immune response in the reaction,the pathways of STING as the key part of the immune response across the membrane protein,play a crucial role in the immune response,thus activating the second messenger cGAMP to STING protein is the target of the research hot.cGAMP previous strategy more focused on lipid particles package or modification of phosphate groups,but not fundamentally solve the metabolic stability and transmembrane transportation difficult problem,small molecule STING agonist due to small molecule compounds library is limited,it is difficult to find a real activity activated by high-throughput screening STING protein of small molecules,the development of high-throughput screening has hit a bottleneck.Based on the current research status,this paper proposes to start with the key compound cGAMP,utilize the characteristics of PNA to simulate DNA,replace the natural cGAMP nucleotide skeleton with the peptide nucleic acid skeleton,synthesize the cGAMP analogue of the peptide nucleic acid skeleton,simulate its binding with cGAS or STING protein,and then develop relevant small drug molecules.The details are as follows:(1)According to the current popular immune checkpoint inhibitors,cancer vaccines,CAR-T cell therapy,etc.,the research status,advantages and disadvantages of immunotherapy in anticancer were described,as well as the research progress of cGAS-STING target mechanism and STING agonists.(2)A series of related cGAMP analogues with peptide nucleic acid as the skeleton were designed and synthesized,and the synthesis of cyclic peptide nucleic acid skeleton molecules was explored and realized,which provided a certain basis for future research based on this skeleton compound.In addition,the structure of benzimidazole STING small molecule agonist with good anticancer activity was explored to some extent.