CN114195865A - SH3BGRL3 derivative polypeptide and application thereof - Google Patents
SH3BGRL3 derivative polypeptide and application thereof Download PDFInfo
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- CN114195865A CN114195865A CN202111589768.3A CN202111589768A CN114195865A CN 114195865 A CN114195865 A CN 114195865A CN 202111589768 A CN202111589768 A CN 202111589768A CN 114195865 A CN114195865 A CN 114195865A
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- sh3bgrl3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
The invention provides SH3BGRL3 derivative polypeptide and application thereof, belonging to the technical field of biological medicines. According to the invention, an asthma mouse model is constructed through HDM, different peptides of lung tissues of an asthma mouse and a non-asthma mouse are compared by adopting a label-free liquid chromatography/mass spectrometry (LC-MS/MS) technology, and then the differentially expressed polypeptides are researched by utilizing GO analysis, KEGG analysis and STRING database, so that SH3BGRL3 derived polypeptides are found to be related to asthma, a new thought is provided for the pathogenesis of asthma, and a new potential treatment target point is found.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to SH3BGRL3 derived polypeptide and application thereof.
Background
Asthma, bronchial asthma, is a chronic inflammatory disease affecting the airways. The clinical manifestations are recurrent wheezing, shortness of breath, chest distress or cough, which usually attacks or aggravates at night and in the morning, and most patients can relieve themselves or relieve through treatment. As a heterogeneous disease, the development of asthma involves gene-environment interactions and multi-type cell interactions. Allergic asthma is the most common phenotype, due to the high sensitivity of the airways to allergens in the environment, mediated primarily by the Th2 immune response, with Th2 cells mediating the immune response by producing cytokines such as IL-4, IL-5 and IL-13. It is mainly characterized by chronic eosinophilic inflammation and airway remodeling, including smooth muscle proliferation, subepithelial fibrosis, and goblet cell proliferation.
Asthma cannot be cured radically, and is generally treated by adopting medicaments, namely control medicaments and relieving medicaments. The controlled drug is a drug for long-term use, mainly maintains the clinical control of asthma through anti-inflammatory action, and comprises inhaled glucocorticoid, systemic hormone, leukotriene regulator, and long-acting beta2Receptor agonists, extended release theophylline, cromolyn sodium, anti-IgE monoclonal antibodies and other drugs that help to reduce systemic hormone dosage; the drug for relieving asthma symptoms by rapidly relieving bronchospasm, which is also called emergency drug, comprises quick-acting inhalation and short-acting oral beta2Receptor agonists, systemic hormones, inhaled anticholinergic agents, short acting theophyllines, and the like.
Based on pathogenesis, many interventions have been successfully used to alleviate asthma symptoms, such as inhaled bronchodilators, corticosteroids, avoidance of allergens, biotherapeutics (omalizumab or meplizumab, etc.). But current treatments only alleviate symptoms. It has been reported that polypeptides can play a therapeutic role in asthma by modulating immune responses, and polypeptide drugs such as CKLF1-C19, TFF, etc. provide effective treatments for alleviating asthma symptoms. For example, patent CN201611207485.7 provides a novel polypeptide, i.e., a novel fusion polypeptide is obtained by connecting DiTOX polypeptide or PADRE polypeptide to the nitrogen terminal of E3 polypeptide, and the polypeptide can be used as a main active ingredient to prepare an asthma vaccine, can effectively induce specific humoral immunity, and break immune tolerance, and has a good application prospect in the aspect of being used as an asthma therapeutic polypeptide vaccine. Patent CN201880026131.3 provides a method for treating asthma, including severe asthma and eosinophilic asthma, using antibodies specific for Thymic Stromal Lymphopoietin (TSLP). However, the underlying molecular mechanisms by which polypeptides are involved in the pathogenesis of asthma have not been elucidated.
The SH3 domain is combined with glutamic acid-rich protein-like protein 3(SH3 domain binding glutamic acid-rich protein like 3, SH3BGRL3) and is a member of thioredoxin supergene family, the gene is positioned at 1p34.3-p35, and the gene codes 93 amino acids. The protein coded by the protein is similar to Glutaredoxin (GRX) 1 of escherichia coli, and is a small oxidoreductase. SH3BGRL3 lacks the CXXC active domain consisting of 2 cysteine residues of GRX enzyme and therefore lacks GRX enzyme activity. In addition, it is considered that SH3BGRL3 protein may be involved in inhibiting tumor necrosis factor-alpha (TNF-alpha) mediated apoptosis, and is called TNF inhibiting protein (TIP-B1). It has been found that SH3BGRL3 is also a new epidermal growth factor receptor binding partner, but its exact function is poorly understood.
In conclusion, a polypeptide drug with a definite mechanism for treating asthma is needed to be found, and a new therapeutic target and a new concept are provided for treating asthma.
Disclosure of Invention
Aiming at the defects, the invention provides an SH3BGRL3 derivative polypeptide and application thereof. According to the invention, an asthma mouse model is constructed through HDM, different peptides of lung tissues of an asthma mouse and a non-asthma mouse are compared by adopting a label-free liquid chromatography/mass spectrometry (LC-MS/MS) technology, and then the differentially expressed polypeptides are researched by utilizing GO analysis, KEGG analysis and STRING database, so that SH3BGRL3 derived polypeptides are found to be related to asthma, a new thought is provided for the pathogenesis of asthma, and a new potential treatment target point is found.
In order to achieve the above object, the technical solution of the present invention is as follows:
in one aspect, the invention provides an SH3BGRL3 derived polypeptide, wherein the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1 and/or SEQ ID NO. 2.
In another aspect, the invention provides a series of nucleic acid molecules encoding said polypeptides.
In particular, the nucleic acid molecule comprises one or more codon-optimized nucleic acid molecules.
In yet another aspect, the invention provides a series of vectors comprising one or more nucleic acid molecules as described herein.
Specifically, the vector includes but is not limited to plasmid, virus, phage.
In a further aspect, the invention provides a series of host cells comprising a nucleic acid molecule as described above or a vector as described above.
Specifically, the host cell includes but is not limited to a microorganism, a plant or an animal cell, and the vector of the present invention can be introduced into the host cell by a method known to those skilled in the art, such as electroporation, lipofectine transfection, lipofectamine transfection, and the like.
In still another aspect, the present invention provides the use of the above-mentioned polypeptide, nucleic acid molecule, vector or host cell in the preparation of a medicament for treating asthma.
In yet another aspect, the present invention provides an asthma medicament comprising the polypeptide, nucleic acid molecule, vector or host cell described above.
Specifically, the medicament further comprises an optional pharmaceutically acceptable carrier.
Further specifically, the pharmaceutically acceptable carrier includes, but is not limited to: diluents, excipients, fillers, wetting agents, disintegrants, flavoring agents and binders.
In yet another aspect, the present invention provides the use of the above-mentioned polypeptide for the preparation of a medicament for the treatment, prevention and/or diagnosis of asthma.
Compared with the prior art, the invention has the advantages that:
the invention provides SH3BGRL3 derivative polypeptide, which is characterized in that by analyzing an asthma mouse model, different peptides of lung tissues of an asthma mouse and a non-asthma mouse are compared by adopting a label-free liquid chromatography/mass spectrometry (LC-MS/MS) technology, and then the differentially expressed polypeptide is researched by utilizing GO analysis, KEGG analysis and STRING database, so that SH3BGRL3 derivative polypeptide is found to be related to the occurrence of asthma, a new thought is provided for the pathogenesis of asthma, and a new potential treatment target point is searched.
Drawings
FIG. 1 is a graph showing the results of HE staining of lung tissues and bronchi of mice, wherein A is HE staining of lung tissues of HDM group and Ctrl group, and B is HE staining of bronchi of HDM group and Ctrl group.
FIG. 2 is a graph of the results of differential expression detection of peptides between HDM and Ctrl groups, wherein A is a composite pie graph of differential peptide fragments, B is a volcano graph, and C is hierarchical clustering analysis.
FIG. 3 is a graph showing the results of basic characteristics of significantly differentially expressed peptides, wherein A is the amino acid number of the identified peptide, B is the MW of the identified peptide, C is the PI of the identified peptide, D is the cleavage site at the N-terminus and C-terminus in the peptides identified in the upregulated group, E is the cleavage site at the N-terminus and C-terminus in the peptides identified in the downregulated group, and F is a peptide derived from the same precursor protein.
FIG. 4 is a GO/KEGG analysis.
FIG. 5 is a graph showing the results of the detection of the involvement of epithelial-mesenchymal transition (EMT) in the development of asthma, wherein A is the Western blot analysis of the EMT marker E-cadherin and B is the protein expression level of E-cadherin relative to GAPDH.
FIG. 6 is a schematic representation of domains and molecular formulae of peptides associated with asthma development, wherein A is a peptide derived from mouse and human domains, B is a molecular formula of STSVTGSREIKSQQSEVTR (SEQ ID NO:1), and C is a molecular formula of VEAVEQDTLQEFLKLA (SEQ ID NO: 2).
FIG. 7 is a graph of the expression of polypeptides "STSVTGSREIKSQQSEVTR" and "VEAVEQDTLQEFLKLA" in the mouse asthma model of example 2.
Detailed Description
The present invention will be further illustrated in detail with reference to the following specific examples, which are not intended to limit the present invention but are merely illustrative thereof. The experimental methods used in the following examples are not specifically described, and the materials, reagents and the like used in the following examples are generally commercially available under the usual conditions without specific descriptions.
Example 1.
1. Preparation of asthma model mice and pathological changes of lung tissues
C57BL/6 mice, 4 to 6 weeks old, were used as model building subjects and were randomly divided into House Dust (HDM) treated and control (Ctrl) groups. HDM group was injected intraperitoneally with HDM (80. mu.L, 10HEP/mL) on days 0, 7 and 14, followed by intranasal treatment with HDM (10. mu.L/day) on days 15-19. Ctrl groups were treated with PBS instead of HDM. On day 20, two different concentrations of acetylcholine sprays (12.5, 25, 100 mg/mL. times.2 mL, respectively) were given. After the molding was completed, the experimental animals were sacrificed, and the thoracic cavity was opened to lavage the lung tissue with PBS. The isolated lung tissue was then used for tissue sectioning and LC-MS/MS analysis. Animal experiments were approved by the animal ethics committee of the children hospital Shanghai (ethical number: LLSC 2019038).
HE staining results showed severe lung tissue damage in the HDM group, manifested by increased eosinophil infiltration in lamina propria, basal lamina and submucosa (fig. 1A), thickening of bronchial walls, swelling and congestion of mucosa (fig. 1B). And the lung tissue structure of Ctrl group is normal, and eosinophil infiltration is less.
Differentially expressed peptides between HDM and Ctrl groups
And extracting and purifying the lung tissue peptide sections of the HDM group and the Ctrl group for LC-MS/MS detection. The results identified 1564 peptide fragments, of which 108 were statistically differentially expressed (fold change >2 or fold change <0.5, p <0.05), comprising 44 up-regulated peptides and 64 down-regulated peptides. Volcano plots were performed to identify peptides that were significantly different between the two groups (FIG. 2B), and hierarchical clustering analysis revealed precursor proteins for the peptides between the two groups (FIG. 2C).
3. Differential peptide fragment characterization
The number of amino acids for most of the identified peptides ranged between 9-25 (FIG. 3A). Most of the identified peptides have Molecular Weights (MW) in the range of 1100-2300Da, and the isoelectric Points (PI) of the peptides are distributed between 3.0 and 10.0 (FIGS. 3B-3C). Furthermore, peptides were determined to some extent by enzymatic cleavage, and we analyzed the amino and carboxyl termini (N-or C-termini) of the peptides. Cleavage sites analyzed included the C-terminus of the previous peptide, the N-and C-termini of the identified peptides, and the N-termini of the subsequent peptides (FIGS. 3D-3E). Common sites for the upregulation group are alanine (a), phenylalanine (F), leucine (L), arginine (R). In the down-regulation group, the common sites are serine (S), methionine (M), alanine (A), and arginine (R). Among them, hemoglobin subunit α (HBA) has the largest number of related peptides (fig. 3F).
4. GO/KEGG analysis of differential polypeptide precursor proteins
GO and KEGG pathway analysis was used to predict biological progression, cellular components, molecular functions and mechanistic pathways targeted by the precursor protein. For biological progression, the most abundant classes are actin polymerization or depolymerization, modulation of actin filament-based processes, receptor-mediated endocytosis (RME), and lipid transport (fig. 4A). As for the cellular components, targeting of blood microparticles, focal adhesions, cell-substrate junctions, adhesion junctions, and actin cytoskeleton was the most (fig. 4B). For molecular function, binding of actin, phospholipids and cytoskeletal proteins is a highly abundant subcategory (fig. 4C). The precursor proteins of the peptides were identified to be involved in vitamin digestion and absorption, soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) interaction in vesicle trafficking, bacterial invasion of epithelial cells, PPAR signaling pathways, tight junctions, oxidative phosphorylation, vascular smoothing KEGG pathway analysis showing muscle contraction and chemokine signaling pathways (fig. 4D). 5. Epithelial-mesenchymal transition (EMT) involved in asthma development
Western blot analysis was performed on E-cadherin as EMT marker (FIG. 5). The expression of E-cadherin was down-regulated in the HDM group.
EMT is involved in asthma development
Using the UniProt database to analyze the domains, it was found that the up-regulated peptides "STSVTGSREIKSQQSEVTR" (SEQ ID NO:1) and "VEAVEQDTLQEFLKLA" (SEQ ID NO:2) developed from the glutaredoxin domain were involved in the pathophysiological processes of asthma. Peptide "STSVTGSREIKSQQSEVTR" (SEQ ID NO:1) has 100% amino acid sequence identity to human, and peptide "VEAVEQDTLQEFLKLA" (SEQ ID NO:2) has 93.8% amino acid sequence identity to human (FIGS. 6A-C).
Example 2.
The expression of peptides "STSVTGSREIKSQQSEVTR" (SEQ ID NO:1) and "VEAVEQDTLQEFLKLA" (SEQ ID NO:2) during the modeling of asthma in mice ( days 1, 7, 14, 20) was examined using targeted mass spectrometry, respectively. It was found that "STSVTGSREIKSQQSEVTR" increased from day 14 of molding (FIG. 7A), while "VEAVEQDTLQEFLKLA" continued to be highly expressed throughout the molding process (FIG. 7B). This indicates that "STSVTGSREIKSQQSEVTR" and "VEAVEQDTLQEFLKLA" have important roles in asthma development and can be used as biological targets for treating and/or preventing asthma development.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Sequence listing
<110> Hospital of Shanghai city
<120> SH3BGRL3 derived polypeptide and application thereof
<130> 20211108
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<170> SIPOSequenceListing 1.0
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<211> 19
<212> PRT
<213> Artificial sequence (artificial sequence)
<400> 1
Ser Thr Ser Val Thr Gly Ser Arg Glu Ile Lys Ser Gln Gln Ser Glu
1 5 10 15
Val Thr Arg
<210> 2
<211> 16
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<213> Artificial sequence (artificial sequence)
<400> 2
Val Glu Ala Val Glu Gln Asp Thr Leu Gln Glu Phe Leu Lys Leu Ala
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Claims (10)
1. An SH3BGRL 3-derived polypeptide, comprising: the amino acid sequence of the polypeptide is shown as SEQ ID NO. 1 and/or SEQ ID NO. 2.
2. A series of nucleic acid molecules encoding the polypeptide of claim 1.
3. A series of vectors comprising one or more nucleic acid molecules of claim 2.
4. The carrier of claim 3, wherein: the vector comprises a plasmid, a virus or a phage.
5. A series of host cells comprising the nucleic acid molecule of claim 2 or the vector of claim 3.
6. The host cell of claim 5, wherein: the host cell includes a microorganism, a plant or an animal cell.
7. Use of the polypeptide of claim 1, the nucleic acid molecule of claim 2, the vector of claim 3, or the host cell of claim 5 in the preparation of a medicament for treating asthma.
8. An asthma medicine, which is characterized in that: the medicament comprises the polypeptide of claim 1, the nucleic acid molecule of claim 2, the vector of claim 3, or the host cell of claim 5.
9. The medicament of claim 8, wherein: the medicament further comprises an optional pharmaceutically acceptable carrier.
10. Use of a polypeptide according to claim 1 for the preparation of a medicament for the treatment, prevention and/or diagnosis of asthma.
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| CN101273144A (en) * | 2005-07-27 | 2008-09-24 | 肿瘤疗法科学股份有限公司 | Method of diagnosing esophageal cancer |
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