STING is a receptor central to an innate immune pathway that detects cytosolic double-stranded DNA and mediates antiviral and anticancer immunity. STING activation hinges on its nanomolar affinity binding to a small-molecule second messenger, 2’,3’-cGAMP, making this pathway uniquely chemically tractable amongst innate immune mechanisms. For this reason, agonists of STING are in intense clinical development as a means of stimulating anticancer immunity at the innate immune level, but few inhibitors of STING are known. However, in a broad range of tissue-specific and systemic autoimmune diseases, failure to regulate self-DNA leads to mis-activation of the STING pathway, resulting in unwanted inflammation. It is thus of therapeutic interest to investigate how inhibition of the STING pathway is relevant in broad range of disease contexts. We hypothesize that examining the molecular mechanism of STING activation can inform new approaches to inhibit this innate immune pathway. We previously described a model of STING activation where STING is basally autoinhibited. We showed that autoinhibition is relieved by 2’,3’-cGAMP binding, and can be exploited to achieve STING inhibition. Here, we elaborate on this model and show that peptides can be used to mimic autoinhibition in the native cellular context. Furthermore, we developed assays to quantify peptide binding to STING, and established residue-affinity relationships. This work paves the way for the development of molecular tools to inhibit STING signaling to study its functional consequences in various disease outcomes.

Inhibition of STING signaling by harnessing its autoinhibitory mechanism

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.