CN101638431B - Polypeptide capable of combining with NKp80 receptor and application thereof - Google Patents
Polypeptide capable of combining with NKp80 receptor and application thereof Download PDFInfo
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- CN101638431B CN101638431B CN2009100920243A CN200910092024A CN101638431B CN 101638431 B CN101638431 B CN 101638431B CN 2009100920243 A CN2009100920243 A CN 2009100920243A CN 200910092024 A CN200910092024 A CN 200910092024A CN 101638431 B CN101638431 B CN 101638431B
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Abstract
The invention discloses a polypeptide and the polypeptide provided in the invention is the polypeptide which is composed by amino acid sequence as shown in sequence one in the sequence table. The polypeptide of the invention can be combined with NKp80, can effectively seal off the binding sites between NKp80 and AICL, can inhibit the cytotoxic activity of NK cells, and can be used as an inhibitor of NK cells to treat autoimmune disease; in addition, the polypeptide has small molecular weight, seldom causes the immunological response of the organism; the polypeptide has good solubility and strong permeability, thus being easy to reach the site of action to exert the function.
Description
Technical field
The present invention relates to field of immunology, particularly can with the polypeptide and the application thereof of NKp80 receptors bind.
Background technology
An of paramount importance class cell is natural killer cell (Natural Killer, a NK cell) in the natural immune system, and it waits by granzyme, secrete cytokines, TRAIL, FasL and kills and wounds infected cells and cancer cells in the body.NK cell surface distributing a series of reactivity acceptors and inhibition acceptor will transmit in cell behind its part of inhibition receptors bind and suppress signal, suppress the activation of NK cell.The KIR acceptor of NK cell surface expression is typical inhibition acceptor, and it can discern the MHC-I quasi-molecule, and normal cell is all expressed the MHC-I quasi-molecule in the body, can suppress signal by the transmission of KIR acceptor, prevents that the NK cell is activated the attack normal cell.By the cell of courses of infection and cancer cells owing to lost the MHC-I quasi-molecule, therefore can be by the NK cell killing.To cause the NK cell activation behind its part of reactivity receptors bind, and then exercise killing ability.But the over-drastic activation can cause the NK cell to attack normal cell in the body, causes autoimmune disorder.In the normal body, the signal that the reactivity acceptor of NK cell and inhibition acceptor are transmitted is in equilibrium state, makes the NK cell can exercise immune surveillance function, can not kill and wound normal cell again.
The NKp80 acceptor is the reactivity acceptor on the NK cell of finding recently, and its part is AICL.When AICL with after NKp80 combines, will in the NK cell, transmit activation signals.When activation signals is strong excessively, then can break the balance of NK cell activation signal and inhibition signal, cause the activation of NK cell transition.The overactivity of NK cell can make it attack normal cell, causes autoimmune disorder.The conventional means of treatment autoimmune disorder is to use immunosuppressor at present, but immunosuppressor poor specificity commonly used, all sites all can suppress immunne response in body, and life-time service can cause body immunity low comprehensively, is easy to take place secondary infection.At present existing prepared in laboratory goes out recombinant expressed AICL molecule extracellular fragment albumen, with the NKp80 acceptor of this recombinant protein in conjunction with the NK cell surface, can suppress the activation of NK cell, reduce the cytotoxic activity (Welte of NK cell, S., et al., Mutual activation of natural killer cells and monocytes mediated byNKp80-AICL interaction.Nat Immunol, 2006.7 (12): p.1334-42.).This method has certain specificity, and the NK cell is had reasonable inhibition effect, but recombinates proteic preparation of AICL extracellular fragment and purifying cost height, and the production cycle is long; Molecular weight of albumen is big, and amino-acid residue is many, and is low at the body intrinsic permeability, is difficult to arrive effectively lesions position; High molecular weight protein brings out body easily and produces antibody, in and pharmaceutical protein, lessen the curative effect.
Summary of the invention
The object of the present invention is to provide a kind of can with the polypeptide of NKp80 receptors bind.
Polypeptide provided by the invention is the polypeptide that the aminoacid sequence shown in the sequence 1 is formed in the sequence table.
This polypeptide be can with NKp80 receptor-specific bonded part, can be directly synthetic with artificial synthesis, also the encoding gene of these polypeptide can be merged or be inserted into expression vector respectively, transfection host cell is produced with gene engineering method then.
The application of above-mentioned polypeptide in the medicine of preparation inhibition PBMCs cytotoxic activity also belongs within protection scope of the present invention.
The application of above-mentioned polypeptide in the medicine of preparation inhibition NK cytotoxic activity also belongs within protection scope of the present invention.
The application of above-mentioned polypeptide in preparation treatment autoimmune disorder medicine also belongs within protection scope of the present invention.
Above-mentioned autoimmune disorder is the cell-mediated autoimmune disorder of NK.
Another object of the present invention is to provide a kind of medicine for the treatment of autoimmune disorder.
The activeconstituents of medicine provided by the invention is above-mentioned polypeptide.
Above-mentioned autoimmune disorder is the cell-mediated autoimmune disorder of NK.
Said medicine can comprise one or more pharmaceutically acceptable carriers.
Above-mentioned carrier can be thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and/or lubricant.
Said medicine also can comprise flavouring agent or sweeting agent.
Said medicine all can be prepared following formulation according to the ordinary method of pharmaceutical field: capsule, injection liquid, soft capsule, tablet, dripping pill, freeze-dried powder, oral liquid or dispersible tablet.
The part AICL that the NKp80 of NK cell expressing and target cell are expressed in conjunction with after can activation NK cell, the activation factor that adds other NK cells is easy to cause the overactivity of NK cell, causes the pathology damage autoimmune disorder.Experiment confirm: polypeptide of the present invention can combine with NKp80, can effectively seal the binding site of NKp80 and AICL, suppresses the cytotoxic activity of NK cell, can be used as the agent of NK cell inhibiting, is used for the treatment of autoimmune disorder.
The present invention is a reference template with the AICL molecule, design, synthetic one group can with the micromolecule polypeptide of NKp80 specific combination, can optionally suppress the activation of NK cell transition, rather than reduce the immunne response ability of body comprehensively, help the side effect of avoiding the life-time service immunosuppressor to be caused; Institute's synthetic polypeptide molecular weight is little, seldom causes the immune response of body, and solvability is good, permeability is strong, is easy to arrive site of action and plays a role; End user PBMCs and NK cell experimentize, and polypeptide can be realized and the restraining effect of NKp80 monoclonal antibody and solubility AICL extracellular fragment protein similar, also avoid the side effect of protein macromolecule simultaneously; Polypeptide of the present invention can adopt the existing conventional method to prepare, and technology maturation can be used for treating autoimmune disorder.
Description of drawings
Fig. 1 is a polypeptide design diagram of the present invention, and wherein A is a CD69 molecule three-D space structure synoptic diagram; B is an AICL molecular simulation three-D space structure synoptic diagram; C is the position of reference template in AICL molecular simulation three-D space structure synoptic diagram of polypeptide of the present invention.
Fig. 2 is that polypeptide of the present invention is to the retarding effect of NKp80 monoclonal antibody in conjunction with NKp80.
Fig. 3 kills and wounds the retarding effect of U937 cytosis to PBMCs for polypeptide of the present invention.
Fig. 4 is the retarding effect of polypeptide of the present invention to NK cell killing U937 cytosis.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Among the following embodiment, if no special instructions, be ordinary method.
The used instrument of embodiment is as follows: micropipet is available from French Gilson company, the MACS magnetic separator is available from Miltemyi Biotec company, whizzer is available from German Hettich company, and clean work station is available from Jinan City, Shandong Province air purifying and sterilizing instrument factory, CO
2Incubator is available from Thermo Forma company, and flow cytometer is available from BD company, the γ calculating instrument available from good photoelectric instrument company.
Synthetic and the Function detection of embodiment 1, polypeptide of the present invention
One, the design of the polypeptide ligand of NKp80 acceptor and synthetic
1, the design of the polypeptide ligand of NKp80 acceptor
1) sets up the simulation three-dimensional structure of AICL
The AICL three-dimensional structure is not resolved as yet, and search is found in albumen database PDB: resolved in the albumen of three-dimensional structure, CD69 and AICL homology are the highest.Based on the three-dimensional structure (Figure 1A) of CD69, the AICL aminoacid sequence (sequence number Q92478 in the database) according to the Uniprot database provides calculates simulation by software 3D-JIGSAW, constructs the simulation three-dimensional structure (Figure 1B) of AICL
2) AICL conservative property sequence screening
The AICL aminoacid sequence is carried out BLAST analyze, obtain to have all albumen information of homology with AICL.Therefrom select 7 albumen that sequence homology is higher,, finally in the AICL aminoacid sequence, find out 7 conservative property zones with the aminoacid sequence of ClustalW2 software analysis they and AICL.
3) determine the interactional site of AICL and NKp80
According to evolutionsim, proteinic conserved sequence region often has important biological function, otherwise it will change during evolution.AICL is as the part of NKp80 acceptor, and main biological function is to combine with NKp80, activation NK cell.
The site that ligand-receptor interaction takes place is usually located at the outside surface of albumen space structure, and the AICL virtual space structure according to setting up has 3 outside surfaces (Fig. 1 C) that are positioned at AICL in 7 conservative property sequence areas of AICL.
2, the polypeptide ligand of NKp80 acceptor is synthetic
Therefore be template according to these three conservative property sequence areas, the polypeptide of design aminoacid sequence shown in sequence in the sequence table 1, called after P1, its iso-electric point is 8.85, molecular weight is 1128.31.
In addition, the irrelevant peptide in the core polypeptide district that design HBsAg is discerned by mouse TCR, as negative control, called after Px.Aminoacid sequence is shown in sequence 2.
The polypeptide P1 of design and Px are synthetic by Shanghai Sangon Biological Engineering Technology And Service Co., Ltd, and purity＞95% is used for following experiment.
Two, the Function detection of polypeptide
1, polypeptide of the present invention suppresses combining of NKp80 monoclonal antibody and NKp80
Experiment material: healthy human peripheral blood is taken from Anhui Province's Blood Center, and lymphocyte separation medium is available from Solarbio company, and APC Rat anti-human NKp80 is available from R﹠amp; D company (Cat#:FAB1900A), PE Mouseanti-human CD56 is available from BD company (Cat#:555516), PerCP-CY5.5Mouse anti-humanCD3 is available from BD company (Cat#:340949), and the RPMI-1640 substratum is available from Invitrogen company.
1) separation of healthy human peripheral blood mononuclearcell (PBMCs) obtains
With adding to centrifugal 15 minutes of the enterprising line density gradient centrifugation of lymphocyte separation medium: 380g, 20 ℃ behind the concentrated tunica albuginea layer of PBS (pH=7.2) dilution peripheral blood; Draw the mononuclearcell of median surface layer, use PBS (pH=7.2) washing 2 times, centrifugal 5 minutes of 500g; After the cell counting, using the RPMI-1640 perfect medium to adjust cell concn is 1 * 10
7Cell/ml, 37 ℃, 5%CO
2Cultivate, obtain the PBMCs cell suspension.
2) polypeptide and PBMCs are hatched and antibody labeling altogether
In the fresh PBMCs cell suspension that step 1) obtains, add PBS (pH=7.2) dissolved P1 to final concentration 500nM, incubated at room 2 hours; Negative control group is to change P1 into Px, and other step is identical; Blank group directly adds isopyknic PBS (pH=7.2).After polypeptide is hatched, according to the routine operation of flow cytometry, add PE mouse anti-human CD56, PerCP CY5.5mouse anti-human CD3, APC ratanti-human NKp80 hatches that (using dosage of antibody is carried out in strict accordance with the antibody specification sheets, 10 μ L/10
6Individual cell), carry out Flow cytometry.
3) Flow cytometry
Choose NK cell (CD3-CD56+) analyze APC rat anti-human NKp80 in conjunction with situation, experiment repeats 3 times, the result is shown in Fig. 2 (on behalf of fluorescence intensity, ordinate zou, X-coordinate represent cell count), PBS group NKp80 positive rate is 87.75%, negative control group (irrelevant peptide Px) NKp80 positive rate is 82.00%, and P1 experimental group NKp80 positive rate is 73.30%.Irrelevant peptide has slight restraining effect, belongs to non-specific binding, and P1 can significantly suppress the NKp80 monoclonal antibody in conjunction with NKp80.
2, polypeptide of the present invention is to the restraining effect of PBMCs cytotoxic activity
Experiment material: healthy human peripheral blood is taken from Anhui Province's Blood Center, and lymphocyte separation medium is available from Solarbio company, Sodium chromate (
51Cr) available from PerkinElmer company, U937 clone is available from the biological product collecting center (ATCC) of USS, catalog number is CRL-1593.2, and the RPMI-1640 substratum is available from Invitrogen company, and new-born calf serum (super) is available from Shanghai Excell Biology Product Co., Ltd..
PBMCs expresses NKp80, U937 cell expressing AICL.This experiment is the effector cell with PBMCs, and the U937 cell is a target cell, adds the peptide section, uses
51Cr isotropic substance method for releasing is measured the killing-efficiency (every in an embodiment experimental group is established 3 of parallel controls) of PBMCs.
1) polypeptide and effector cell are hatched altogether
Add 4 * 10 to each hole of 96 hole circle base plates
5Individual effector cell PBMCs (the acquisition step of PBMCs is identical with step 1) (imitating target than 40: 1) adds PBS (pH=7.2) dissolved P1 and Px simultaneously in different holes, the wherein irrelevant negative contrast of peptide Px.Effector cell and polypeptide totally are 100 μ L, and the polypeptide final concentration is 10nM.The blank group adds the PBS (pH=7.2) of equal volume.37 ℃, 5%CO
2Hatch 1 hour, standby.
2)
51Cr labels targets cell (U937 cell)
With the Sodium chromate of 200 microcuries (
51Cr) mark 10
6Individual target cell U937,37 hatched 1 hour, rocked one time the mixing cell in per 10 minutes; RPMI-1640 perfect medium washed cell 3 times, centrifugal 5 minutes of 3000rpm; With the RPMI-1640 perfect medium cell concn is adjusted into 1 * 10
5Individual/ml, standby.
3) effector cell kills and wounds target cell
Target cell is added to the 96 hole circle base plates that mix up effector cell's quantity in advance, and every hole adds 100 μ L.Set maximum release group (10 in the experiment
4Individual target cell adds 2%TritonX-100 solution, cumulative volume 200 μ L) and natural release group (10
4Individual target cell, cumulative volume 200 μ L), after finishing culture plate is done slightly centrifugal, 37 ℃, 5%CO
2Hatched 4 hours, and got 100 μ L supernatants and carry out the γ counting, calculate kill rate according to following formula:
Kill rate=(experimental group CPM value-natural release group CPM value)/(maximum release group CPM value-natural release group CPM value) * 100%
Experiment repeats 3 times, CPM numerical value is as shown in table 1, the result who is converted into kill rate as shown in Figure 3, the PBMCs of P1 group is 36.44% to the kill rate of target cell, the PBMCs of negative control group (Px) is 47.33% to the kill rate of target cell, the PBMCs of blank group (PBS) is 45.20% to the kill rate of target cell, and peptide section P1 can suppress PBMCs and kill and wound target cell U937, and blank (PBS) and irrelevant peptide negative control (Px) all do not have restraining effect.
The CPM numerical value of each experimental group of table 1. (being standard deviation in the bracket)
| Experimental group CPM value | Nature release group CPM value | Maximum release group CPM value | |
| Experimental group (P1) | 5518.00(461.04) | 1237.33(69.58) | 12986.00(262.52) |
| Blank experimental group (PBS) | 6547.33(324.30) | 1237.33(69.58) | 12986.00(262.52) |
| Negative control experimental group (Px) | 6798.00(423.21) | 1237.33(69.58) | 12986.00(262.52) |
3, polypeptide of the present invention is to the restraining effect of the cytotoxic activity of NK cell
This experiment is the effector cell with the NK cell, and the U937 cell is a target cell, adds the peptide section, uses
51Cr isotropic substance method for releasing is measured the killing-efficiency (every in an embodiment experimental group is established 3 of parallel controls) of NK cell.
1) separation of NK cell
PBMCs (the acquisition step of PBMCs is identical with the step 1) back that lymphocyte separation medium density gradient centrifugation obtains is resuspended with MACS buffer, carries out cell counting, adjusts cell concn and makes 40 μ L cell suspensions have 2 * 10
7Individual cell; Carry out mark (participating in the Kit specification sheets) with the antibody, the magnetic bead reagent that provide among the NK cell isolation kit (Miltemyi Biotec company (Cat#130-092-657)); With MACS buffer rinse MACS separator column, slowly add the cell suspension of mark, collect effluent liquid, be the NK cell.Identify that through flow cytometry the NK cell purity is greater than 85%.
2) polypeptide is hatched the NK cell
Add 5 * 10 to each experimental port of 96 hole circle base plates
4Individual effector cell NK cell adds PBS (pH=7.2) dissolved P1 and Px simultaneously in different holes, the wherein irrelevant negative contrast of peptide Px.Effector cell and polypeptide totally are 100 μ L, and the polypeptide final concentration is 10nM.The blank group adds the PBS (pH=7.2) of equal volume.37 ℃, 5%CO
2Hatch 1 hour, standby.
3) 51Cr labels targets cell U937
With the Sodium chromate of 200 microcuries (
51Cr) mark 10
6Individual target cell U937,37 hatched 1 hour, rocked one time the mixing cell in per 10 minutes; RPMI-1640 perfect medium washed cell 3 times, centrifugal 5 minutes of 3000rpm; With the RPMI-1640 perfect medium cell concn is adjusted into 1 * 10
5Individual/ml, standby.
4) effector cell kills and wounds target cell
Target cell is added to the 96 hole circle base plates that mix up effector cell's quantity in advance, and every hole adds 100 μ L.Set maximum release group (10 in the experiment
4Individual target cell adds 2%TritonX-100 solution, cumulative volume 200 μ L) and natural release group (10
4Individual target cell, cumulative volume 200 μ L), after finishing culture plate is done slightly centrifugal, 37 ℃, 5%CO
2Hatched 4 hours, and got 100 μ L supernatants and carry out the γ counting, calculate kill rate according to following formula:
Kill rate=(experimental group CPM value-natural release group CPM value)/(maximum release group CPM value-natural release group CPM value) * 100%
Experiment repeats 3 times, CPM numerical value is as shown in table 2, the result who is converted into kill rate as shown in Figure 4, the NK cell of P1 group is 29.59% to the kill rate of target cell, the NK cell of negative control group (Px) is 36.41% to the kill rate of target cell, the NK cell of blank group (PBS) is 38.56% to the kill rate of target cell, and peptide section P1 can suppress NK cell killing target cell U937, and blank and irrelevant peptide negative control all do not have restraining effect.Experimental result is consistent with PBMCs.
The CPM numerical value of each experimental group of table 2. (in the bracket is standard deviation)
| Experimental group CPM value | Nature release group CPM value | Maximum release group CPM value | |
| Experimental group (P1) | 6873.33(530.74) | 1824.67(56.72) | 18888.67(451.89) |
| Blank experimental group (PBS) | 8404.00(68.01) | 1824.67(56.72) | 18888.67(451.89) |
| Negative control experimental group (Px) | 8037.33(507.71) | 1824.67(56.72) | 18888.67(451.89) |
Sequence table
＜110〉China Science ﹠ Technology University
＜120〉can with the polypeptide and the application thereof of NKp80 receptors bind
<130>CGGNARL92519
<160>2
<210>1
<211>8
<212>PRT
＜213〉synthetic
<220>
<230>
<400>1
Glu?Met?Asn?Phe?Leu?Arg?Arg?Tyr
1 5
<210>2
<211>8
<212>PRT
＜213〉synthetic
<220>
<230>
<400>2
Ile?Leu?Ser?Pro?Phe?Leu?Pro?Leu
1 5
Claims (4)
1. a peptide species, its aminoacid sequence is shown in sequence in the sequence table 1.
2. the application of the described polypeptide of claim 1 in the medicine of preparation inhibition NK cytotoxic activity, thus the described polypeptide of claim 1 suppresses described NK cytotoxic activity by suppressing AICL and NKp80 receptors bind.
3. the application of the described polypeptide of claim 1 in preparation treatment autoimmune disorder medicine; Described autoimmune disorder is the cell-mediated autoimmune disorder of NK; Thereby the described polypeptide of claim 1 is treated the cell-mediated autoimmune disorder of described NK by suppressing AICL and NKp80 receptors bind.
4. medicine for the treatment of autoimmune disorder, its activeconstituents is the described polypeptide of claim 1;
Described autoimmune disorder is the cell-mediated autoimmune disorder of NK, thereby the described polypeptide of claim 1 is treated the cell-mediated autoimmune disorder of described NK by suppressing AICL and NKp80 receptors bind.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096962A (en) * | 1992-12-02 | 1995-01-04 | 洛克菲勒大学 | The dynorphin A of suppression of natural killer cytoactive |
| WO2008028501A1 (en) * | 2006-09-05 | 2008-03-13 | Eberhard-Karls-Universität Tübingen | Methods for blocking the interaction between nkp80 and its ligand aicl |
-
2009
- 2009-09-04 CN CN2009100920243A patent/CN101638431B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096962A (en) * | 1992-12-02 | 1995-01-04 | 洛克菲勒大学 | The dynorphin A of suppression of natural killer cytoactive |
| WO2008028501A1 (en) * | 2006-09-05 | 2008-03-13 | Eberhard-Karls-Universität Tübingen | Methods for blocking the interaction between nkp80 and its ligand aicl |
Non-Patent Citations (2)
| Title |
|---|
| Sabrina Kuttruff等.NKp80 defines and stimulates a reactive subset of CD8 T cells.《Blood》.2008,(第113期),358-369. * |
| Stefan Welte等.Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction.《Immunology》.2006,第7卷(第12期),1334-1342. * |
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Effective date of registration: 20190314 Address after: 230001 Room 01, 21 Floor, F5 Building, Phase II, Innovation Industrial Park, 2800 Innovation Avenue, Hefei High-tech Zone, Anhui Province Patentee after: Hefei Ruida immune Drug Research Institute Co Ltd Address before: 230026 No. 96, Jinzhai Road, Hefei, Anhui Patentee before: University of Science and Technology of China |