Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists.
Sci Adv
; 6(3): eaay8230, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31998845
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cicatrización de Heridas
/
Linfocitos
/
Diseño de Fármacos
/
Receptores de Hidrocarburo de Aril
/
Inmunomodulación
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Adv
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos