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Broad-spectrum anti-inflammatory polypeptide compound with NMDA and p55PIK as targets and preparation method and application thereof

A peptide compound and broad-spectrum technology, applied in the field of peptide inhibitors, can solve the problems of reducing the risk of suicide and restricting development, and achieve the effects of long duration of drug effect, fast onset of action, and reduced transcriptional activity

Pending Publication Date: 2021-09-07
宋云强
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, with the in-depth research on the pathogenesis of depression, some new antidepressant molecular targets based on non-monoamine transmitters have been discovered, N-methyl-D-aspartic acid (N-methyl-D-aspartic acid, NMDA) receptor antagonist ketamine can quickly relieve depression symptoms, the effect can last for 7 days, can reduce the risk of suicide, and the clinical antidepressant effect is better, but ketamine is a drug, and its addiction limits its development

Method used

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  • Broad-spectrum anti-inflammatory polypeptide compound with NMDA and p55PIK as targets and preparation method and application thereof
  • Broad-spectrum anti-inflammatory polypeptide compound with NMDA and p55PIK as targets and preparation method and application thereof
  • Broad-spectrum anti-inflammatory polypeptide compound with NMDA and p55PIK as targets and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 A preparation method of broad-spectrum anti-inflammatory polypeptide compound Dec-MTG-17

[0061] Peptide sequence: Dec-PEG2-MMTYSTELIFYIEMDPG-NH 2 ;

[0062] Three character symbol:

[0063] Dec-AEEA-Met-Met-Thr-Tyr-Ser-Thr-Glu-Leu-Ile-Phe-Tyr-Ile-Glu-Met-Asp-Pro-Gly-NH 2 ;

[0064] Chinese sequence: n-decanoic acid-AEEA-methionine-methionine-threonine-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-iso Leucine-Glutamic Acid-Methionine-Aspartic Acid-Proline-Glycineamide;

[0065] Molecular weight: 2339.78g / mol;

[0066] Molecular formula: C 108 h 167 N 19 o 32 S 3 ;

[0067] Isoelectric point: 3.9;

[0068] Net charge at PH=7: -2.0;

[0069] Average hydrophilicity: 0.4;

[0070] Hydrophilic residue ratio: 24%;

[0071] The structural formula is as follows:

[0072]

[0073] Concrete preparation method comprises the following steps:

[0074] 1. Resin swelling

[0075] Weigh 2.0g of Rink Amide MBHA Resin wi...

Embodiment 2D

[0126] The preparation method of embodiment 2Dec-MTP-16 polypeptide compound

[0127] Peptide sequence: Dec-PEG2-MMTYSTELIFYIEMDP-NH2

[0128] Three character symbol:

[0129] Dec-AEEA-Met-Met-Thr-Tyr-Ser-Thr-Glu-Leu-Ile-Phe-Tyr-Ile-Glu-Met-Asp-Pro-NH2

[0130] Chinese sequence: n-decanoic acid-AEEA-methionine-methionine-threonine-tyrosine-serine-threonine-glutamic acid-leucine-isoleucine-phenylalanine-tyrosine-iso Leucine-glutamic acid-methionine-aspartic acid-prolinamide molecular weight: 2282.73g / mol;

[0131] Molecular formula: C 106 h 164 N 18 o 31 S 3 ;

[0132] Isoelectric point: 3.9;

[0133] Net charge at PH=7: -2.0;

[0134] Average hydrophilicity: 0.4;

[0135] Hydrophilic residue ratio: 25%;

[0136] The structural formula of the Dec-MTP-16 polypeptide compound is as follows:

[0137]

[0138]In the coupling reaction, the amino acids protected by the Fmoc group follow the coupling order of the active peptide from the C-terminal to the N-terminal: Fm...

Embodiment 3

[0197] Drug efficacy evaluation of embodiment 3 dry eye animal model

[0198] 1. Drug administration technology and ocular tissue sampling

[0199] Topical ocular administration: conjunctival sac eye drops; vitreous injection; anterior chamber injection; retrobulbar injection; subretinal injection ocular tissue sampling: cornea, aqueous humor, conjunctiva, iris, lens, retina

[0200] 2. Animal models of ophthalmic pharmacodynamics

[0201] 1) Hyoscyamine-induced dry eye (C57 mice or SD rats); acute glaucoma induced by anterior chamber injection of viscoelastic (New Zealand rabbits);

[0202] Corneal endothelial injury model (New Zealand rabbit); choroidal neovascularization (NHP) induced by laser photocoagulation

[0203] 2) Hyperoxia-induced retinal neovascularization (C57 suckling mice); STZ-induced diabetic retinopathy (BN rats); optic nerve injury model (SD rats); benzalkonium bromide-induced dry eye (SD rats)

[0204] 3) Ischemia-reperfusion induced by elevated intraoc...

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Abstract

The invention discloses a broad-spectrum anti-inflammatory polypeptide compound with NMDA and p55PIK as targets and a preparation method and application thereof. The broad-spectrum anti-inflammatory polypeptide compound comprises an active peptide fragment, the amino acid sequence of the active peptide fragment is MMTYSTELIFYIEMDP or MMTYSTELIFYIEMDPG, the broad-spectrum anti-inflammatory polypeptide compound further comprises a transmembrane structure or fatty acid loaded at the N-terminal of the active peptide fragment, the fatty acid is capric acid, lauric acid or palmitic acid, the polypeptide compound with the structure is a non-steroidal inhibitor, taking a PI3K subtype member, p55PIK, as a target can effectively inhibit the occurrence of inflammation, the saturated fatty acid is connected to the N-terminal, so as to be able to effectively help an active region to penetrate through a cell membrane, reach a target site and exert effects, bridging polyethylene glycol can enhance polarity to be easy to penetrate through the membrane, and can also increase water solubility to make the druggability strong, and the C-terminal structure can increase the stability of the preparation, so as to achieve good druggability.

Description

technical field [0001] The invention belongs to the field of polypeptide inhibitors in biomedicine, and specifically relates to a broad-spectrum anti-inflammatory polypeptide compound targeting NMDA and p55PIK, its preparation method and application. Background technique [0002] The body tissue defends and repairs the damage caused by various internal and external causes, causing inflammation. The basic pathological changes include deterioration, exudation and hyperplasia. The clinical manifestations are redness, swelling, heat, pain and dysfunction. The systemic reaction is fever. , Leukocytosis etc. [0003] Inflammation is ubiquitous in life, affects everyone, and is the greatest enemy of human health. Therefore, the treatment of inflammation is a huge unmet medical need. Due to the limitation of targets, the side effects of steroid hormones cannot be eliminated. Since the discovery, no replacement drugs have appeared, and steroid hormone anti-inflammatory drugs urgentl...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/16C07K1/06C07K1/04C07K19/00C07K1/107A61K38/10A61P29/00A61P37/02A61P37/06A61P25/24A61P27/02
CPCC07K7/08A61P29/00A61P37/02A61P37/06A61P25/24A61P27/02C07K2319/03A61K38/00Y02P20/55
Inventor 宋云强宋俊宜
Owner 宋云强
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