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Polypeptide for inhibiting p38 kinase activity and its application

A kinase activity and polypeptide technology, which is applied in the field of peptides that inhibit p38 kinase activity, can solve problems such as the advent of p38 kinase inhibitory polypeptide molecules, and achieve the effect of inhibiting inflammatory responses

Active Publication Date: 2007-02-14
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no inhibitory polypeptide molecule targeting p38 kinase at home and abroad

Method used

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  • Polypeptide for inhibiting p38 kinase activity and its application
  • Polypeptide for inhibiting p38 kinase activity and its application
  • Polypeptide for inhibiting p38 kinase activity and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1. Design, screening and synthesis of polypeptides that inhibit p38 kinase activity

[0030] 1. Design and activity screening of polypeptides that inhibit p38 kinase activity

[0031] The results of structural biology research on p38 kinase and its upstream and downstream molecules show that the upstream and downstream binding proteins of p38 contain a sequence with similar structure, which mediates the specific binding of related molecules to p38; and these proteins are all bound to p38 the same site. It can be deduced that if an exogenous specific binding sequence is added to occupy the binding site in p38, it will competitively inhibit the binding and interaction between p38 and its endogenous upstream and downstream molecules, thereby blocking the signal transmission of the p38 pathway.

[0032] Selected and compared p38 binding site sequences derived from several p38 upstream and downstream molecules MKK3b, MKK6, MEF2A and MEF2C: MKK3b (KGKSKRKKDLRISCNS), ...

Embodiment 2

[0042] Example 2, the effect of the membrane-penetrating polypeptide that inhibits p38 kinase activity on the inhibition of intracellular p38 activity

[0043] 1. TAT-MKK3b-pep specifically inhibits the phosphorylation and activation of p38 in macrophages induced by LPS

[0044] Materials: macrophage cell line (RAW264.7) (purchased from ATCC); lipopolysaccharide (lipopolysaccharide, LPS derived from E.coli 055: B5) was purchased from Sigma; cell culture medium RPMI 1640 was purchased from Hyclone; calf serum Purchased from Yuanheng Sanma Company; PVDF membrane was purchased from PALL Company; phosphorylated JNK, phosphorylated ERK, and phosphorylated p38 antibodies were purchased from CST Company; p38 antibody was purchased from Santa Cruz Company. TAT control peptide: YGRKKRRQRRR (synthesized by Jill Biochemical (Shanghai) Co., Ltd., with a purity of more than 95%).

[0045] The macrophage cell line RAW264.7 was incubated in RPMI 1640 cell culture medium containing 10% FBS a...

Embodiment 3

[0049] Example 3. Inhibitory effect of the membrane-penetrating polypeptide TAT-MKK3b-pep that inhibits the activity of p38 kinase on the secretion of inflammatory factors in the acute inflammation model of mice

[0050] Materials: The sources of LPS and mouse TNFα Elisa kit are the same as above. BALB / C mice were purchased from Beijing Weitong Lihua Company.

[0051] Male BALB / C mice (body weight 20±1g) were randomly divided into 6 groups, and were injected intraperitoneally with TAT control polypeptide, TAT-MKK3b-pep polypeptide at a dose of 25 mg / kg or injected with an equal volume of sterile water, and after half an hour, press 1.25 200 μl of endotoxin LPS or an equal volume of PBS control was injected intraperitoneally at a dose of mg / kg, and the mice were anesthetized for blood collection 90 minutes later. After the serum was diluted 1:10, the secretion of TNFα in the serum was detected and compared using the mouse TNFα Elisa kit. Three parallel samples were set for th...

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Abstract

The present invention discloses one kind of polypeptide with p38 kinase inhibiting activity and its application. The polypeptide has one of the following amino acid residue sequence: 1. SEQ ID No. 1 in the sequence list; 2. SEQ ID No. 2 in the sequence list; and 3, the amino acid residue sequence of SEQ ID No. 1 or SEQ ID No. 2 through substitution, deletion and / or addition of one or several amino acid residues and with protein possessing p38 kinase inhibiting activity related function. The polypeptide of the present invention can enter to cell to inhibit p38 kinase activity specifically and block the signal transmission of p38 channel, and can inhibit inflammation reaction.

Description

technical field [0001] The invention relates to a polypeptide for inhibiting the activity of p38 kinase and its application, in particular to a polypeptide for specifically inhibiting the activity of mitogen-activated protein kinase p38, and its application as or preparation of medicament for treating inflammatory diseases. Background technique [0002] Abnormal cell signaling is closely related to human diseases. Protein kinases, which play key roles in signal transduction, are currently one of the most important targets for disease treatment. The MAPK (Mitogen-Activated Protein Kinase) superfamily of eukaryotic cells includes ERK1 / 2, JNK1 / 2 / 3, p38α / β / γ / δ, ERK4 / 5 and ERK5 / BMK1, which are responsible for Signals from extracellular stimuli are transmitted to the nucleus to regulate gene expression. Among them, mitogen-activated protein kinase p38MAPK is involved in signal transduction in physiological and pathological processes such as inflammation, emergency, development, ...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K19/00A61K38/10A61K38/16A61P29/00
Inventor 顾军傅璟
Owner PEKING UNIV
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