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Linear mimic peptide combined with cN-II and application of linear mimic peptide

A peptidomimetic, linear technology, applied in the field of biotechnology medicine, can solve problems such as drug resistance, recurrence, and drug resistance

Active Publication Date: 2020-07-10
CHILDRENS HOSPITAL OF CHONGQING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy is the most important treatment at present, and the cure rate is only 40%. About 20% of children have drug resistance and relapse. Some children are resistant to chemotherapy drugs, and the children have received excessively high-intensity chemotherapy.

Method used

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  • Linear mimic peptide combined with cN-II and application of linear mimic peptide
  • Linear mimic peptide combined with cN-II and application of linear mimic peptide
  • Linear mimic peptide combined with cN-II and application of linear mimic peptide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] cN-II (cytoplasmic-5'-nucleotidase-II) forms a tetramer with two homologous identical dimers to play a biological role in vivo. A large number of mimetic peptides (cN-II mimeticpeptide, cNMP) that can bind to cN-II were screened by ribosome display technology; the crystal structure of cN-II was analyzed, and through repeated homology modeling, and ZDOCK of discovery studioTM , RDOCK tools for molecular docking and other bioinformatics analysis of the mimic peptides; further in vitro tests were performed to optimize the mimic peptides with obvious inhibitory effect on the expression of leukemia cell cN-Ⅱ, thus obtaining the specific binding simulation of cN-Ⅱ Peptide, which has cN-Ⅱ antagonistic effect and reverses the effect of nucleoside analog drug resistance in ALL cells, it can act on cN-Ⅱ dimer, can exert inhibitory effect on dimer formation, or act on already formed dimer or tetramer inhibits tetramer formation and its function. Figure 5 It is the dimer structur...

Embodiment 2

[0035] The preparation of the polypeptide described in the present invention can be obtained by DNA recombination technology, and can also be synthesized by chemical synthesis, such as by using Fmoc solid-phase polypeptide synthesis method. Using Wang resin as a solid-phase reaction substrate, the -COOH of the C-terminal amino acid of the target peptide chain is connected to the solid-phase resin with a coupling reagent, and then its -NH is removed 2 The above protecting group then reacts with the -COOH of the next amino acid to form a peptide bond, and this repeated operation can grow the peptide chain, that is, coupling reaction, washing, removing the amino protecting group, washing, and a new round of coupling, until Synthesize the target peptide, and finally cut the target peptide from the solid phase carrier with a cleavage reagent, and then obtain the target peptide after some processing.

[0036] The specific steps of the Fmoc solid-phase peptide synthesis method:

[0...

Embodiment 3

[0062] Cytarabine (Ara-C) belongs to cytarabine (Ara-C) is a pyrimidine anti-metabolite drug, mainly used for the treatment of acute leukemia and malignant lymphoma, especially for acute myeloid leukemia. Well, according to relevant reports: the rate of complete remission after treatment with Ara-C-containing chemotherapy regimens in patients with newly diagnosed acute myeloid leukemia is 65% to 80%. However, most patients who achieve complete remission will relapse within two years after the diagnosis, which may be related to the resistance of tumor cells to drugs, resulting in poor curative effect of subsequent treatment. After Ara-C enters tumor cells, it undergoes a two-step phosphorylation and activation reaction to generate the active product Ara-CTP, which inhibits DNA synthesis. Similarly, cN-II can also hydrolyze Ara-CMP, the monophosphate activation product of Ara-C, and inhibit its continued phosphorylation and activation, resulting in drug failure.

[0063] 6-MP (...

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Abstract

The present invention relates to a linear mimic peptide combined with cN-II. The linear mimic peptide has amino acid sequences as shown in SEQ ID NO:11-20. The mimic peptide can be combined with the cN-II, and has the antagonistic effect on the cN-II. The linear mimic peptide RP1 with the representative amino acid sequence as shown in the SEQ ID NO:11 can inhibit high expression of the cN-II in Jurkat cells, and co-culture can effectively improve the proliferation inhibition rate and the apoptosis rate of the cells under the action of araC and 6-MP, thereby reducing the drug resistance of thenucleoside analogs such as the araC and 6-MP in ALL disease treatment and the disease relapse.

Description

technical field [0001] The invention belongs to the field of biotechnology medicine, relates to a linear mimic peptide combined with cN-II, and also relates to the application of the mimic peptide in the preparation of drugs related to nucleoside analog drug resistance diseases. Background technique [0002] II Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in childhood, a malignant proliferative disease of the hematopoietic system, and has become the main cause of death from malignant tumors in children. The manifestation is that leukemia cells stagnate at different stages of cell development, lose the ability to differentiate and mature, and proliferate malignantly. The malignant cloned leukemia cells not only inhibit the normal hematopoiesis of bone marrow and other hematopoietic tissues, but can further infiltrate other organs and tissues. The clinical manifestations are acute onset, rapid progression, and dangerous conditions, which serio...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K19/00A61K38/10A61P35/02
CPCA61K38/00A61P35/02C07K7/08C07K2319/30
Inventor 宋林王书峰张若琪贾运涛刘彬陈勇刚刘耀
Owner CHILDRENS HOSPITAL OF CHONGQING MEDICAL UNIV
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