CN-122005550-A - AHR ligand 5-methoxy-2 methyl-3-indoleacetic acid and application thereof

Abstract

The invention belongs to the technical field of aromatic hydrocarbon receptor ligands, and particularly relates to an AHR ligand 5-methoxy-2 methyl-3-indoleacetic acid and application thereof. The invention takes a compound of 5-methoxy-2 methyl-3-indoleacetic acid (MMIA) as an Aromatic Hydrocarbon Receptor (AHR) ligand, and discloses application of MMIA in the aspects of enhancing AHR stability, promoting AHR to enter cell nucleus, relieving colonitis and the like. The results of the examples show that MMIA can specifically bind and activate AHR, and MMIA gastric lavage treatment can exert anti-inflammatory effect and effectively relieve colonitis symptoms. AHR is a key molecule for regulating intestinal canal steady state, can inhibit pro-inflammatory pathways such as NF- κB, reduce secretion of pro-inflammatory factors such as IL-6, TNF-alpha, repair damaged mucous membranes, restore intestinal barrier integrity, and radically improve colonitis related symptoms.

Inventors

• WU HAO
• PU SICHENG
• XU QINGBIAO
• DU YUFENG

Assignees

• 华中农业大学

Dates

Publication Date

20260512

Application Date

20260210

Claims (10)

1. 1. An AHR ligand comprising 5-methoxy-2 methyl-3-indoleacetic acid.
2. Use of 5-methoxy-2 methyl-3-indoleacetic acid as AHR ligand.
3. 3. The use according to claim 2, wherein the AHR ligand is an AHR agonist.
4. Use of 5-methoxy-2 methyl-3-indoleacetic acid for enhancing AHR stability.
5. Use of 5-methoxy-2 methyl-3-indoleacetic acid for promoting AHR entry into the nucleus.
6. Use of 5-methoxy-2 methyl-3-indoleacetic acid in promoting AHR binding XRE reaction elements.
7. Use of 5-methoxy-2 methyl-3-indoleacetic acid for promoting expression of a target gene downstream of AHR.
8. Use of 5-methoxy-2 methyl-3-indoleacetic acid for inhibiting the NF- κb pro-inflammatory pathway, reducing IL-6 and TNF- α pro-inflammatory factor secretion, repairing damaged mucosa or restoring intestinal barrier integrity.
9. Application of 5-methoxy-2 methyl-3-indoleacetic acid in preparing anti-inflammatory drugs.
10. 10. A pharmaceutical composition for treating or alleviating colitis, the medicament comprising 5-methoxy-2 methyl-3-indoleacetic acid.

Description

AHR ligand 5-methoxy-2 methyl-3-indoleacetic acid and application thereof Technical Field The invention belongs to the technical field of aromatic hydrocarbon receptor ligands, and particularly relates to an AHR ligand 5-methoxy-2 methyl-3-indoleacetic acid and application thereof. Background Aromatic Hydrocarbon Receptors (AHR) are ligand-dependent transcription factors that are widely expressed in a variety of tissues and cells in humans. The method plays an important regulatory role in the aspects of interaction of microorganisms and hosts, maintenance of physiological homeostasis of organisms and the like, and is also a research hotspot and a potential target in the fields of tumor immunotherapy, metabolic regulation and the like. In the absence of ligand binding, AHR forms cytoplasmic complexes with heat shock protein 90 (HSP 90), AHR interacting protein (XAP 2), and the like. When bound to a specific ligand, the AHR conformation changes, enters the nucleus and forms a heterodimer with an aromatic hydrocarbon receptor nuclear translocator (ARNT), thereby regulating transcription of a downstream target gene, and completing the signaling process. Presently known AHR ligands are structurally diverse, including environmental pollutants, plant natural products, human or commensal microbial metabolites, and the like. Among them, indole compounds produced by tryptophan metabolism by some microorganisms have been reported as endogenous ligands for AHR. Studies have shown that such ligands interact with conserved amino acid residues in the PAS-B domain of AHR, primarily through binding, thereby driving receptor activation. Although some indole derivatives have been shown to activate AHR and participate in physiological regulation, the known AHR ligands have shortcomings in terms of binding specificity, stability, etc. Therefore, the development of novel AHR ligand with novel structure and definite activity has important significance for further revealing the regulation and control mechanism of AHR signal channel and expanding the targeting application of AHR signal channel. Disclosure of Invention The invention aims to provide an Aromatic Hydrocarbon Receptor (AHR) ligand 5-methoxy-2 methyl-3-indoleacetic acid (MMIA) and application thereof as an AHR ligand. In order to achieve the above object, the present invention provides the following technical solutions: The present invention provides an AHR ligand comprising 5-methoxy-2 methyl-3-indoleacetic acid (MMIA). The invention also provides an application of the 5-methoxy-2-methyl-3-indoleacetic acid as an AHR ligand. Preferably, the method comprises the steps of, use as AHR agonists. The invention also provides the following applications: use of 5-methoxy-2 methyl-3-indoleacetic acid for enhancing AHR stability. Use of 5-methoxy-2 methyl-3-indoleacetic acid for promoting AHR entry into the nucleus. Use of 5-methoxy-2 methyl-3-indoleacetic acid to promote AHR binding XRE reaction elements. Use of 5-methoxy-2 methyl-3-indoleacetic acid for promoting expression of AHR downstream target genes. Use of 5-methoxy-2 methyl-3-indoleacetic acid for inhibiting the NF- κb pro-inflammatory pathway, reducing IL-6 and TNF- α pro-inflammatory factor secretion, repairing damaged mucosa or restoring intestinal barrier integrity. Application of 5-methoxy-2 methyl-3-indoleacetic acid in preparing anti-inflammatory drugs. Preferably, the anti-inflammatory is the treatment or alleviation of colitis. The invention also provides a pharmaceutical composition for treating or relieving colonitis, which comprises 5-methoxy-2 methyl-3-indoleacetic acid. Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients. The beneficial effects are that: the invention discovers that the compound 5-methoxy-2 methyl-3-indoleacetic acid (MMIA) is an AHR ligand for the first time, and is proved by biochemical and molecular biological experiments. MMIA is an indoleacetic acid compound, has an AHR binding core structure, is firmly combined, and can be used as a stable tool molecule for AHR mechanism research. The invention discloses an application of MMIA in relieving colonitis, and shows remarkable application potential in the field. The examples prove that the stomach lavage treatment can play an anti-inflammatory role and effectively relieve the colonitis symptoms. AHR is a key molecule for regulating intestinal canal steady state, can inhibit pro-inflammatory pathways such as NF- κB, reduce secretion of pro-inflammatory factors such as IL-6, TNF-alpha, repair damaged mucous membranes, restore intestinal barrier integrity, and radically improve colonitis related symptoms. Compared with the existing medicine and potential ligand, MMIA improves AHR binding specificity and stability by virtue of a unique structure, accurately regulates and controls inflammatory microenvironment, reduces side effects, and lays a foundation for clinical transformation due to the safet