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Target RAGE cytoplasm inner segment adaptor SLP76 and application of SAM

A TAT-SAM, cytoplasmic technology, applied in the field of biomedicine, can solve the problem of not significantly improving the survival time of patients with sepsis

Active Publication Date: 2019-04-02
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, neither the TLR4 receptor itself nor the TLR4 signal transduction pathway, nor the intervention of anti-cytokines (TNF-α, IL-1, etc.) can significantly improve sepsis in clinical treatment of sepsis patients. patient survival time
[0005] Although the current studies on multipl

Method used

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  • Target RAGE cytoplasm inner segment adaptor SLP76 and application of SAM
  • Target RAGE cytoplasm inner segment adaptor SLP76 and application of SAM
  • Target RAGE cytoplasm inner segment adaptor SLP76 and application of SAM

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0041] Example 1.

[0042] A SAM functional domain that targets the adaptor protein SLP76 of the intracytoplasmic segment of RAGE. After entering the cell, it binds to the intracytoplasmic segment of the cell membrane surface receptor RAGE, antagonizes the binding of SLP76 protein to the RAGE receptor, and inhibits RAGE-mediated downstream Signal transduction, reducing the release of cytokines.

[0043] Among them, the SAM functional domain of the SLP76 protein is brought into the cell through the cell penetrating peptide, and specifically can be brought into the cell through the TAT cell penetrating peptide.

[0044] The above-mentioned SAM functional domain of the adaptor protein SLP76 targeting the intracytoplasmic segment of RAGE has an amino acid sequence of YGRKKRRQRRRVLAWNSDNLADYF RKLNYRDCEKAVKKYHIDGARFLNLTENDIQKFPKLRMPLLSKLSQDINKNEER.

[0045] The SAM functional domain of the adaptor protein SLP76 targeting the intracytoplasmic segment of RAGE has a clear application as a medi...

Example Embodiment

[0052] Example 2.

[0053] A targeted drug for the treatment of sepsis TAT ​​and SAM functional domain fusion protein of SLP76 protein, with a fusion protein of TAT and SAM functional domain of SLP76 protein.

[0054] The targeted drug for the treatment of sepsis TAT ​​and the SAM functional domain fusion protein of SLP76 protein is intravenous injection.

[0055] The targeted drugs targeting the SAM functional domain of SLP76 protein for the treatment of sepsis include small molecule compounds, dyes, polypeptides, polypeptide nucleic acids, proteins, plasmid DNA, siRNA, 200nm liposomes, phage particles, and ultra Paramagnetic particles, etc. mediate the way that the SAM functional domain of SLP76 protein enters the cell.

[0056] TAT is a cell penetrating peptide protein with a length of 11 amino acid residues, and the basic amino acid sequence is YGRKKRRQRRR. The advantages of the cell penetrating peptide protein as a carrier are low toxicity and no restriction of cell type. The f...

Example Embodiment

[0058] Example 3.

[0059] A screening method for identifying interacting proteins in the cytoplasm of the RAGE receptor: phage clones that can bind to the cytoplasm of RAGE are obtained from a cDNA library by phage display technology, and after 3 rounds of screening, a phage clone that can bind to the cytoplasm of RAGE is obtained. SLP76 protein bound to the inner segment. The cDNA library of the present invention is a human lung cDNA library. The screening times of the present invention are 2 to 5 times. The specific screening times in this embodiment are 3 times.

[0060] It should be noted that the screening times of the present invention may be 3 times, or 2, 4, or 5 times, and the specific implementation situation depends on the actual situation.

[0061] The present invention uses T7 phage display experiments to obtain phage clones that can bind to the intracytoplasmic segment of RAGE from the human lung cDNA library through 3 rounds of screening. After verification and DNA...

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Abstract

Fusion protein of an SAM functional structure region of TAT and SLP76 protein has the effect of restraining inflammatory reaction in a sepsis process. Cell-penetrating peptides TAT are used for bringing the SAM functional structure region of the SLP76 protein into cells, through competitive binding to the cytoplasm inner segment of an RAGE acceptor, and in the generation and development of antagonism sepsis, RAGE and endogenous adaptor protein SLP76 interact to mediate signal transduction, so that the release of inflammatory factors in a sepsis process is alleviated, and the effect of treatment of sepsis or improvement of prognosis is exerted. The SAM functional structure region fusion protein of the TAT and the SLP76 protein can be used as a target drug for treating the sepsis, and can directly penetrate through cell membranes to enter polypeptides in the cells in the non-classical endocytosis manner. The fusion protein has the important characteristics that the fusion protein can carry bioactive substances of various different size and nature to enter the cells.

Description

Technical field [0001] The present invention belongs to the field of biomedicine, and particularly relates to the use of a SAM functional domain targeting RAGE cytoplasmic linker protein SLP76 (SH2domain containing leukocyte protein of 76kDa) as a medicine for treating RAGE-related inflammatory diseases. Background technique [0002] Sepsis (sepsis) is a systemic inflammatory response syndrome (SIRS) caused by pathogenic microorganism infection. It is a common complication of severe trauma, burns, and major surgical operations and other critically ill patients, and it also induces septic shock ( septic shock), acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (multiple organdysfunction syndrome, MODS). The incidence of sepsis is high. There are more than 18 million cases of severe sepsis worldwide each year, and this number is still rising at a rate of 1.5% to 8.0% per year. Epidemiological investigations have shown that the fatality rate of seps...

Claims

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Application Information

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IPC IPC(8): C07K14/00C07K19/00A61K38/16A61K47/42A61P29/00A61P35/00A61P9/00A61P9/10A61P25/28A61P31/04
CPCA61K38/00A61K47/42A61P9/00A61P9/10A61P25/28A61P29/00A61P31/04A61P35/00C07K14/00C07K2319/10
Inventor 姜勇闫征征罗海华
Owner SOUTHERN MEDICAL UNIVERSITY