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People who are working on STING
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STING (Stimulator of Interferon Genes) is an important protein involved in the response to foreign or damaged DNA or RNA in a cell’s cytosol. When the cGAS (cyclic GMP-AMP synthase) protein, acting as a nucleic acid sensor, encounters foreign DNA or RNA in the cytosol, it converts GTP and ATP to cyclic GMP-AMP (cGAMP, a.k.a. 2’,3’-cGAMP). The cGAMP is bound by the STING protein located at the endoplamic reticulum (cytosolic side). STING then generates activated transcription factors NF-kβ (by way of IKK) and IRF-3 (by way of TBK-1) which enter the nucleus and initiate transcription of interferon and cytokine genes. The interferons and cytokines then can promote an anti-inflammatory response. The cGAS/cGAMP/STING pathway is an important part of the innate immune response.
Our interest is to find both inhibitors and enhancers of STING. Enhancers of STING can increase the immune response to tumor cells which would contain abnormal DNA that occur from uncontrolled replication and chromatin fragmentation. Inhibitors of STING can help treat autoimmune disorders where there may be constitutive activation of STING that leads to an overly aggressive immune response to self-DNA. STING has been a difficult target for development of therapeutics since the mouse STING shows different properties when compared to the human STING.
Our approach is to computational screen tens of thousands of compound structures against the known binding sites on STING to identify those compounds that show significant interactions. We then do experimental confirmation of the best of the identified compounds to narrow our compound list to just a few. Experimental in vitro approaches include Thermal Shift Assays and Surface Plasmon Resonance binding and we use Western blots to monitor cellular STING activity in the presence of the compounds. We then design analogs that can improve the binding characteristics of the lead compounds and we computationally model these analogs as well as synthesize the analogs to test experimentally. Ultimately, we will advance at least one promising optimized analog into clinical trials.
Our interest is to find both inhibitors and enhancers of STING. Enhancers of STING can increase the immune response to tumor cells which would contain abnormal DNA that occur from uncontrolled replication and chromatin fragmentation. Inhibitors of STING can help treat autoimmune disorders where there may be constitutive activation of STING that leads to an overly aggressive immune response to self-DNA. STING has been a difficult target for development of therapeutics since the mouse STING shows different properties when compared to the human STING.
Our approach is to computational screen tens of thousands of compound structures against the known binding sites on STING to identify those compounds that show significant interactions. We then do experimental confirmation of the best of the identified compounds to narrow our compound list to just a few. Experimental in vitro approaches include Thermal Shift Assays and Surface Plasmon Resonance binding and we use Western blots to monitor cellular STING activity in the presence of the compounds. We then design analogs that can improve the binding characteristics of the lead compounds and we computationally model these analogs as well as synthesize the analogs to test experimentally. Ultimately, we will advance at least one promising optimized analog into clinical trials.