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CN-121971615-A - Application of P4HA1 inhibitor in preparation of medicines for treating congenital megacolon-associated enterocolitis

CN121971615ACN 121971615 ACN121971615 ACN 121971615ACN-121971615-A

Abstract

The invention discloses application of a P4HA1 inhibitor in preparing a medicament for treating congenital megacolon-related enterocolitis, and further discloses an immune metabolism axis of P4HA 1-hydroxyproline-eIF 5A-IRF4-IL17, and a novel mechanism of metabolite hydroxyproline for promoting nuclear translocation of IRF4 by regulating and controlling eIF5A activity so as to further enhance T H 17 cell-mediated inflammatory reaction. This provides a new perspective for understanding the metabolic immune regulation of intestinal inflammation. The P4HA1 inhibitor (such as 1, 4-DPCA) can effectively inhibit the secretion of IL-17, obviously lighten intestinal inflammation injury of a mouse with a HAEC model, and HAs definite pharmacodynamics basis.

Inventors

  • CHEN XUYONG
  • FENG JIEXIONG
  • Meng Xinyao
  • YANG SHIMIN
  • Mao Handan
  • HU QINGHUI
  • ZHANG CHU

Assignees

  • 华中科技大学同济医学院附属同济医院

Dates

Publication Date
20260505
Application Date
20260126

Claims (10)

  1. Use of a P4HA1 inhibitor or an agent that knocks down P4HA1 expression in the preparation of a medicament for the prevention and/or treatment of congenital megacolon-associated enterocolitis.
  2. 2. The method of claim 1, wherein the P4HA1 inhibitor comprises a small molecule inhibitor of P4HA 1.
  3. 3. The method of claim 2, wherein the small molecule inhibitor of P4HA1 comprises 1,4-DPCA, PX-478, GSK360A, or IOX2.
  4. 4. The method of claim 1, wherein the agent that knocks down expression of P4HA1 comprises an siRNA, shRNA, or antibody that targets P4HA 1.
  5. 5. The use according to claim 4, wherein the sense strand nucleotide sequence of the siRNA is shown as SEQ ID NO.1, 5'-TAGCTCCTCTGTGGTGAATTATT-3', the antisense strand nucleotide sequence is shown as SEQ ID NO. 2, 5'-TAATTCACCACAGAGGAGCTATT-3', or The nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 3, 5'-CAGAGAGCTAATGGTAACTTATT-3', the nucleotide sequence of the antisense strand is shown as SEQ ID NO. 4, 5'-TAAGTTACCATTAGCTCTCTGTT-3', or The nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 5, 5'-CAGGGTGGTAATATTGGCATTTT-3', and the nucleotide sequence of the antisense strand is shown as SEQ ID NO. 6, 5'-AATGCCAATATTACCACCCTGTT-3'.
  6. 6. The method according to claim 4, wherein the shRNA has a nucleotide sequence shown in SEQ ID NO. 7, 5'-GCGAGATTTCTACCATAGATA-3', or The shRNA has a nucleotide sequence shown in SEQ ID NO. 8, which is 5'-CCAGTGGAGAAGGAGATTATA-3', or The nucleotide sequence of the shRNA is shown as SEQ ID NO. 9, and is 5'-CCAGTGCTAGTTGGCAACAAA-3'.
  7. 7. The method of claim 4, wherein the antibody is an Anti-P4HA1 antibody.
  8. 8. The use according to claim 1, wherein the P4HA1 inhibitor or the agent that knocks down P4HA1 expression significantly inhibits IL-17 secretion in T H cells, reduces infiltration of inflammatory cells in intestinal tissue, reduces intestinal mucosal damage, and thereby reduces the severity of congenital megacolon-associated enterocolitis.
  9. 9. Use of a pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of congenital megacolon-associated enterocolitis, characterized in that the pharmaceutical composition comprises a P4HA1 inhibitor or an agent for knockdown of P4HA1 expression according to any of claims 1-8.
  10. 10. The method of claim 9, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

Description

Application of P4HA1 inhibitor in preparation of medicines for treating congenital megacolon-associated enterocolitis Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of a P4HA1 inhibitor in preparation of a medicine for treating congenital megacolon-associated enterocolitis. Background Congenital megacolon (HSCR) is a common digestive tract deformity characterized by the loss of distal colonic ganglion cells. Congenital megacolon-associated enterocolitis (Hirschsprung disease-associated enterocolitis, HAEC) is the most common and life-threatening complication of HSCR, and can occur at any stage from neonatal to adolescent. Despite the considerable maturity of surgical treatments, the morbidity and mortality of HAEC remains high. Currently, clinical treatment of HAEC relies mainly on broad-spectrum antibiotics, intestinal decompression and supportive treatment, lacking specific targeted drugs for its pathological mechanisms. Existing studies indicate that an imbalance of the intestinal immune system plays a key role in the pathogenesis of HAEC. Although the pro-inflammatory activation of macrophages is known to lead to destruction of the intestinal barrier, the specific distribution, function and mechanism of adaptive immune cells (particularly CD4 + T cells) in HAEC are not well understood. Hydroxyproline (Hydroxyproline) is the main component of collagen, and its metabolic pathway plays an important role in maintaining cellular redox balance and immune response. However, whether the hydroxyproline metabolic pathway is involved in the development of HAEC and whether the key metabolic enzyme P4HA1 can serve as a therapeutic target for HAEC HAs not been reported before. Therefore, a new target for regulating and controlling HAEC immune inflammatory response is sought, and a novel therapeutic drug is developed, so that the method has important clinical significance. Disclosure of Invention The invention aims to provide an application of a P4HA1 inhibitor in preparing medicines for treating congenital megacolon-associated enterocolitis, and the invention discloses a key role of a P4HA 1-mediated proline metabolic pathway in a HAEC pathological process for the first time based on single cell transcriptome sequencing (scRNA-seq), single cell metabonomics, multiple immunohistochemistry (mIHC) and other technologies, and obviously relieves intestinal inflammation by inhibiting P4HA 1. In order to achieve the above purpose, the present application adopts the following technical scheme: in a first aspect, the invention provides the use of a P4HA1 inhibitor or an agent that knocks down P4HA1 expression in the manufacture of a medicament for the prevention and/or treatment of congenital megacolon-associated enterocolitis. In the above technical scheme, the P4HA1 inhibitor comprises a small molecule inhibitor of P4HA 1. In the above technical scheme, the small molecule inhibitor of P4HA1 comprises 1,4-DPCA, PX-478, GSK360A, or IOX2. In the above technical scheme, the agent for knocking down the expression of P4HA1 comprises siRNA, shRNA, or antibody targeting P4HA 1. In the technical proposal, the nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 1, 5'-TAGCTCCTCTGTGGTGAATTATT-3', the nucleotide sequence of the antisense strand is shown as SEQ ID NO. 2, 5'-TAATTCACCACAGAGGAGCTATT-3', or The nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 3, 5'-CAGAGAGCTAATGGTAACTTATT-3', the nucleotide sequence of the antisense strand is shown as SEQ ID NO. 4, 5'-TAAGTTACCATTAGCTCTCTGTT-3', or The nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 5, 5'-CAGGGTGGTAATATTGGCATTTT-3', and the nucleotide sequence of the antisense strand is shown as SEQ ID NO. 6, 5'-AATGCCAATATTACCACCCTGTT-3'. In the technical scheme, the nucleotide sequence of the shRNA is shown as SEQ ID NO. 7, is 5'-GCGAGATTTCTACCATAGATA-3', or The shRNA has a nucleotide sequence shown in SEQ ID NO. 8, which is 5'-CCAGTGGAGAAGGAGATTATA-3', or The nucleotide sequence of the shRNA is shown as SEQ ID NO. 9, and is 5'-CCAGTGCTAGTTGGCAACAAA-3'. In the above technical scheme, the antibody is an Anti-P4HA1 antibody. In the technical scheme, the P4HA1 inhibitor or the agent for knocking down the expression of the P4HA1 obviously inhibits the secretion of IL-17 in T H cells, reduces infiltration of inflammatory cells in intestinal tissues, and reduces damage to intestinal mucosa, thereby relieving the severity of the congenital megacolon-associated enterocolitis. In a second aspect, the invention provides the use of a pharmaceutical composition comprising a P4HA1 inhibitor or an agent for knockdown of P4HA1 expression as described above for the manufacture of a medicament for the prevention and/or treatment of congenital megacolon-associated enterocolitis. In the above technical scheme, the medicament further comprises pharmaceu