NIH Awards BellBrook Labs Phase II Grant to Develop HTS Assays
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Detection of foreign nucleic acids is an essential first line of defense in the immune response to microbial pathogens. However, aberrant induction of type I interferons (IFN) by self-nucleic acids causes devastating autoimmune diseases such as Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). Production of the unique cyclic dinucleotide, cGAMP, by the cytosolic DNA sensor, cGAS is a key molecular trigger for nucleic acid-driven type I IFN induction. The cGAS apoenzyme is enzymatically inactive; binding of non-specific dsDNA induces a transition to an active conformation that catalyzes the formation of cGAMP from ATP and GTP. cGAMP binds to the STING (stimulator of interferon genes) receptor to initiate the signaling for induction of type I IFNs. Thus, the cGAS enzyme senses the primary signal for a type I IFN response and amplifies it in the form of a second messenger. Knockout studies in animal models have clearly indicated that inhibiting cGAS is a promising approach for therapeutic intervention in monogenic type I interferonopathies such as AGS and, by extension, complex diseases such as SLE.
In phase, I, researchers at BellBrook Labs successfully developed an HTS compatible biochemical assay to discover and develop small molecule modulators targeting the enzyme cGAS. Cellular assays will be used to test the activity of cGAS modulators identified in biochemical screens and to allow cellular screening for compounds that activate or inhibit cGAS via diverse mechanisms. Assays for detecting cGAMP in cell and tissue samples would provide a simple, direct way to monitor the action of lead molecules targeting cGAS, and eventually for identification of responders in clinical studies. For example, Lupus patients with high levels of cGAMP could be candidates for cGAS inhibitors.
Combining results from biochemical screening with accurate validation in cellular assays will accelerate the discovery of potent modulators of the enzyme. The availability of assays to measure cGAMP in human samples will facilitate the development of personalized therapeutic approaches for debilitating autoimmune diseases.