Polypeptide compound taking PD-1 receptor as target point as well as preparation method and application thereof

A technology of PD-1 and peptide compounds, which is applied in the field of peptide compounds, can solve problems such as hindering applications, and achieve the effects of easy purification, improved pharmacokinetic properties, and simple synthesis

Active Publication Date: 2021-09-21
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, opioids have been widely used in the clinical treatment of non-cancer chronic pain, but opioids inevitably cause drug tolerance, physical and mental dependence, gastrointestinal function inhibition, nausea, sedation, irritability, hallucinations, and Side effects such as motor function impairment are the main problems hindering its application in clinical treatment

Method used

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  • Polypeptide compound taking PD-1 receptor as target point as well as preparation method and application thereof
  • Polypeptide compound taking PD-1 receptor as target point as well as preparation method and application thereof
  • Polypeptide compound taking PD-1 receptor as target point as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Solid phase synthesis of Compound 1 ~ 5

[0038] The synthesis of the compounds 1 to 5 of the present invention employs a FMOC-solid phase synthesis method, and the solid phase carrier is WANG-resin. The release reagent of the amino protecting group 9-fluorenoxycarbonyl (FMOC) is 20% hexapyridine N, N-dimethylformamide solution. The peptide chain extension desired condensation reagent is N, N-diisopropyl ethylamine / 1-hydroxybenzene triazole / O-benzotriazole-tetramethylurea hexafluorophosphate, the required amount of resin used The amount of material is 3 to 6 times. The crude peptide cuts from the resin to a mixture of trifluoroacetic acid / triisopropylsilane / double vapor solution of 95: 2.5: 2.5. The composition and ratio of the condensation reagent, the FMOC removal reagent, the fmoC removal reagent, the indanjense reagent is known to those skilled in the art.

[0039] 1) Synthesis of Compound 1

[0040]Weigh WANG resin, dichloromethane swelling, methyl me...

Embodiment 2D

[0059] Example 2DRG neuron calcium imaging experiment

[0060] The suppression effect of the compound 1 to 5 on the pain signal conduction by DRG neuronal calcium imaging technique, specifically includes the steps of:

[0061] 3 weeks of female ICR mice were extracted by acute separation, with a sterile console to extract DRG, collagenase A, and trigrase sequentially. Complete medium containing serum terminates the pancreatic enzyme cleavage, 800R centrifugation, abandoned, add NEUROBASAL medium (including 2% B27, Clutanine 1%, and 1% penicillin-streptomycin dual anti-solution), after average Culture 48 h in a versa of PDL. After the experiment, FLOU-4 / AM label DRG neurons were used. After pretreatment of different doses 1 to 5 / or the like, the high K + solution stimulated DRG neurons, and the laser co-focus was detected by the DRG neuron cell free calcium ion concentration. The change.

[0062] Experimental results of calcium imaging figure 2 As shown: Compound 4 pretreatment...

Embodiment 3

[0063] Example 3 Formallin - induced inflammatory pain experiment

[0064] The present invention selects an ICR male mole having a weight range of 25-30 g, and is placed in an observation chamber to accommodate 15 min, injection of different doses of compound 4 (5 nmol, 10 nmol, 30 nmol) or physiological saline, 5 minutes after 5 minutes. The formalin solution (20 μL) was immediately placed in the observation chamber, and the accumulation time of the pain behavior (licking, bite, injection) in the period of 0-10 min, 10-45min period, respectively.

[0065] In the pain model induced by Holmalin, after the mouse was subcutaneously injected with formalin, mice showed pain, bite, claw and telescopic legs. The injection of the formalin was 0-10min for I phase, mainly caused by direct activation of injury neurons; 10-35min is II phase, mainly caused by formalin induced inflammatory responses. Experimental results image 3 As shown, Compound 4 significantly shortens the pain behavior of t...

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Abstract

The invention discloses a polypeptide compound taking a PD-1 receptor as a target spot. The polypeptide compound comprises a compound 1, a compound 2, a compound 3, a compound 4 and a compound 5, wherein the amino acid sequences of the compounds 1-5 are as shown in SEQ ID NO: 1-5. The invention also discloses a preparation method of the polypeptide compound taking the PD-1 receptor as the target spot, and the preparation method comprises the following processes: coupling amino acids of compounds 1-5 to solid-phase resin in sequence according to a peptide sequence by utilizing a solid-phase synthesis mode, cracking by a cutting reagent, freeze-drying, preparing and purifying to obtain the target compound. The invention also discloses application of the polypeptide compound taking the PD-1 receptor as the target spot in preparation of analgesic drugs. According to the small molecule polypeptide, compounds 1-5 can be combined with PD-1, and the obvious inhibition effect on inflammatory pain and visceral pain is achieved under intrathecal administration; and synthesis is simple, purification is easy, and large-scale synthesis is facilitated.

Description

Technical field [0001] The present invention belongs to the field of biopharmaceutical technology, and more particularly to a polypeptide compound according to a PD-1 receptor as a target, the preparation method thereof and the application thereof. Background technique [0002] In recent years, many chronic pain in low back pain, arthritis, postoperative persistent pain, fibrous tissue muscle pain, neuropathological disease is a very common social problem today, more than 20% of adults in developed countries are suffering Chronic pain torture (J. Neurosci.2021, 41, 855-865). Although the chronic pain is immersed, it has not been treated, which gives a serious burden to the society and the economy. Although the signal transduction between immunocytes, gum cells and neurons is now considered to be indispensable to cause and maintain chronic pain, most of the therapeutic drugs are still only for neurons. [0003] Currently, opioids have been widely used in clinical treatment of non ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P29/00
CPCC07K7/06A61P29/00A61K38/00Y02P20/55
Inventor 陈罡赵龙罗浩杨日云陆沐幸
Owner NANTONG UNIVERSITY
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