CN103539834B - Chemotactic element derived peptide and expressing gene thereof and application - Google Patents
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Abstract
A kind of chemotactic element derived peptide, for having the polypeptide of following structural formula: Xaa1 Leu Gln Val Ala Leu Glu Glu Phe His；Wherein, Xaa1It is any one in 20 L aminoacid.Above-mentioned chemotactic element derived peptide is polypeptide due to its chemical nature, thus overcome traditional natural chemotactic element and molecular weight that digestion products has is relatively large, preparation difficulty, there is the shortcoming such as antigenicity, poor stability, can produce and carry out big animal and the experimentation of human body and drug development in enormous quantities.The invention also discloses the expressing gene of this chemotactic element derived peptide and in treatment cancer, obesity, fatty liver, diabetes, cardiovascular disease nervous system, reproduction and the application of metabolic syndrome.
Description
[technical field]
The present invention relates to polypeptide drugs field, particularly relate to a kind of chemotactic element derived peptide and expressing gene thereof and application.
[background technology]
Protein is a most important class biomacromolecule in body, at present by widely as medicine controlling for disease
Treat (Li Wei 2004).But, protein drug also has shortcoming, as big in molecular weight, preparation difficulty, exist antigenicity, internal easily
Degraded etc..The good news is, it has been found that the polypeptide of some molecular weight has the activity of analogous protein equally, and function is more
Significantly.These have bioactive polypeptide content in vivo few (even without) but effect is extremely strong, the generation of numerous disease,
Development all unbalance relevant with them, drug development prospect is the best, therefore, the research and development of polypeptide drugs Cheng Liao state
Biological high-tech area emerging on border, has great market potential.
To late 1990s, existing tens thousand of kinds more than of the natural polypeptides class physiologically substance that scientist has been found that, relate to
To hormone, nerve, cell growth, reproduction, neoplastic lesion, the neuro hormone transmission field such as matter and immunomodulating, 2006, the whole world
Protein/polypeptide class medicine total sales volume is more than 60,000,000,000 dollars of high pointes, it is contemplated that within 2008, be up to 75,000,000,000 ~ 80,000,000,000 dollars,
Annual rate of growth reaches more than 20%.Although as long as the existing a century of the discovery of polypeptide, but it only has short by 20 as the performance history of medicine
Year.In these 20 years, the polypeptide drug at least kind more than 100 of countries in the world exploitation listing, as being in great demand on current international market
Leuprorelin, gray(Gy) woods, buserelin, metakentrin antagonist, Fuzeon and utilize that biological engineering means produce each
Kind of medicine (as human growth hormone, white between element, insulin human, interferon and granulocyte colony somatomedin etc.).Report according to the parties concerned
Road, 2006, whole world protein/polypeptide class medicine total sales volume was more than 60,000,000,000 dollars of high pointes, it is contemplated that within 2008, be up to
75000000000～80,000,000,000 dollars, annual rate of growth reaches more than 20%.Polypeptide drug had become an important big class on international market already.
Compared with most organic molecule medicines, the active height of polypeptide drug, dosage is little, toxic and side effects is low,
Metabolic end product is the outstanding features such as aminoacid；Compared with protein-based, less peptide is almost without immunogenicity；Chemically close
Becoming, product purity is high, quality controllable.It's a pity, there is a considerable amount of polypeptide in organism, the polypeptide having now been found that is only
1% or less.Therefore, necessary excavation and research and develop the new polypeptide with physiologically active, new polypeptide may represent new
Treatment means.
At present, the polypeptide drug on market is mainly derived from animal tissue and extracts, chemosynthesis and DNA recombinant expression
Three productions mode.It is reported, due to cost of material reduction, scale and benefit and the progress of isolation technics, chemistry Peptide systhesis is special
It not that Solid phase peptide synthssis cost is remarkably decreased.
It is introduced, compared with chemosynthesis, gene recombinaton mode is more suitable for the preparation of long peptide；And entering along with technology
Step, the cost producing polypeptide drugs in gene recombinaton mode is also constantly reducing.
Mo Nita thinks in research report, and the polypeptide drugs extracted from animal tissue will progressively be eliminated, and chemistry closes
Become and DNA recombinant expression will become the polypeptide drugs mode of production complemented one another within a very long time.
Chemotactic element (Chemerin), also referred to as retinoic acid receptors reactive protein 2 (retinoic acid receptor
Responder2, RARRES2), Tazarotene-induced gene 2 (tazarotene-induced gene2, TIG2) encode, be
G protein coupled receptor chemerin R, also referred to as ChemR23 or chemokine receptors 1(chemokine-like
Receptor1, CMKLR1) native ligand (Wittamer et al.2003, Zabel et al.2005), because having chemotactic
Effect that antigen-presenting cell is assembled and gain the name, be also the Adipocyte Factor (Bozaoglu et al.2007) newly confirmed for 2007.
The most also find that the CCRL2 on GPCRs family member GPRl and mastocyte is also the receptor of chemotactic element, but they are the most direct
Support chemotaxis (chemotaxis) (Barnea et al.2008, Zabel et al.2008).
Chemotactic element is in the Various Tissues wide expression of human body, at fatty tissue, adrenal gland, liver, lung, pancreas, Placenta Hominis, ovum
Nest, skin etc. have expression, be mainly expressed in white adipose tissue, liver and lung (summary: Wang Xiaojuan and Yan Jianying,
2010).Chemotactic element function is extensive, such as chemotaxis, the suppression of promotion dendritic cell, macrophage and NK cell to inflammation sites
Pro-inflammatory mediator TNF α and the synthesis of IL-6, increase adiponectin generation, promote the differentiation of adipose cell with ripe, to improve fat thin
Born of the same parents to the sensitivity of insulin and the picked-up of glucose, regulation lipolysis, increase the synthesis of TNF β, improve the activity of NF κ β,
Increase the synthesis of VEGF and MMPs and regulate new vessels generation and revascularization etc. (Kukla et al.2011).Therefore,
Chemotactic element (relates to obesity, fatty liver, diabetes and Metabolic syndrome at immunne response, inflammatory reaction, lipogenesis with lipid metabolism
Levy) etc. aspect played important function, application prospect is preferable.
Chemotactic element conservative in the biologies such as people, mice and rat is stronger.As it is shown in figure 1, mankind's TIG2 gene expression is turned over
The protein translated is chemotactic element preproprotein, is " Pre-prochemerin ", is made up of, at N-terminal 163 aminoacid
There are 20 amino acid whose signal peptides (table 1, Du and Leung.2009, Ernst and Sinal.2010).This signal peptide is cut
Chemotactic element precursor (prochemerin) is formed after cutting.Body each tissue (except peripheral blood leucocyte) in normal state produces
Chemotactic element be secreted into extracellular with its precursor forms proChemerin, proChemerin activity is the lowest, at different albumen water
Solve the lower chemotactic element producing multi-form of effect of enzyme, there is immune chemotaxis (table 1, Du and in various degree
Leung.2009, Ernst and Sinal.2010).As can be seen from Table 1, the natural chemotactic element up to the present found
(Chem21-157, Chem21-155 and Chem21-154) and enzyme action formed chemotactic element (Chem21-158, Chem21-156,
Chem21-152) it is all protein, the most not less than 50 amino acid whose polypeptide.Once other people were had to invent people's weight in application aspect
Group chemerin albumen, recombinant vector and transformant and preparation method thereof.
But, in conjunction with Fig. 1 it can be seen that internal discovery multiple natural chemotactic element (chemerin) and digestion products thereof,
It is all protein, has that molecular weight is relatively large, preparation difficulty, there is the shortcoming such as antigenicity, poor stability, be difficult to high-volume raw
Produce and carry out big animal and the experimentation of human body and drug development.
The multi-form of table 1. chemotactic element and the chemotactic activity that has thereof
List of references:
Barnea et al.The genetic design of signaling cascades to record
receptor activation.Proc.Natl.Acad.Sci.USA2008.105:64–69.
Bozaoglu et al.Chemerin is a novel adipokine associated with obesity
And metabolic syndrome ［ J ］ .Endocrinology, 2007,148(10): 4687-4694.
Cash et al.Synthetic chemerin-derived peptides suppress inflammation
through ChemR23.J Exp Med.2008;205(4):767-75.
Du and Leung.Proteolytic regulatory mechanism of chemerin
bioactivity.Acta Biochim Biophys Sin(Shanghai).2009;41(12):973-9.
Ernst and Sinal.Chemerin:at the crossroads of inflammation and
obesity.Trends Endocrinol Metab.2010;21(11):660-7.
Goralski et al.Chemerin:a novel adipokine that regulates adipogenesis
And adipocyte metabolism ［ J ］ .J Biol Chem, 2007,282 (38): 28175-28188.
Kukla et al.Potential role of leptin,adiponectin and the novel
adipokines-visfatin,chemerin and vaspin-in chronic hepatitis.Mol
Med.2011.doi:10.2119/molmed.2010.00105.
Wittamer et al.Specific recruitment of antigen-presenting cells by
chemerin,a novel processed ligand from human inflammatory
fluids.J.Exp.Med.2003.198:977-985.
Wittamer et al.The C-terminal nonapeptide of mature chemerin
Activates the chemerin receptor with low nanomolar potency ［ J ］ .J Biol Chem,
2004,279(11): 9956-9962.
Zabel et al.Chemoattractants,extracellular proteases,and the
integrated host defense response.Exp.Hematol.2006.34:1021-1032.
Zabeletal.Chemokine-likereceptor 1 expression and chemerin-directed
chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human
blood.J.Immunol.2005.174:244251.
Zabel et al.Mast cell-expressed orphan receptor CCRL2 binds chemerin
and is requiredfor optimal induction of IgE-mediated passive cutaneous
anaphylaxis.J.Exp.Med.2008.205:2207–2220.
Li Wei Shanghai medicine 200425(3): 119-121.
Wang Xiaojuan and face build the progress world obstetrics and gynecology magazine (JInt of English Adipocyte Factor chemerin
Obstet Gynecol) 201037(1): 43-46.
[summary of the invention]
Based on this, it is necessary to provide a kind of chemotactic element derived peptide and expressing gene thereof and application.
A kind of chemotactic element derived peptide, for having the polypeptide of following structural formula:
Xaa1-Leu-Gln-Val-Ala-Leu-Glu-Glu-Phe-His；
Wherein, Xaa1It is any one in 20 l-amino acids.
Preferably, for having the polypeptide of following sequence:
Polypeptide as shown in SEQ ID No.1, or
Polypeptide as shown in SEQ ID No.2.
A kind of expressing gene, its expression product includes above-mentioned chemotactic element derived peptide.
Above-mentioned chemotactic element derived peptide is in treatment cancer, obesity, fatty liver, diabetes, cardiovascular disease and metabolism
Application in syndrome medicament.
Above-mentioned chemotactic element derived peptide is polypeptide due to its chemical nature, thus overcomes traditional natural chemotactic element and enzyme thereof
Cut that the molecular weight that product has is relatively large, preparation difficulty, there is the shortcoming such as antigenicity, poor stability, can produce in enormous quantities
With experimentation and the drug development carrying out big animal and human body.
[accompanying drawing explanation]
Fig. 1 is precursor sequence in the biologies such as the mankind, mice and rat before chemotactic element；Indicate respectively in square frame is letter
Number peptide, there is the people Chem of chemotaxis149-157With the mice Chem with antiinflammatory action140-154Sequence.
Fig. 2 is precursor (Pre-prochemerin) amino acid whose sequence alignment figure before different plant species chemotactic element.
Fig. 3 is the isotope Binding experiment of chemotactic element derived peptide N10 and CCRL2 recipient cell；
Fig. 4 is the mass spectrometry results figure after thrombin and fibrinolysin Combined Treatment Mus restructuring chemotactic fibroin；
Fig. 5 is that quantitative PCR method detection CCRL2mRNA is in cerebral cortex, terminal mucro, cerebellum, spinal cord, hypothalamus and hypophysis
Expression of results figure；
Fig. 6 is that quantitative PCR method detection CCRL2mRNA is at testis, epididymis, deferent duct, seminal vesicle, prostate, heart, kidney
With the expression of results figure in the fatty tissue of epididymis；
Fig. 7 is that quantitative PCR method detects CCRL2mRNA expression of results figure in cancer cell.
[detailed description of the invention]
In recent years in order to study the active peptide segment of chemotactic element, the many chemotactic element precursor carboxyl terminal districts of people's synthetic
The peptide fragment in source, territory, finds that the shortest chemotactic element biological activity peptide fragment is people Chem149-157The also referred to as chemotactic element C9 peptide of people
(chemerin9), this 9 peptide has strong chemotactic activity (Wittamer et al.2004)；In mice, 15 aminoacid groups
The chemotactic element C15 peptide (Chem become140-154), there is antiinflammatory action (Cash et al.2008).This explanation, derives from chemotactic element
Polypeptide be activated.This discovery has pointed out us: excavate internal existence and activated natural chemotactic element polypeptide is obvious
Providing for the application of chemotactic element that low cost, technique is simple, the more preferable form of stability, the development for relevant new drug provides newly
Convenient effective way.
People Chem149-157With the Chem in mice140-154, although be all combined with CMKLR1 and/or GPR1, and have one
Fixed biological activity, but there is certain problem:
(1) belonging to the polypeptide of synthetic, restriction enzyme site does not have conservative between different plant species, points out the two polypeptide
It it not the form of endogenous existence；
(2) do not have detailed information display both polypeptide and chemotactic element chemerin three kinds of receptors (CMKLR1,
CCRL2, GPR1) between relation.Because different receptors, its biological function is not quite similar, without illustrating and which
Receptor combines, and is difficult to determine the aglucon that both polypeptide are three receptors, or the aglucon of simply certain receptor, thus, very
Difficulty determines the definite biological function of two peptide species and medical value.
Utilize bioinformatics tools, have the special feature that according to polypeptides/proteins hormone, and combine inventor for many years send out
The accumulation of the newest knowledge and experience in terms of polypeptides/proteins hormone, thus excavated internal existence, endogenic and
There is chemotactic element derived peptide biologic activity, natural, new, be designated as N10.This peptide species safety is higher, being subject to of combining
Body and biological activity are more precisely, low cost, technique are simple, stability is more preferable, are the succedaneum of natural chemotactic element, both can substitute
Natural chemotactic element carries out deep function, the research of mechanism, it is also possible to substitutes natural chemotactic element and carries out deep materia medica research；
Searching for the drug tar-get of known three receptors provides new tool, and the development for relevant new drug provides new way.
As seen from Figure 2, in different plant species, precursor (Pre-prochemerin) amino before different plant species chemotactic element
The sequence of acid is the most conservative.Wherein, gray background part is respectively the sequence of newfound N10.
Being briefly described as a example by people's chemotactic element derived peptide N10, its sequence is as follows: Gly29-Leu30-Gln31-
Val32-Ala33-Leu34-Glu35-Glu36-Phe37-His38。
For people's chemotactic element derived peptide N10, the 29th amino acid whose sequence can change close aminoacid sequence into, to chemotactic element
The biologic activity impact of derived peptide N10 will not be the biggest；But Leu30-Gln31-Val32-Ala33-Leu34-Glu35-Glu36-
Phe37-His38Sequence the most conservative, it is impossible to change, if having changed aminoacid sequence, it is likely that can affect its biology live
Property.
Based on this, it is provided that a kind of chemotactic element derived peptide N10, for having the polypeptide of following structural formula:
Xaa1-Leu-Gln-Val-Ala-Leu-Glu-Glu-Phe-His；
Wherein, Xaa1It is any one in 10 l-amino acids.
This chemotactic element derived peptide N10 sequence in each different plant species is as follows:
People's chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Orangutan chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Monkey chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Rabbit chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Canis familiaris L. chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Pig chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Cattle chemotactic element derived peptide N10(G29-H38): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Rat chemotactic element derived peptide N10(G31-H40): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Hamster chemotactic element derived peptide N10(G31-H40): GLQVALEEFH, for the polypeptide shown in SEQ ID No.1；
Mice chemotactic element derived peptide N10(S31-H40): SLQVALEEFH, for the polypeptide shown in SEQ ID No.2.
Chemotactic element derived peptide N10 can be according to its sequence, and synthesis prepares in vitro.It expresses base can also to use synthesis
Cause, after expressing in other biological body, purification obtains.
Also providing for a kind of expressing gene, its expression product includes chemotactic element derived peptide N10 simultaneously.
Existing research display, chemotactic element and three receptors CMKLR1, CCRL2 and GPR1 inflammatory reaction, chemotaxis,
Cancer, obesity, fatty liver, diabetes, cardiovascular disease and metabolic syndrome all have effect.From now on, more and more
Research association excavates three receptors, CMKLR1, CCRL2 and GPR1, more, biological function more precisely.
Chemotactic element derived peptide N10 and iodine target people's chemotactic element, and has transfected the recipient cell competitive binding of people CCRL2,
Obtain Fig. 3.
As seen from Figure 3, display people's chemotactic element derived peptide N10 is combined with CCRL2 receptor.
It can thus be seen that chemotactic element derived peptide N10 is the aglucon of CCRL2 receptor.Therefore, chemotactic element derived peptide N10 or
Person is as the activator (agonist) of CCRL2 receptor, or the antagonist (antagonist) as CCRL2 receptor, and it is biological
Learn function relevant to the function of CCRL2 receptor.Chemotactic element derived peptide N10 will be the part of further investigation CCRL2 biological function.
After using thrombin (Thrombin) and fibrinolysin (Plasmin) Combined Treatment Mus restructuring chemotactic fibroin, mass spectrum
Analysis result is as shown in Figure 4.As seen from Figure 4, combine enzyme action through thrombin (Thrombin) and fibrinolysin (Plasmin) to obtain
To chemotactic element derived peptide N10 that molecular weight is 1171.
Further, it is also possible to use protaminase (Carboxypeptidase B) and thrombin (Thrombin) to be used in combination,
Chemotactic fibroin is carried out enzyme action and can also arrive chemotactic element derived peptide N10.
The above results illustrates, in human body or animal body, has in the tissue of above protease, organ, all can be with enzyme action
Provide chemotactic element derived peptide N10 activated, endogenic.
Utilizing real-time quantitative PCR method to detect, testing result is as shown in Fig. 5 ~ Fig. 7.As seen from Figure 5, CCRL2mRNA exists
Cerebral cortex, terminal mucro, cerebellum, spinal cord, hypothalamus and hypophysis in central nervous system all has expression, in hypophysis therein
Express the highest.As seen from Figure 6, CCRL2mRNA testis, epididymis, deferent duct, seminal vesicle, prostate, heart, kidney and
The fatty tissue of epididymis also has expression.As seen from Figure 7, at certain cancers cell, especially human breast cancer cell, people's
Endometrial Carcinoma Cells, mouse mastopathy cell and mouse prostate cancerous cell there is high expressed.
The above results illustrates, as the part of CCRL2, chemotactic element derived peptide N10, can act on above expression
Tissue or the organ of CCRL2mRNA and play an important role.In hypophysis, there are somatotroph and mammotroph,
Can secrete respectively on growth hormone (GH) and prolactin antagonist (PRL), thyrotroph, TSH cell, gonadotroph and rush kidney
Glandular hormone cell, thyrotroph, TSH cell secretion thyrotropin (TSH), adrenotrophic hormone emiocytosis promotees adrenal gland
Hormone (ACTH), mainly glucocorticoid.Gonadotroph secretion lutropin (LH) and follicule-stimulating hormone (FSH)
(FSH).Hypophysis is also secreted the melanocyte of melanophorin (MSH).As the part of CCRL2, chemotactic element derives
Peptide N10 will to pituicyte secretion growth hormone, prolactin antagonist, thyrotropin, adrenotrophic hormone, lutropin and
The regulation of follicule-stimulating hormone (FSH) and melanophorin has an impact.
Chemotactic element derived peptide N10 may be used for preparation treatment cancer, obesity, fatty liver, diabetes, cardiovascular disease with
And Metabolic syndrome disease drug, will be at inflammatory reaction, chemotaxis, cancer, obesity, fatty liver, diabetes, the heart with CCRL2
The new drug candidate that angiopathy and metabolic syndrome are correlated with.
Chemotactic element derived peptide N10 is polypeptide due to its chemical nature, thus overcomes traditional natural chemotactic element and enzyme thereof
Cut that the molecular weight that product has is relatively large, preparation difficulty, there is the shortcoming such as antigenicity, poor stability, can produce in enormous quantities
With experimentation and the drug development carrying out big animal and human body.Meanwhile, chemotactic element derived peptide N10 has clear and definite, specific
Receptor, special physiologically active, thus have safety higher, active good, that low cost, technique are simple, stability is more preferable etc. is excellent
Point.
Embodiment described above only have expressed one or more embodiments of the present invention, and it describes more concrete and detailed
Carefully, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that, for the common skill of this area
For art personnel, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement, these broadly fall into this
Bright protection domain.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (1)
1. a chemotactic element derived peptide, it is characterised in that
Described chemotactic element derived peptide is the polypeptide as shown in SEQ ID No.1；Described chemotactic element derived peptide can be with CCRL2 receptor
In conjunction with.
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| WO2019119307A1 (en) * | 2017-12-20 | 2019-06-27 | 深圳先进技术研究院 | Cmklr1 antagonist polypeptide, and derivative and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1464057A (en) * | 2002-06-03 | 2003-12-31 | 北京大学 | Chemokine-like factor superfamily having skeletal muscle stimulating activity and immunoregulation function |
| US8003347B2 (en) * | 2001-07-09 | 2011-08-23 | Euroscreen S.A. | Nucleic acids encoding ChemerinR ligands |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8003347B2 (en) * | 2001-07-09 | 2011-08-23 | Euroscreen S.A. | Nucleic acids encoding ChemerinR ligands |
| CN1464057A (en) * | 2002-06-03 | 2003-12-31 | 北京大学 | Chemokine-like factor superfamily having skeletal muscle stimulating activity and immunoregulation function |
Non-Patent Citations (1)
| Title |
|---|
| proteolytic cleavage of chemerin protein is necessary for activation to the active form, chem157s, which functions as a signaling molecule in glioblastoma;Yasuto Yamaguchi;《J Biol Chem》;20110923;第286卷(第45期);39510-39519 * |
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