Structural basis of nucleic acid recognition for the development of immune modulators

Abstract

Immune modulator is one of the important remedies for cancer and autoimmune disease. STING is involved in DNA sensing and responsible for the innate immune stimulatory effect. It has been reported some anticancer drugs or antiviral drugs has the species-specific binding activity of STING. Most of the drugs have ability to bind mouse STING and failed to bind to human STING. Clarifying the mechanism of species-specificity of STING can be helpful to design the chemical which can bind specific to human STING. STING agonists such as DMXAA, CMA, FAA share flavone skeleton. With the flavonoid derivatives with various functional groups, the binding ability of human and mouse STING was tested to identify structure and species-specific activity relationship. Also, C7-functionalized DMXAA was synthesized and conducted the biological activity, while DMXAA has efficient antitumor activity in mouse but not in human. Cyclic di-nucleotides, which were synthesized in human body and activate STING, have phosphate backbone that cannot penetrate cellular membrane and can be hydrolyzed by phosphodiesterase. Instead of the phosphate group, amide bond was introduced to cyclic di-nucleotides and the resulting cyclic peptide nucleic acid doesn’t have overall charge so that could pass the cell membrane and have resistance to phosphodiesterase. In case of STING agonists, they can modulate the innate immune response so there are possibilities to utilize them as cancer immunotherapeutics or adjuvants for antiviral agents. RIG-I detects intracellular RNA, induces interferon production and activates interferon signaling. CypA is a target for an immune suppressor cyclosporine A and related to various cellular process including protein folding, cell signaling, inflammation and tumorigenesis. A recent study indicates CypA activates RIG-I signaling through modulate ubiquitination of RIG-I and MAVS. Biochemical and biophysical experiments were made for understanding the interaction between RIG-I and CypA.