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Peptides as inhibitors of fibrotic matrix accumulation

A cyclic peptide and sequence technology, applied to medical preparations containing active ingredients, peptides, cyclic peptide components, etc., can solve problems such as little knowledge of risks

Pending Publication Date: 2022-04-15
MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN EV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preclinical data suggest that integrin targeting may be a promising treatment for fibrotic diseases, yet little is known about the risks of these interventions

Method used

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  • Peptides as inhibitors of fibrotic matrix accumulation
  • Peptides as inhibitors of fibrotic matrix accumulation
  • Peptides as inhibitors of fibrotic matrix accumulation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1: Peptide Synthesis

[0144] Synthesis of the peptide Gly-Leu-Gln-Gly-Glu (GLQGE) in linear form as Gly-Leu-Gln-Gly-Glu-NH 2 (Also known as Linear GLQGE-NH 2 ), and in linear form as acetic acid-Gly-Leu-Gln-Gly-Glu (also known as linear Ac-GLQGE), and in cyclic form as cyclic Gly-Leu-Gln-Gly-Glu (also known as is a cyclic GLQGE with no C-terminal amide and no N-terminal acetate). The peptide Pro-Gly-Leu-Gln-Gly-Glu (also known as cyclic PGLQGE) was synthesized only in cyclic form. The control peptides Gly-Leu-Asn-Gly-Glu (also known as linear CT1 (linear GLNGE)) and Gly-Leu-Hyp-Gly-Glu (also known as linear CT2 (linear GLOGE)) are both characterized by having a C-terminal amide Chemical (GLNGE-NH 2 and GLOGE-NH 2 ) and N-terminal acetylation (Ac-GLNGE and Ac-GLOGE), can also be synthesized in a cyclic form with and without proline (cyclic GLNGE or cyclic PGLNGE and cyclic GLOGE or cyclic PGLOGE )synthesis. Table 1 lists the names of all peptides used i...

Embodiment 2

[0180] Example 2: Effect of cyclic and amidated linear peptides with proline on chemically induced liver fibrosis in mice.

[0181] Inject mice with CCl 4 6 weeks to induce liver fibrosis. Starting on day 32, mice received daily intraperitoneal injections of the peptide at a final dose of 25 mg / kg / mouse / day (diluted in 0.9% NaCl) for 10 days. In these experiments, the following peptides were tested: cyclic peptide Pro-Gly-Leu-Gln-Gly-Glu, cyclic peptide Pro-Gly-Leu-Asn-Gly-Glu, cyclic peptide Pro-Gly-Leu-Hyp-Gly- Glu, linear peptide Gly-Leu-Gln-Gly-Glu-NH 2 , linear peptide Gly-Leu-Asn-Gly-Glu-NH 2 , linear peptide Gly-Leu-Hyp-Gly-Glu-NH 2 .

[0182] The results showed that using CCl 4 Treatment with Glycine significantly induced collagen production (a marker of matrix accumulation) in the liver, and the cyclic peptide Pro-Gly-Leu-Gln-Gly-Glu was able to significantly reduce collagen accumulation. Linear peptide GLQGE-NH 2 Also able to significantly reduce CCl 4 In...

Embodiment 3

[0183] Example 3: Effects of cyclic peptides (without proline) and acetylated linear peptides on chemically induced liver fibrosis in mice use.

[0184] Inject mice with CCl 4 6 weeks to induce liver fibrosis. Starting on day 32, mice received daily intraperitoneal injections of the peptide at a final dose of 25 mg / kg / mouse / day (diluted in 0.9% NaCl) for 10 days. In these experiments, the following peptides were tested: cyclic peptide Gly-Leu-Gln-Gly-Glu, cyclic peptide Gly-Leu-Asn-Gly-Glu, cyclic peptide Gly-Leu-Hyp-Gly-Glu, linear peptide Ac- Gly-Leu-Gln-Gly-Glu, linear peptide Ac-Gly-Leu-Asn-Gly-Glu, linear peptide Ac-Gly-Leu-Hyp-Gly-Glu.

[0185] The results showed that using CCl 4 Treatment with ® significantly induced collagen production (a marker of matrix accumulation) in the liver, and the cyclic peptide Gly-Leu-Gln-Gly-Glu was able to significantly reduce collagen accumulation. In addition, the linear peptide Ac-Gly-Leu-Gln-Gly-Glu was able to significantly ...

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Abstract

The present invention relates to peptides that inhibit the excessive production and / or accumulation of an extracellular matrix in an organ or tissue. The peptides of the invention have the general formula sequence Xa-Leu-Gln-Gly-Xb (SEQ ID NO: 1) wherein Xa is selected from the group consisting of Pro-Gly, Gly and Ac-Gly and Xb is selected from the group consisting of Glu and Glu-NH2, which peptides are capable of inhibiting excessive production and excessive accumulation of extracellular matrix in organs or tissues in the form of linear peptides and cyclic peptides. In particular, the peptides disclosed herein are useful for the treatment of fibrotic disorders characterized by excessive accumulation of extracellular matrix, such as liver fibrosis, cirrhosis, pulmonary fibrosis, chronic respiratory failure, cardiac fibrosis, ischemic heart disease, heart failure, diabetic nephropathy, glomerulonephritis, myelofibrosis, and various types of cancers, such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, chronic respiratory failure, cardiac fibrosis, ischemic heart disease, heart failure, diabetic nephropathy, glomerulonephritis, myelofibrosis, and the like. Such as breast cancer, uterine cancer, prostate cancer, pancreatic cancer, colon cancer, skin cancer, blood cell cancer, central nervous system cancer, fibromyoma, fibroma, fibroadenoma and fibrosarcoma.

Description

[0001] The present invention relates to peptides that inhibit the overproduction and / or overaccumulation of extracellular matrix in organs or tissues. The peptide of the present invention has the general sequence Xa-Leu-Gln-Gly-Xb (SEQ ID NO: 1), wherein Xa is selected from Pro-Gly, Gly and Ac-Gly, Xb is selected from Glu and Glu-NH 2 , said peptide is capable of inhibiting the overproduction and overaccumulation of extracellular matrix in an organ or tissue, both in the form of a linear peptide and a cyclic peptide. In particular, the peptides disclosed herein are useful in the treatment of fibrotic disorders characterized by excessive accumulation of extracellular matrix, such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, chronic respiratory failure, cardiac fibrosis, ischemic heart disease, cardiac Failure, diabetic nephropathy, glomerulonephritis, myelofibrosis and various types of cancer such as breast cancer, uterine cancer, prostate cancer, pancreatic cancer, co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64A61K38/12A61K38/08A61P1/16A61P11/00A61P9/00A61P9/10A61P9/04A61P13/12A61P19/08A61P35/00
CPCC07K7/06C07K7/64A61K38/00A61P1/16A61P11/00A61P35/00C07K7/52
Inventor I·纳克驰邦第S·哈梅尔曼S·尤贝尔
Owner MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN EV
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