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PKM2 tetramer allosteric activation peptide and application thereof in reversing Warburg effect and chemosensitization in tumors

A tetramer, activating peptide technology, applied in the field of biomedicine, can solve the problem of not maintaining the persistence of PKM2 allosteric effect

Active Publication Date: 2022-08-09
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Serine, a natural ligand for PKM2, has been shown to activate PKM2 tetramerization but not maintain the persistence of PKM2 allosteric effects
However, there is no report that can be used to sustain the PKM2 allosteric activator and then be used to inhibit tumor related research.

Method used

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  • PKM2 tetramer allosteric activation peptide and application thereof in reversing Warburg effect and chemosensitization in tumors
  • PKM2 tetramer allosteric activation peptide and application thereof in reversing Warburg effect and chemosensitization in tumors
  • PKM2 tetramer allosteric activation peptide and application thereof in reversing Warburg effect and chemosensitization in tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1P

[0039] Example 1 Preparation and molecular structure of PKM2 tetramer allosteric activation peptide

[0040] 1. Preparation of PKM2 tetramer allosteric activation peptide PAC ((S(GlcNAc)-K(TPA-1)LVFF), which can react with excess OGA enzyme in renal cell carcinoma (RCC) region to remove N-acetylglucosamine (GLcNAc) exposes serine, promotes the conversion of PKM2 from dimer to tetramer form, and self-assembles in situ to form water-insoluble nanofibers, achieve long-term retention and generate fluorescent signal, the PKM2 tetramer allosteric activation peptide It consists of the following three parts:

[0041] 1) The serine functional motif covered by N-acetylglucosamine (GLcNAc), the amino acid sequence of which is shown in formula I, can react with the OGA enzyme in the renal cell carcinoma (RCC) region to remove N-acetylglucosamine (GLcNAc) and then Expose serine to promote the conversion of PKM2 from dimer to tetramer;

[0042]

[0043] 2) The amino acid sequence that ...

Embodiment 2

[0048] Example 2 Polypeptide PAC undergoes allostery and self-assembly into water-insoluble nanofibers after removing N-acetylglucosamine (GLcNAc) through OGA enzyme reaction and exposing serine.

[0049] 1. Prepare a phosphate solution and gradually dissolve OGA to a pH of 6.5. Add PAC and PAC-C to the solution containing OGA enzyme, so that the final concentration of PAC and PAC-C is 100 μM. After 2 hours, use transmission electron microscopy to observe PAC and PAC-C solution samples.

[0050] The result is as figure 2 From the results, it can be seen that the polypeptide PAC can transform and self-assemble into hydrophobic nanofibers in the solution containing OGA enzyme, while PAC-C cannot undergo allosteric and self-assembly behavior in the solution containing OGA enzyme.

[0051] 2. Prepare a phosphate solution and gradually dissolve OGA to a pH of 6.5. Add PAC to the solution containing OGA enzyme to make the final concentration of PAC 100 μM. After co-incubating for ...

Embodiment 3

[0053] Example 3 Cell test administration method

[0054] Humanized renal carcinoma cells 786-O and ACHN cells with high expression of OGA enzyme and normal renal cortical proximal convoluted tubule epithelial cells (HK-2 cells) were selected as control cells. The PAC and PAC-C polypeptides were dissolved in DMSO solvent to prepare a polypeptide nanomaterial solution with a solution concentration of 10 mM. The experimental cells in good condition and in logarithmic growth were randomly divided into PAC, PAC-C and PBS (phosphate buffered saline) groups. The effect of PAC-C and PBS solution on cell survival.

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Abstract

The invention discloses a PKM2 tetramer allosteric activating peptide and an application thereof in reversing a Warburg effect in tumors and enhancing sensitivity in chemotherapy, and belongs to the field of biomedicine. The PKM2 tetramer allosteric activation peptide comprises a serine motif coated with N-acetylglucose, a self-assembly motif capable of forming a hydrophobic nano-composite, and a fluorescence signal motif with an aggregation-induced emission function. The polypeptide can react with OGA enzyme overexpressed in a renal cell carcinoma area to remove N-acetylglucosamine, so that a PKM2 tetramer activator serine is exposed, PKM2 is promoted to be converted from a dimer form to a tetramer form, an in-situ self-assembly function of a self-assembly motif is triggered, a nano-composite insoluble in water is formed, and the PKM2 can be used for treating renal cell carcinoma. The in-situ residence time of serine is prolonged, the AIE fluorescence signal intensity is improved, and finally the effects of reversing the Warburg effect and improving the chemotherapy sensitivity are achieved. The invention provides a new direction for the treatment of renal cell carcinoma.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a PKM2 tetramer allosteric activation peptide and its application in reversing Warburg effect and chemotherapy sensitization in tumors. Background technique [0002] Renal Cell Carcinoma (RCC) is one of the ten most common malignant tumors, and it is also the malignant tumor with the highest mortality rate in the urinary system. It has the characteristics of rapid progression, prone to early metastasis and insensitivity to chemotherapy, radiotherapy and other treatments, which are considered to be the main reasons for treatment failure. More than 30% of kidney cancer patients have metastasized at the time of diagnosis and missed the best opportunity for surgery. With chemotherapy, even patients who initially respond to treatment develop resistance within 10-14 months. These factors lead to the high mortality rate of renal cell carcinoma, which is a serious threat to human life and he...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47C07K1/107A61K38/17A61P35/00A61P35/02
CPCC07K14/4711A61P35/00A61P35/02A61K38/00
Inventor 徐万海王璐王浩李莉莉侯大勇吕玉林付博杨光于家傲
Owner HARBIN MEDICAL UNIVERSITY
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