Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists
Jiaxuan Chen, Carolyn A. Haller, Finith E. Jernigan, Steffi Koerner, Daniel J. Wong, Yiqiang Wang, Jae Eun Cheong, Revanth Kosaraju, Julian Kwan, Dayoung Park, Beena Thomas, Swati S. Bhasin, Roberto C. De La Rosa, Alykhan Premji, Liying Liu, Eden Park, Alan C. Moss, Andrew Emili, Manoj Bhasin, Lijun Sun, Elliot L. Chaikof
Abstract
Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.