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CN-121974986-A - Polypeptide for treating visceral hypersensitivity and application thereof

CN121974986ACN 121974986 ACN121974986 ACN 121974986ACN-121974986-A

Abstract

The invention discloses a polypeptide for treating visceral hypersensitivity and application thereof, belonging to the technical field of biological medicine. The polypeptide can specifically interfere with the binding of the protease activated receptor 1 (PAR 1) to the beta-arestin 2, so that abnormal activation of a signal channel dependent on the beta-arestin 2 is selectively inhibited, but normal physiological functions of the PAR1 are not affected. The invention provides the amino acid sequence (SEQ ID NO. 1) of the polypeptide and the coding gene (SEQ ID NO. 2) thereof, and further comprises a recombinant expression vector and a pharmaceutical composition thereof. Experiments show that the symptoms of visceral hypersensitive model animals can be obviously relieved by applying the polypeptide in a local administration mode. The polypeptide provides a new strategy with high accuracy, high efficiency and low side effect risk for treating diseases characterized by visceral hypersensitivity.

Inventors

  • Miao bei
  • CHENG CONGCONG
  • GU JISHENG
  • LI YANRU
  • ZHANG YANG
  • WANG ZHONGSHAN
  • LI LI

Assignees

  • 徐州医科大学附属医院

Dates

Publication Date
20260505
Application Date
20260205

Claims (10)

  1. 1. A polypeptide is characterized in that the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1.
  2. 2. An isolated nucleic acid molecule, characterized in that, the nucleic acid molecule encodes the polypeptide of claim 1.
  3. 3. An isolated nucleic acid molecule according to claim 2, wherein the nucleotide sequence of said nucleic acid molecule is set forth in SEQ ID No. 2.
  4. 4. A recombinant expression vector comprising the nucleic acid molecule of claim 2 or 3.
  5. 5. A host cell comprising the recombinant expression vector of claim 4, or having integrated into its genome the nucleic acid molecule of claim 2 or 3.
  6. 6. A pharmaceutical composition comprising a therapeutically effective amount of the polypeptide of claim 1, the nucleic acid molecule of claim 2 or 3, the recombinant expression vector of claim 4, or the host cell of claim 5, and a pharmaceutically acceptable carrier or adjuvant.
  7. 7. Use of a polypeptide according to claim 1, a nucleic acid molecule according to claim 2 or 3, a recombinant expression vector according to claim 4, a host cell according to claim 5, or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the prevention and/or treatment of a disease characterized by visceral hypersensitivity.
  8. 8. The use according to claim 7, wherein the disease characterized by visceral hypersensitivity is irritable bowel syndrome.
  9. 9. The use according to claim 7, wherein the medicament exerts a therapeutic effect by specifically interfering with the interaction of PAR1 with β -arestin 2.
  10. 10. The use according to claim 7, wherein the pharmaceutical dosage form is any pharmaceutically acceptable dosage form.

Description

Polypeptide for treating visceral hypersensitivity and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a polypeptide for treating visceral hypersensitivity and application thereof. Background Protease activated receptor 1 (Protease-ACTIVATED RECEPTOR, PAR 1) is an important member of the G Protein Coupled Receptor (GPCR) family, and is widely distributed in various cells and tissues such as vascular endothelial cells, platelets, gastrointestinal mucosal epithelium, and enteric nervous system. It is involved in regulating and controlling various key physiological and pathological processes such as coagulation, inflammatory reaction, cell proliferation, gastrointestinal tract feeling and movement and the like through a unique protease cleavage activation mechanism. The structure of PAR1 comprises an extracellular region, seven transmembrane α -helical domains, and an intracellular region, wherein the carboxy-terminal intracellular domain plays a central role in signal transduction, internalization, and functional regulation upon receptor activation. In the gastrointestinal tract, PAR1 is expressed in both the intestinal mucosal epithelium, the intramuscular plexus and the submucosal plexus. Studies have shown that aberrant activation of PAR1 can affect intestinal barrier function, promote inflammatory factor release, and directly participate in the transmission and regulation of intestinal sensory signals through G-protein dependent signaling pathways. In recent years PAR1 has been found to play an important role in the development of high sensitivity to internal organs. Visceral hypersensitivity is one of the core pathophysiological features of irritable bowel syndrome (Irritable Bowel Syndrome, IBS), manifested by a reduced threshold of perception of physiological or slightly deleterious stimuli in the gut and an enhanced pain response. Global IBS prevalence is about 11%, which places a heavy burden on the patient's quality of life and the health and medical system. Existing evidence indicates that PAR1 expression is abnormal in intestinal tissues of IBS patients, and that it initiates G-protein independent signal transduction not only through the classical G-protein pathway but also through specific interaction with the scaffold protein β -arestin 2 after activation. Specifically, after PAR1 is activated, the intracellular carboxyl terminal of the PAR1 is combined with beta-arestin 2, so that the beta-arestin 2 is recruited to a receptor, and signal cascade reactions such as endocytosis, desensitization and downstream MAPK activation are mediated, and finally primary afferent nerve signals are amplified, and visceral hypersensitive state is induced or aggravated. At present, medicines for relieving visceral hypersensitivity, such as 5-HT4 receptor agonists and the like, have relatively wide action targets, often accompany systemic adverse reactions such as cardiovascular systems and the like, and have obviously limited clinical application. For the intervention strategy of PAR1, the existing means are mainly traditional small molecule antagonists (such as Vorapaxar), which can block receptor activation, but the effect of the antagonists usually lacks signal path selectivity, and the normal physiological functions (such as cytoprotection, mucous membrane repair and the like) of PAR1 mediated by G protein can be interfered while pathological PAR 1/beta-arestin 2 interaction is inhibited, so that bleeding risk is increased or other side effects can be caused, and the long-term application value of the PAR1 in chronic gastrointestinal diseases is limited. Thus, the development of an intervention tool that can precisely and specifically block the interaction of PAR1 with beta-arestin 2 without affecting the other normal signaling pathways of PAR1 has become an urgent need for the treatment of visceral hypersensitivity and related PAR1 mediated diseases (e.g., IBS). Polypeptide drugs have great potential in this field due to their advantages of high specificity, low toxicity, ease of rational design, and the like. However, up to now, no polypeptide drug capable of specifically interfering with the interaction of PAR1 and β -arestin 2 has been developed or reported, and a significant technical gap exists in the field. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a polypeptide for treating visceral hypersensitivity and application thereof, and the polypeptide can specifically interfere the interaction of PAR1 and beta-arestin 2, so that accurate intervention on visceral hypersensitivity pathological signals is realized, and the risk of systemic side effects caused by widely inhibiting PAR1 functions is obviously reduced while disease symptoms are effectively relieved. The invention is realized by the following technical scheme: a polypeptide with the amino acid sequence shown in SEQ ID NO