IDO1 Selective Agonists for Treating Autoimmune Disorders
Docket # 19-3557
The Groves lab in the Department of Chemistry at Princeton University has identified a new pathway in suppressing immune responses which may lead to novel compounds for treating autoimmune diseases. Proof of concept and a lead compound have been identified allowing for the development of novel derivatives through further drug discovery and medicinal chemistry efforts.
Indoleamine 2,3-dioxygenase (IDO1) is a heme enzyme that catalyzes the oxygenation of the indole ring in tryptophan to afford N-formylkynurenine. The oxidation of tryptophan through IDO1 activity plays a central role in immune regulation and provides a necessary brake to prevent autoimmunity and damaging inflammation. Princeton researchers show that polysulfides bind to IDO1 and reduce it to the active ferrous state, linking the immune response in a novel way to sulfide signaling. Further, the Groves Lab has demonstrated that 3-mercaptoindole (3MI) replicates these effects, which inspires a new class of selective IDO1-reducing agonists.
By activating IDO1, 3MI and related derivatives hold potential as therapeutic agents to increase IDO1 activity leading to a decrease in inflammation from autoimmune disorders and offer the potential in preventing immune rejection of transplanted tissue.
•Proof of Concept and lead compound for novel drug development/medicinal chemistry program
•Treatment of Autoimmune Diseases
•Suppression of Immune Responses
•Prevention of Immune Rejection
•High selectivity for human IDO1
•Activate IDO1 to maximal turnover even at low, physiologically significant concentrations
Stage of Development
Proof of concept has been demonstrated to show that 3MI is a selective agonist of purified human IDO1.This is the only known compound to activate IDO1.
Micah T. Nelp, Vincent Zheng, Katherine M. Davis, Katherine J. E. Stiefel, and John T. Groves. “Potent Activation of Indoleamine 2,3-Dioxygenase by Polysulfides.” J. Am.Chem. Soc. 2019, 141, 15288–15300 (September 25, 2019): . https://doi.org/10.1021/jacs.9b07338
John T. Groves is the Hugh Stott Taylor Chair of Chemistry and a Professor of Chemistry at Princeton University. He graduated with his B.S. in chemistry from Massachusetts Institute of Technology in 1965 and received his Ph.D. from Columbia University in 1969, where he researched with Prof. Ronald Breslow on the synthesis and characterization of cyclopropenyl cation. Current research focuses of the Groves Lab at Princeton University include the design of new, biomimetic catalysts and the molecular mechanisms of these processes, the design and assembly of large scale membrane-protein-small molecule constructs, studies of host-pathogen interactions related to iron acquisition by small molecule siderophores and molecular probes of the role of peroxynitrite in biological systems.
Micah T. Nelp is a Post-Doctoral Researcher at the Groves Lab.
Intellectual Property Status
Patent protection is pending.
Industry collaborators are sought to further develop and commercialize this technology.
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