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Fungus-derived cyclic peptidomimetic as well as preparation method and application thereof

A circular and homologous technology, applied in the field of biomedicine, can solve problems such as high prices, achieve stable and reliable quality, improve the survival rate of mice, and relieve rectal atrophy

Active Publication Date: 2021-11-02
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007]However, hormones and small molecule drugs (aminosalicylic acids, immunosuppressants, antimetabolites) in the above clinically used drugs are drugs that have been used for many years. and have certain side effects
Biological agents (monoclonal antibodies) are newly developed and marketed drugs in recent years, which have the advantages of few side effects and clear therapeutic effects, but the price is high

Method used

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  • Fungus-derived cyclic peptidomimetic as well as preparation method and application thereof
  • Fungus-derived cyclic peptidomimetic as well as preparation method and application thereof
  • Fungus-derived cyclic peptidomimetic as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of linear peptidomimetic intermediate

[0052] In the preparation process of the linear peptidomimetic intermediate, N-acetyl-L-cysteine ​​(CAS: 616-91-1, purchased from the market), 2-amino-3-mercapto-propionamide (ie L- Carboxyl amidated derivatives of cysteine, provided by Hangzhou Zhongpei Biochemical Co., Ltd.), and natural L-type amino acids (glutamine Gln, serine Ser, isoleucine Ile, glycine Gly, arginine Arg, lysine Amino acid Lys, phenylalanine Phe, glycine Gly, tyrosine Tyr) are used as raw materials, and condensation links are carried out on the solid phase resin carrier in sequence according to the structure of the designed target molecule. Using 9-fluorenylmethoxycarbonyl (FMOC) as the protecting group at the amino terminal, select 4-(2′,4′-dimethoxyphenyl-fluorenylmethoxycarbonyl-aminomethyl)-phenoxyacetamido- Methylbenzhydrylamine resin (Rink amide MBHA resin) is a solid-phase resin carrier for the synthesis of peptidomimeti...

Embodiment 2

[0053] Example 2: Synthesis of cyclic peptoids

[0054] Using the linear peptidomimetic intermediate prepared in Example 1 as a raw material, take 10 mg of the linear peptidomimetic intermediate in a 20 mL plastic centrifuge tube, wrap the centrifuge tube with tinfoil to keep it from light, and add 10 mL of it at a concentration of 0.15M (pH=8.0 ) Tris-HCl buffer. Tighten the cap of the centrifuge tube and seal it with Pharfim sealing film, and confirm that there is no leakage. Invert the centrifuge tube to completely dissolve the intermediate of the linear peptidomimetic, and immediately place the centrifuge tube in a constant temperature shaker at (25±2)°C, incubate at a speed of 50-60rpm for about 30 hours to accelerate the sulfhydryl groups at both ends of the linear peptidomimetic. Groups form intramolecular disulfide bonds to form cyclic peptidomimetics.

[0055] Purified by preparative RP-HPLC using a C18 reverse preparative column (300mm×30mm, 10μm). Mobile phase: A...

Embodiment 3

[0056] Example 3: Determination of hemolytic activity of cyclic peptoids

[0057] Extract fresh blood from a healthy human body, separate human erythrocytes, and make it into erythrocyte suspension, sterilized saline as a negative control, and 1% Triton X-100 as a positive control, and measure the cyclic peptidomimetic obtained in Example 2 hemolytic activity.

[0058] The specific steps are as follows: draw fresh blood from a healthy person into an EDTA anticoagulant tube, and gently invert it so that the blood fully contacts the anticoagulant at the bottom of the anticoagulant tube and the inner wall of the tube. Centrifuge at 1000rpm for 5min at room temperature, discard the upper layer of plasma and keep the lower layer of red blood cells. Add 2 to 3 times the volume of medical normal saline injection, gently invert to suspend the red blood cells at the bottom of the centrifuge tube, repeat the above steps until the supernatant becomes colorless; use medical normal saline...

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Abstract

The invention discloses a fungus-derived cyclic peptidomimetic and a preparation method and application thereof. The template molecule of the cyclic peptidomimetic is a segment of conditional pathogenic fungus polypeptide, and during preparation, natural amino acid and sulfydryl-containing amino acid with a protected reaction group are gradually coupled to form a linear peptidomimetic intermediate of the cyclic peptidomimetic; and then covalently coupling sulfydryl in the linear peptidomimetic intermediate molecule to form a disulfide bond, thereby forming the cyclic peptidomimetic. When the concentration of the cyclic peptidomimetic reaches up to 1mg / mL, the hemolysis rate of the cyclic peptidomimetic does not exceed 5%, and the cyclic peptidomimetic has better safety; after a dextran sodium sulfate induced inflammatory bowel disease model mouse is treated by the cyclic peptidomimetic, the weight loss degree is remarkably improved, the disease activity index is remarkably reduced, the colonic atrophy is remarkably relieved, and the levels of cell factors IL-1[beta] and TNF-alpha in colon homogenate are remarkably reduced. The cyclic peptidomimetic is simple in preparation process, easy to purify, low in toxicity, clear in pharmacological activity and obvious in animal level treatment effect.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a cyclic peptidomimetic derived from fungi, a preparation method and application thereof. Background technique [0002] Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) is a type of chronic immune disease characterized by non-specific intestinal inflammation, has become the second most common chronic inflammatory disease in the world, mainly including ulcerative colitis ( Ulcerative colitis (UC) and Crohn's disease (Crohn's disease, CD) have the characteristics of recurrent attacks and protracted healing. The main clinical manifestations are diarrhea, abdominal pain, mucus and bloody stools and other digestive system symptoms, as well as systemic symptoms such as fatigue, weight loss, and anemia. symptom. The pathogen is prone to occur in economically developed regions such as North America and Europe. However, with the rapid development of my country's economy, the continuo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/37C07K1/10A61K38/12A61P29/00
CPCC07K14/37A61P29/00A61K38/00Y02P20/55
Inventor 沈秉正姚朝辉孟兰霞王娜胡振夏熊远果张璐刘盈沈瑶陈坤林
Owner WUHAN UNIV
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