CN1872879A - Anagonism active polypeptide of CXCR4 acceptor from inflammation protein of virus macrophage - Google Patents
Anagonism active polypeptide of CXCR4 acceptor from inflammation protein of virus macrophage Download PDFInfo
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- CN1872879A CN1872879A CN 200610036137 CN200610036137A CN1872879A CN 1872879 A CN1872879 A CN 1872879A CN 200610036137 CN200610036137 CN 200610036137 CN 200610036137 A CN200610036137 A CN 200610036137A CN 1872879 A CN1872879 A CN 1872879A
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Abstract
This invention discloses a method for preparing CXCR4-receptor antagonistic peptide from virus macrophage inflammatory protein. The method comprises: analyzing based on bioinformation to obtain the binding sites of vMIP-II and CXCR4-receptor, and preparing the peptide by chemical synthesis or genetic engineering. The peptide can specifically bond with a certain chemokine receptor, while does not cause the lymphocyte chemotactic movement and calcium ion fluxion, thus is a high efficiency anatagonist. The peptide can be used to treat CXCR4-chemokine-related diseases, such as HIV infection, metastasis of malignant tumor, severe anemia, stem cell mobilization and atherosclerosis.
Description
Technical field
The present invention relates to derive from of the application of inflammation protein of virus macrophage (vMIP-II) polypeptide, especially derive from the CXCR4 receptor antagonist activity polypeptide and the application thereof of inflammation protein of virus macrophage at pharmacy field.
Background technology
The HIV/ HIV (human immunodeficiency virus) infection, hepatitis B, the transfer of malignant tumour, the chronic immunity inflammation, immunosuppression, significant anaemia, disease treatments such as atherosclerosis, prevention, control difficulty are brought great misery to people.Because the mechanism of above-mentioned disease is extremely complicated, also there is not relevant specific treatment control medicine at present.
Various immunocytes directional migration between the recycle system and histoorgan is being controlled in the interaction of chemokine and its acceptor, make it to arrive infection, wound and abnormality proliferation position, carry out and remove the source of infection, promote wound healing and eliminate the abnormality proliferation cell, keep histocyte equilibrated function.Therefore the chemokine system is in key position in each link that function of immune system is exercised, and all plays an important role at growth, trauma repair, tumour formation and the aspects such as transfer, transplantation immunity repulsion thereof of removing, inflammatory reaction, pathogenic infection, cell and the organ of pathogenic agent thus.With chemokine and acceptor molecule thereof is drug target, conduct the function of chemokine system by the signal of activation or antagonism Chemokine Receptors, can be used for control and treatment relative disease, for example treat the HIV/ HIV (human immunodeficiency virus) infection, hepatitis B, the transfer of malignant tumour, the chronic immunity inflammation, immunosuppression, significant anaemia, atherosclerosis, or the like.Chemokine and their analogue have the good curing prospect in these diseases.
Inflammation protein of virus macrophage-II (virus macrophage inflammatory protein-II, vMIP-II) be a kind of viral chemokine by the K4 genes encoding of human herpes virus 8, with people CC class chemokine bigger homology being arranged, is the analogue of human chemokine.95 amino acid of the full genes encoding of vMIP-II, the first two 13 is signal peptide sequence, a last arginine also is removed after protein folding is finished, and the albumen of bringing into play function at last has 71 amino-acid residues, and this albumen and people's MIP homology is up to 41%.VMIP-II with do not cause born of the same parents after Chemokine Receptors combines in Ca2+ rapidly in stream, conduct so do not cause signal, thereby chemokine played antagonistic action with combining of corresponding acceptor.VMIP-II and CC, CXC Chemokine Receptors can both in conjunction with, so chemokine there is the antagonistic action of wide spectrum.The unique features that vMIP-II is different from other chemokines is that it can comprise CCR1 by antagonism, CCR2, and CCR3, CCR5, CXCR4 and CX3CR etc. particularly have higher avidity to CCR5 and CXCR4 at interior multiple Chemokine Receptors.At present, structural similarity according to chemokine family, by to vMIP-II and other chemokine sequence and molecular structure modeling contrast, seek the chemokine high conservative region relevant with receptors bind, synthetic corresponding site derive from polypeptide that vMIP-II can have a CXCR4 receptor-binding activity with and the report of application facet also do not occur.
Summary of the invention
The present invention derive from the CXCR4 receptor antagonist activity polypeptide of inflammation protein of virus macrophage and application aims thereof provide derive from polypeptide that inflammation protein of virus macrophage (vMIP-II) can have a CXCR4 receptor-binding activity with and in treatment HIV/ HIV (human immunodeficiency virus) infection, the transfer of malignant tumour, significant anaemia, Chemokine Receptors relative disease such as atherosclerosis and the maturation and the migration that promote stem cell play the stem cell mobilization effect.
The present invention realizes like this:
The CXCR4 receptor antagonist activity polypeptide that the present invention derives from inflammation protein of virus macrophage is to utilize chemokine family height homologous characteristics, carry out based on the multisequencing comparative analysis of structure seek and a plurality of chemokines of CXCR4 receptors bind between high conservative region, zone or the residue that they may be relevant with the CXCR4 receptors bind just.Whether the method that shows by molecule three-dimensional space is analyzed and is selected some on the basis of locus in these sites and include the CXCR4 receptor binding site and polypeptide fragment that derive from the full molecule of vMIP-II, and utilize the molecule modeling technique that these polypeptide are carried out the molecule three dimensional structure simulation to have and the similar space structure of molecule corresponding site entirely to understand these polypeptide.Obtain the CXCR4 receptor antagonist activity polypeptide that comes from vMIP-II accordingly then.
The CXCR4 receptor antagonist activity polypeptide that the present invention derives from inflammation protein of virus macrophage includes the binding site of associated receptor, and vMIP-II contains body in conjunction with the polypeptide of CXCR4 acceptor G2 among the vMIP-II, K10 residue.
Polypeptide of the present invention can obtain the binding site of vMIP-II and CXCR4 acceptor on the basis of bioinformatic analysis, obtain by chemical synthesis or genetic engineering technique means then.
Polypeptide of the present invention has the effect of specificity in conjunction with CXCR4, and to the not effect of other Chemokine Receptors, is single chemokine receptor anagonists.
Polypeptide of the present invention can be in the HIV/ HIV (human immunodeficiency virus) infection, the transfer of malignant tumour, significant anaemia, aspect application such as CXCR4 Chemokine Receptors relative disease such as atherosclerosis and the maturation that promotes stem cell and migration.
CXCR4 receptor-specific polypeptide of the present invention can enter target cell thereby effectively block the HIVX4 strain by antagonism and sealing CXCR4 acceptor, has the effect of anti-HIV/ HIV (human immunodeficiency virus) infection, and is especially effective especially to the patient of period of disease.
Polypeptide of the present invention can be competed binding chemotactic factor receptor with the body physiological chemokine, thereby leukocyte chemotaxis activity and intracellular calcium that blocking-up physiological chemokine causes flow, thereby transfer in Chemokine Receptors relative disease such as malignant tumour, significant anaemia, atherosclerosis etc. have therapeutic action.
Polypeptide of the present invention can be by the CXCR4 receptors bind of expressing with stem cell surface, thereby promotes maturation and the migration of stem cell, plays the effect of stem cell mobilization agent, thereby aspect stem cell transplantation effect is arranged.
Polypeptide of the present invention can by with the CXCR4 receptors bind that in inflammatory reaction, plays an important role, thereby blocking-up CXC class chemokine and CXCR4 receptors bind, in conjunction with the inflammatory reaction that suppresses by their mediation, in the treatment inflammatory reaction, effect is arranged by the blocking-up receptors ligand.
The CXCR4 receptor antagonist activity polypeptide that comes from inflammation protein of virus macrophage of the present invention has the effect of a certain Chemokine Receptors of specific combination, is an efficient and special chemokine receptor anagonists.The energy binding chemotactic factor receptor, do not cause that but activity of lymphocyte chemotactic and calcium ion flow, can be used for the treatment of the HIV/ HIV (human immunodeficiency virus) infection, the transfer of malignant tumour, significant anaemia, stem cell mobilization, CXCR4 Chemokine Receptors relative disease such as atherosclerosis and the maturation and the migration that promote stem cell play the stem cell mobilization effect.
Figure of description
Fig. 1 is the multiple sequence comparative analysis of the vMIP-II of the present invention and the CXCR4 receptors bind factor;
Fig. 2 is the chemotactic activity experiment of polypeptide P1 of the present invention;
Fig. 3 causes the inhibiting rate of cell chemotaxis to SDF-1 for polypeptide P1 of the present invention;
Fig. 4 is the influence of polypeptide P1 PBMC cellular calcium concentration of the present invention;
The influence of the calcium current that Fig. 5 causes CXCR4 atopen SDF-1 α for the P1 of different concns of the present invention;
Fig. 6 is that P1 of the present invention suppresses synplasm formation experiment.
Embodiment
The present invention is further described below in conjunction with drawings and Examples.
The multiple alignment comparative analysis of protein sequence adopts Informax Vector NTI Version 9.0 software packages to finish.Adopt AlignX process wherein to carry out forecast analysis to influence Chemokine Receptors bonded residue: select for use earlier with CXCR4 receptor-specific bonded humanized chemokine sequence and carry out analysiss of aliging of multiple sequence based on structure, in whole chemokine sequences, all exist or the residue of guarding replacement promptly may be with this receptor in conjunction with relevant residue (being the foundation of standard) in conjunction with the residue model.Thereby to draw vMIP-II be vMIP-II and the possible relevant residue of receptors bind with this receptor in conjunction with relevant residue in conjunction with carrying out the multiple sequence comparative analysis in the residue model sequence of vMIP-II to be introduced standard again.For the interference of the irrelevant residue of removing of maximum possible, utilize with the vMIP-II homology higher, but not with this receptor bonded chemokine as exclusion standard, get rid of the residue that also exists as exclusion standard, thereby obtain the residue with the receptors bind height correlation.
From the result of Fig. 1 (square frame in be exclusion standard, the black round dot shows the zone of high conservative) mainly holding at the bigger N that makes a variation of vMIP-II and CXC class Chemokine Receptors binding site as can be seen, there is G2 in main site, K10.According to sequential analysis above Fig. 1 and residue locus analytical results, can design the polypeptide in the theoretical site of corresponding CXCR4 receptors bind.Include G2, the polypeptide in the site of K10 has the activity in conjunction with CXCR4.Analysis by above-mentioned sequential analysis and residue locus, the CXCR4 receptor antagonist activity polypeptide that comes from inflammation protein of virus macrophage of the present invention comprises the polypeptide in corresponding CXCR4 binding isotherm site respectively, and their sequence is respectively LGASWHRPDKCCLGY (P1).
Polypeptide of the present invention is on the basis of bioinformatic analysis, obtains the binding site of vMIP-II and CXCR4 acceptor, prepares by chemical synthesis or genetic engineering technique means then.
Separate PBMCs (mononuclearcell), adjusting cell density is 1 * 10
6/ ml.With containing 0.5% FBSRPMI1640 chemotactic damping fluid hole is blank well; The positive control wells in 0.5%FBS RPMI1640 chemotactic damping fluid hole with the ligands specific SDF-1 α that contains 10ng/ml CXCR4; With the chemotactic damping fluid hole that contains the different concns polypeptide is experimental port.In 24 hole Transwell devices, carry out the chemotactic experiment.With the cell count of chemotactic, input Microsoft Excel software carries out data processing and mapping.Experimental result Fig. 2 shows that polypeptide P1 does not all have the lymphocytic activity of chemotactic.Polypeptide less than effect, is not the Chemokine Receptors activator to the acceptor of chemokine.
Isolating PBMCs, adjusting cell density is 1 * 10
6Individual/ml, use different concns polypeptide P1 (0.1ng/ml, 1ng/ml, 10ng/ml, 100ng/ml) under 4 ℃ of conditions, to handle 30min in advance.Without the cell of any processing as blank, with the positive control wells of cultivation datum hole that contains 10ng/ml SDF-1 α.In 24 hole Transwell devices, carry out chemotactic and suppress experiment.With the cell count of chemotactic, input MicrosoftExcel software carries out data processing and mapping.Experimental result such as Fig. 3 show that polypeptide P1 causes that to SDF-1 cell chemotaxis has dose-dependent blocking effect, is the antagonist of CXCR4 acceptor.After can changing T cell tropism (T-tropic) strain (X4) into after HIV infects, its accessory receptor also transfers to based on CXCR4.Polypeptide P1 can effectively block HIV X4 strain and enter target cell by antagonism and sealing CXCR4 acceptor, has the effect of anti-HIV/ HIV (human immunodeficiency virus) infection, and especially the patient's effect to period of disease is obvious.
Utilize the variation of the method detection polypeptide pair cell calcium ion concn that continuous time, scanning detected, detected the influence of polypeptide P1 the PBMCs intracellular calcium concentration.Experimental result Fig. 4 (being selected from the representative result of 100ng/ml concentration group) shows that (itself all can not cause the variation of the intracellular calcium concentration of PBMCs polypeptide P1 100ng/ml) to different concns for 1ng/ml, 10ng/ml.Intracellular calcium concentration does not take place obviously to change after adding P1.
Polypeptide P1 by having measured different concns respectively is to CCR5, CXCR4, the influence that the calcium ion concn that the physiological chemokine of 9 receptor-specifics such as CCR2 causes changes.Experimental result shows that P1 is to MIP-1 β, IL-8, IP-10, I-309, Exotaxin-2, MIP-3 α, MIP-3 β, the caused PBMCs intracellular free calcium level of MCP-1 changes does not have obviously influence, and P1 has presented the relevant retarding effect of dosage to the calcium ion concn variation that the special chemokine SDF-1a of CXCR4 causes.As shown in Figure 5, the P1 of 1ng/ml, 10ng/ml and 100mg/ml all can suppress the calcium current that SDF-1a causes and certain dose-effect relationship is arranged.When using the P1 processing of 1ng/ml concentration in advance, can change the calcium concn that SDF-1 α causes and play tangible effect, fluorescence obviously weakens, and the flow of calcium ions that SDF-1 α causes when the P1 with 100ng/ml concentration handles is blocked substantially.So polypeptide of the present invention can be competed binding chemotactic factor receptor with the body physiological chemokine, thereby leukocyte chemotaxis activity and intracellular calcium that blocking-up physiological chemokine causes flow, thereby transfer in Chemokine Receptors relative disease such as malignant tumour, significant anaemia, atherosclerosis etc. have therapeutic action.
Whether we can block normal CEMx174 cell infection SIV (simian immunodeficiency virus) by utilizing synplasm formation inhibition experiment to detect polypeptide, thereby determine whether polypeptide has antivirus action.The virus supernatant with do not infect the CEMx174 co-culture of cells normally, in virus culture 3,5, under inverted microscope, observed synplasm (CPE) the formation situation in every hole respectively, and counted average sick cell percentage in 7 days.Polypeptide P1 suppresses synplasm and forms in the experiment, see that (left side figure is that each combination cell space forms number to Fig. 6, right figure is each group inhibiting rate), polypeptide P1 has the obvious suppression effect to CEM * 174 cells form viral synplasm, the P1 of 125ng/ml is better than control group 125ng/ml vMIP-II to the restraining effect that viral synplasm forms, inhibiting rate at 625ng/ml high dose group P1 is 67.99%, utilizes the Reed-Murch method to calculate P1 and suppresses the IC that synplasm forms
50Be 118.11ng/ml.
The CXCR4 receptor antagonist activity polypeptide that the present invention derives from inflammation protein of virus macrophage has comprised the avtive spot of vMIP-II binding chemotactic factor receptor CXCR4, activity with specific combination CXCR4 acceptor, can seal the main co-receptor that HIV infects, and have antivirus action.Simultaneously, it is treating the HIV/ HIV (human immunodeficiency virus) infection as the antagonist of a CXCR4 receptor-specific, the transfer of malignant tumour, and significant anaemia, the disease that CXCR4 acceptors such as atherosclerosis are relevant has good action, has bright prospect in pharmaceutical industry.
Claims (9)
1, a kind of CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage.
2, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 1, it is characterized in that: vMIP-II includes the binding site that body has G2 among the vMIP-II, K10 residue in conjunction with the polypeptide of CXCR4 acceptor.
3, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 2 is characterized in that: the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage obtains by chemical synthesis or genetic engineering technique means.
4, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 3, it is characterized in that: the CXCR4 receptor antagonist activity polypeptide that comes from inflammation protein of virus macrophage has the effect of specificity in conjunction with CXCR4, to the not effect of other Chemokine Receptors, be single chemokine receptor anagonists.
5, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 4 is characterized in that: the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage is used for the treatment of maturation and the migration aspect of Chemokine Receptors relative disease and promotion stem cell.
6, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 4 is characterized in that: derive from the effect that the CXCR4 receptor antagonist activity polypeptide of inflammation protein of virus macrophage has anti-HIV/ HIV (human immunodeficiency virus) infection.
7, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 4, it is characterized in that: derive from of the transfer of the CXCR4 receptor antagonist activity polypeptide of inflammation protein of virus macrophage in Chemokine Receptors relative disease such as malignant tumour, significant anaemia, atherosclerosis etc. have therapeutic action.
8, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 4 is characterized in that: derive from the application of CXCR4 receptor antagonist activity polypeptide aspect stem cell transplantation of inflammation protein of virus macrophage.
9, the CXCR4 receptor antagonist activity polypeptide that derives from inflammation protein of virus macrophage as claimed in claim 4 is characterized in that: derive from the CXCR4 receptor antagonist activity polypeptide of inflammation protein of virus macrophage, the application in the treatment inflammatory reaction.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914135A (en) * | 2010-07-23 | 2010-12-15 | 暨南大学 | Broad-spectrum chemokine receptor antagonistic polypeptide and application thereof |
| CN101730709B (en) * | 2007-07-03 | 2013-06-12 | 法瑞斯生物技术有限公司 | A CXC chemokine receptor 4 (CXCR4) antagonistic polypeptide |
| CN107325187A (en) * | 2017-07-19 | 2017-11-07 | 黄子为 | A kind of polypeptide and its application and pharmaceutical composition with CXCR4 albumen agonist activities |
| CN111214650A (en) * | 2018-11-23 | 2020-06-02 | 广州溯原生物科技有限公司 | Application of dissociation factor of HIV antigen-receptor trimer complex |
| CN113322238A (en) * | 2021-06-17 | 2021-08-31 | 浙江大学 | Monocyte and macrophage with solid tumor directional chemotaxis capability for expressing chemokine receptor, and preparation and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6852508B1 (en) * | 1997-02-28 | 2005-02-08 | Genetics Institute, Llc | Chemokine with amino-terminal modifications |
| CN1777423A (en) * | 2003-04-22 | 2006-05-24 | 阿诺麦德股份有限公司 | Chemokine receptor binding heterocyclic compounds with enhanced efficacy |
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2006
- 2006-06-29 CN CN2006100361378A patent/CN1872879B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101730709B (en) * | 2007-07-03 | 2013-06-12 | 法瑞斯生物技术有限公司 | A CXC chemokine receptor 4 (CXCR4) antagonistic polypeptide |
| CN101914135A (en) * | 2010-07-23 | 2010-12-15 | 暨南大学 | Broad-spectrum chemokine receptor antagonistic polypeptide and application thereof |
| CN101914135B (en) * | 2010-07-23 | 2013-06-12 | 暨南大学 | Broad-spectrum chemokine receptor antagonistic polypeptide and application thereof |
| CN107325187A (en) * | 2017-07-19 | 2017-11-07 | 黄子为 | A kind of polypeptide and its application and pharmaceutical composition with CXCR4 albumen agonist activities |
| CN107325187B (en) * | 2017-07-19 | 2021-11-09 | 黄子为 | Polypeptide with CXCR4 protein agonistic activity and application and pharmaceutical composition thereof |
| CN111214650A (en) * | 2018-11-23 | 2020-06-02 | 广州溯原生物科技有限公司 | Application of dissociation factor of HIV antigen-receptor trimer complex |
| CN113322238A (en) * | 2021-06-17 | 2021-08-31 | 浙江大学 | Monocyte and macrophage with solid tumor directional chemotaxis capability for expressing chemokine receptor, and preparation and application thereof |
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