PD-1 targeting peptide with analgesic activity as well as synthesis method and application thereof

A technology of PD-1 and synthesis method, applied in the field of biomedicine, can solve problems such as limited therapeutic effect and hyperalgesia

Active Publication Date: 2021-07-06
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the therapeutic effects of these drugs are limited, and they are accompanied by adverse reactions such as drug tolerance, drug dependence, respiratory depression, gastrointestinal function suppression, and hyperalgesia.

Method used

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  • PD-1 targeting peptide with analgesic activity as well as synthesis method and application thereof
  • PD-1 targeting peptide with analgesic activity as well as synthesis method and application thereof
  • PD-1 targeting peptide with analgesic activity as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 PD-1 targeting peptide TP-01 was synthesized using the classic Fmoc-solid-phase synthesis method

[0036] The PD-1 targeting peptide TP-01 of the present invention is synthesized by the classic Fmoc-solid-phase synthesis method, which specifically includes the following steps:

[0037]The wang-resin after dichloromethane swelling treatment was selected as the peptide synthesis carrier. The whole synthesis reaction was carried out under the protection of argon. A mixed solution of 20% hexahydropyridine in N,N-dimethylformamide was used as a reagent for removing 9-fluorenylmethoxycarbonyl (Fmoc), and the elution time was 15 minutes (3 times, 5 minutes each time). N, N-diisopropylethylamine / 1-hydroxybenzotriazole / O-benzotriazole-tetramethyluronium hexafluorophosphate is used as a condensation reagent for polypeptide synthesis, and the amount used is the amount of the resin substance 3 to 6 times. The cleavage reagent is trifluoroacetic acid / triisopropylsilan...

Embodiment 2

[0047] Example 2 DRG neuron calcium formation technology identifies the inhibitory effect of PD-1 targeting peptide on pain signal transduction

[0048] The inhibitory effect of PD-1 targeting peptides on pain signal transduction is identified by DRG neuron calcium synthesis technology, which specifically includes the following steps:

[0049] DRG neurons of 3-week-old female mice were extracted by acute isolation. Cells were cultured in vitro for 48 hours in Neurobasal medium (containing 2% B27, 1% Clutanine, and 1% penicillin-streptomycin double antibody solution). DRG neurons were labeled with Flou-4 / AM fluorescent probe, after TP-01 pretreatment, DRG neurons were stimulated by high K+ solution, and intracellular free Ca was detected by laser confocal technology 2+ level changes.

[0050] Free Ca in DRG neurons 2+ It is closely related to nerve excitability and intersynaptic signal transmission, and participates in the regulation of pain information. Various external ...

Embodiment 3

[0052] Example 3 Formalin-induced inflammatory pain experiment

[0053] The formalin-induced inflammatory pain experiment specifically includes the following steps:

[0054] The present invention selects ICR mice with a body weight of 20-25 g, and uses a formalin experiment to detect the application of TP-01 in preparing analgesic drugs. Formalin-induced pain is divided into two phases according to different pain response phases. 0-10min is phase I pain; 10-45min is phase II pain. Inject PD-1-targeted analgesic peptide TP-01 by intrathecal administration, 0.9% normal saline as a negative control group, and inject 20 μl 5% formalin into the hind left paw of the mouse 5 minutes after administration solution. The cumulative time of licking / biting / flicking the injected feet of the mice in the time periods of 0-10min and 10-45min was counted.

[0055] See the experimental results Figure 4 . Through intrathecal administration, at the lowest dose of 1 μg, TP-01 also exhibite...

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Abstract

The invention belongs to the technical field of biological medicines, and discloses a small molecule analgesic peptide TP-01 targeting PD-1, the amino acid sequence of the small molecule analgesic peptide TP-01 targeting PD-1 is ISYGGADYK, and the molecular weight of the small molecule analgesic peptide TP-01 targeting PD-1 is 973.04 g / mol. The small molecule polypeptide can be obtained through classical Fmoc-solid phase synthesis, and plays an important role in research and development of analgesic drugs targeting PD-1. The PD-1 targeting peptide has the advantages that the small molecule peptide TP-01 with analgesic activity of the PD-1 is screened by taking the PD-1 as a target and high-throughput screening of an internal peptide library through a molecular docking technology for the first time. The compound provided by the invention can significantly inhibit calcium ion influx induced by a high K < + > solution. Besides, the peptide shows good analgesic activity in a mouse pain model and can effectively relieve inflammatory pain and visceral pain, so that the research blank of analgesic peptide drugs targeting PD-1 is filled, and a new idea and theoretical basis are provided for research and development of the analgesic drugs targeting PD-1.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a PD-1 targeting peptide with analgesic activity, its synthesis method and its application. Background technique [0002] Pain is an important physiological phenomenon, which can remind the body of existing or potential tissue damage, and is also a common symptom of many clinical diseases. Chronic pain is a global health problem, the incidence rate is as high as 1 / 3 worldwide, and the annual cost of chronic pain treatment is as high as more than 6 trillion US dollars, which not only reduces the quality of life of patients, but also causes serious economic losses. and social issues (Pain. 2019, 160, 53–59). [0003] Current treatment for chronic pain is dominated by medications such as antiepileptics, antidepressants, opioids (such as morphine), capsaicin, botulinum toxin, and nonsteroidal anti-inflammatory drugs (such as aspirin). However, these drugs have limite...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/20C07K1/06C07K1/04A61K38/08A61P29/00
CPCC07K7/06A61P29/00A61K38/00Y02P20/55
Inventor 赵龙陈罡包璟崟潘静莹
Owner NANTONG UNIVERSITY
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