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CN-122005535-A - Application of E3 ubiquitin ligase inhibitor in preparing allergic rhinitis medicine

CN122005535ACN 122005535 ACN122005535 ACN 122005535ACN-122005535-A

Abstract

The invention relates to the technical field of biological medicines, in particular to application of an E3 ubiquitin ligase inhibitor in preparing a medicament for treating allergic rhinitis. The invention discovers that the E3 ubiquitin ligase inhibitor inhibits the ubiquitination degradation of CLDN1 to strengthen the barrier function and relieve the nasal symptoms, can be used for the preventive medication in the high-risk exposure period, effectively reduces the probability of invasion of exogenous pathogens by pre-reinforcing a first defense line, reduces the attack frequency and the severity of diseases, and provides a new target point and a new way for the prevention and treatment of allergic rhinitis.

Inventors

  • ZHANG CHUNYI
  • ZHANG XIAOWEN
  • XU MEIQIAN
  • LIAO WENJING

Assignees

  • 广州医科大学附属第一医院（广州呼吸中心）

Dates

Publication Date
20260512
Application Date
20260312

Claims (10)

  1. Use of an e3 ubiquitin ligase inhibitor in the preparation of a medicament for allergic rhinitis.
  2. 2. The use of an E3 ubiquitin ligase inhibitor according to claim 1 for the manufacture of a medicament for allergic rhinitis, wherein the E3 ubiquitin ligase inhibitor comprises compound 1 of structural formula I and/or compound 2 of structural formula II; the structural formula I is shown as follows: A formula I; the structural formula II is shown as follows: Formula II.
  3. 3. The use of an E3 ubiquitin ligase inhibitor according to claim 1, wherein the allergic rhinitis medicament is in the form of nasal drops, nasal sprays, aerosols or powder mists.
  4. 4. The use of an E3 ubiquitin ligase inhibitor according to claim 1 for the manufacture of a medicament for allergic rhinitis, wherein the medicament for allergic rhinitis is administered orally, intranasally, by injection or by external administration.
  5. 5. The use of an E3 ubiquitin ligase inhibitor according to claim 1, wherein the raw materials for the preparation of allergic rhinitis drugs comprise solvents.
  6. 6. The use of an E3 ubiquitin ligase inhibitor according to claim 5, wherein the solvent comprises 10% dissolving agent and 90% physiological saline by volume fraction.
  7. 7. The use of an E3 ubiquitin ligase inhibitor according to claim 6, wherein the lytic agent comprises at least one of dimethyl sulfoxide, PEG300, PEG400 and Tween-80.
  8. 8. The use of an E3 ubiquitin ligase inhibitor according to claim 5 for preparing a medicament for allergic rhinitis, wherein the raw materials for preparing the medicament for allergic rhinitis further comprise pharmaceutically acceptable auxiliary materials.
  9. 9. The use of an E3 ubiquitin ligase inhibitor in preparing a medicament for allergic rhinitis according to claim 1, wherein the concentration of the E3 ubiquitin ligase inhibitor in the medicament for allergic rhinitis is 0.25-56 μm.
  10. 10. The use of an E3 ubiquitin ligase inhibitor in preparing an allergic rhinitis medicament according to claim 9, wherein the concentration of the compound 1 in the allergic rhinitis medicament is 0.25-10 μm, and the concentration of the compound 2 in the allergic rhinitis medicament is 3.5-56 μm.

Description

Application of E3 ubiquitin ligase inhibitor in preparing allergic rhinitis medicine Technical Field The invention relates to the technical field of biological medicines, in particular to application of an E3 ubiquitin ligase inhibitor in preparing a medicament for treating allergic rhinitis. Background The nasal mucosa serves as the primary interface between the human respiratory tract and the external environment, and the physical and chemical barriers formed by the epithelial cell layers play a central role in defending allergens (such as pollen and dust mites), pathogenic microorganisms (including influenza viruses, coronaviruses and bacteria) and environmental pollutants from invading submucosal tissues. The integrity of the barrier is highly dependent on the tight junction structure between epithelial cells, with the Claudin-1 protein as the most widely distributed and functionally critical transmembrane component in the tight junction family responsible for closing the cell gap, maintaining barrier compactness and limiting paracellular permeability. Clinical pathology studies have fully demonstrated that in inflammatory diseases such as allergic rhinitis, the expression level of Claudin-1 in nasal mucosal epithelial cells is significantly reduced or abnormal internalization (e.g., transfer from cell membrane to cytosol) occurs, leading to disruption of tight junction function, leading to the formation of leaky epithelial states. This barrier defect allows exogenous antigens to readily penetrate the mucosa, continuously stimulating the immune system, triggering and exacerbating inflammatory cascades, causing recurrent episodes of symptoms. Although there are a number of drug options currently available for the treatment of allergic rhinitis, chronic sinusitis and nasal inflammation, the prior art has the following significant drawbacks and unmet clinical needs. First, currently mainstream nasal drugs mainly cover glucocorticoids (e.g. budesonide, mometasone furoate) and antihistamines. The action mechanism of the medicines is mainly to inhibit downstream immune inflammatory reaction or block inflammatory mediator receptors, so as to relieve symptoms such as nasal obstruction, watery nasal discharge, sneeze and the like. However, these drugs cannot directly repair the damaged nasal mucosal epithelium physical barrier. Since the epithelial barrier (tight junction) is not substantially restored, once administration is stopped, external allergens or pathogens are very likely to penetrate the mucosa again, causing recurrent episodes of inflammation that are difficult to heal. Secondly, although the patient's nasal glucocorticoid is a gold standard drug for treatment, long-term high-frequency use may cause problems of nasal mucosa dryness, scabbing, nasal bleeding and the like, and even cause mucosa atrophy or hypoolfaction. Some patients (especially children and those who have fear of hormone) have poor compliance with long-term use of hormonal drugs. In addition, antihistamines have rapid onset of action, but often accompany uncomfortable symptoms such as dry nose, bitter taste, and the like, and have no effect on improving mucosal defense functions. Finally, the existing non-drug nasal products (such as sea salt water flushing liquid and barrier gel) can only play a role in mechanical cleaning or temporary physical covering, and cannot penetrate into the inside of cells to regulate and control the stability of the tight junction protein. It is particularly critical that the prior art system completely lacks intervention means for the Claudin-1 ubiquitination degradation pathway-in the pathological process of allergic rhinitis, the specific E3 ubiquitin ligase mediated excessive ubiquitination of Claudin-1 is a direct cause of its protein level decrease, but no drug can specifically target the enzyme to block the degradation process so as to rescue the expression of Claudin-1 and reconstruct the nasal mucosal biological barrier. The fundamental technology gap enables the clinical lack of a treatment strategy for repairing the epithelial barrier and blocking the inflammatory circulation from the source, and severely restricts the effect of radical treatment of the allergic rhinitis. Therefore, the search for new and more effective diagnosis and treatment techniques has great social significance. Disclosure of Invention In order to overcome the problems in the related art, the invention provides the application of the E3 ubiquitin ligase inhibitor in preparing the allergic rhinitis medicament, the barrier function can be enhanced by inhibiting the ubiquitination degradation of the CLDN1 through the E3 ubiquitin ligase inhibitor, the nasal symptoms can be relieved, the E3 ubiquitin ligase inhibitor can also be used for preventive medication in a high-risk exposure period, the probability of invasion of exogenous pathogens can be effectively reduced by pre-reinforcing a first defense line, and the attack freq