CN103977408A - Integrin alphaMβ2In the preparation of medicaments for treating platelet number related diseases - Google Patents
Integrin alphaMβ2In the preparation of medicaments for treating platelet number related diseases Download PDFInfo
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- CN103977408A CN103977408A CN201410244399.8A CN201410244399A CN103977408A CN 103977408 A CN103977408 A CN 103977408A CN 201410244399 A CN201410244399 A CN 201410244399A CN 103977408 A CN103977408 A CN 103977408A
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- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses integrin alphaMβ2The use of an antagonist of in the preparation of a medicament for the treatment of a disease associated with platelet count. The diseases related to the platelet number comprise primary or secondary thrombocytopenia and primary or secondary thrombocytosis. The integrin alphaMβ2The antagonist of is anti-integrin alphaMβ2Antibody, integrin alpha of (1)Mβ2Amino acid sequence polypeptides and oligopeptides, integrin alphaMβ2The amino acid sequence of is a derivative, analogue or integrin alpha of polypeptide and oligopeptideMβ2The small molecule compound antagonist of (1). The invention provides the integrin alpha for the first timeMβ2The use of an antagonist of in the preparation of a medicament for the treatment of a disease associated with platelet count.
Description
Technical field
The present invention relates to drug world, be specifically related to integrin alpha
Μβ
2the application of antagonist in the medicine of preparation treatment platelet counts relevant disease.
Background technology
The platelet counts that various factors causes clinically can cause relevant disease extremely, as constitutional or secondary thrombocythemia, constitutional or Secondary cases thrombocytopenia, comprises immune thrombocytopenia etc.Thrombocytosis is that a kind of agnogenic paraplasm companion platelet continues to increase is main myeloproliferative disease, its clinical characters is to be more common in 40 years old above adult, often hemorrhage with spontaneous skin mucosa, repeatedly show effect, can have thrombosis, splenomegaly, platelet persistency showed increased, etiology unknown.This sick Pathogenesis of Hemorrhage may strengthen relevant with dysfunction of platelet or fibrinolysis.Epidemiological study according to American-European 5 states to primary thrombocytosis, sickness rate is 0.59/10 ten thousand～2.53/10 ten thousand, over nearly 20 years, sickness rate has increased by 3.2 times of (Johansson P.Epidemiology of the myeloproliferative disorders polycytothemia vera and essential thrombocythemia.Sem Thromb Haemost, 2006,32:171-173).
(the immune thrombocytopenia of immunologic thrombocytopenic purpura in thrombocytopenia, ITP) be clinical common hemorrhage, account for 30% (Hou Ming, Dai Kesheng, Peng Jun of hemorrhage sum, chief editor, " blood platelet disorder ", the second edition, scientific and technical literature publishing house, 2012,142 pages).Research shows that ITP is a kind of autoimmune disease, this disease be owing to producing anti-megalokaryocyte or hematoblastic autoantibody in body, wherein antiplatelet antibody mainly forms (Michelle Lee Webster by the two large antibody-likes of anti-platelet membrane glycoprotein glycoprotein (GP) Ib-IX-V and GPIIb/IIIa, Ebrahim Sayeh, Min Crow, Pingguo Chen, Bernhard Nieswandt, John Freedman, and Heyu Ni.Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIb α antibodies.Blood, 2006108:943-946).Two large antibody-likes are after platelet is combined in patient body, and mainly reticuloendothelial system (reticuloendothelial system, the RES) combination in the Fc end by antibody and human body, causes platelet to be removed by organs such as spleens.
Although in recent years, the study of incident mechanism of ITP has been obtained a series of progress, abnormal at the megalokaryocyte quality and quantity that has proposed autoantibody mediation aspect humoral immunization mechanism.Aspect cellular immune mechanism, propose cytotoxic T cell and directly dissolved hematoblastic theory, still, not yet clear and definite about the definite pathogeny of ITP.
Due to not yet define of pathogeny, therefore, there is no the method for radical cure.American I TP guideline recommendation platelet is lower than 20～30 × 10
9/ L or lower than 50 × 10
9it is hemorrhage and have hemorrhage person receives treatment that/L merges obvious skin mucosa.Main therapeutic strategy is generation and the hematoblastic destruction of suppressing antibody at present, promotes hematoblastic generation, comprises various immunosuppressant, excision spleen, short thrombocytopoiesis etc.The object for the treatment of is to make Platelet counting bring up to level of security, reduces case fatality rate.
Current medicine is mainly glucocorticoid, the monoclonal antibody etc. of Hemopoietic factor thrombopoietin, interleukin-11 and immunologic intervention, but above-mentioned various medicine has limitation separately separately, there is the potential side effect such as thrombosis, myelofibrosis, vein obstruction in medicine RhTPPO RHTPO (rhTPO) as conventional in ITP; Intravenous injection immunoglobulin (IVIG) is applicable to intractable or needs emergency treatment ITP patient, side effect is light, it is unrestricted to use, but because its action time is short, expensive, clinical practice (Beardsley DS, Ertem M.Platelet autoantibodies in immune thrombocytopenic purpura.Transfus Sci.1998 are limited; 19:237-244).Therefore the medicine that finds a kind of effective treatment platelet counts relevant disease is Lin bed Yi Han problem to be solved.
Integrin is the receptor of various kinds of cell epimatrix composition, is extensively present in cell surface, is a sizable receptor family.Integrin is all generally by a α chain and a heterodimer that β chain warp non-covalent bond connects to form.Aminoterminal outside α subunit born of the same parents is the repetitive sequence of 7 homologies, forms 7 β lamellas, is folded into the structure of a propeller sample.In integrin family, have 16 kinds of alpha subunits and 8 kinds of β subunits at least, integrin family can be divided into 8 groups, wherein α by the difference of β subunit
Μβ
2(Mac-1, CD11b/CD18, C3R) belong to beta 2 subunit family, mainly be distributed in leukocyte, it is the important leukocyte factor of a class, participate in sticking between leukocyte (as neutrophilic granulocyte) and endotheliocyte etc., mediated leucocytes function, was acknowledged as at the aspect such as inflammatory reaction, immunoreation in the past and played a crucial role.
Aminoterminal outside the α subunit born of the same parents of Mac-1 is the repetitive sequence of 7 homologies, form 7 β lamellas, be folded into the structure of a propeller sample, 7 β lamellas are named as respectively W1-7, between W2 and W3, there is the insertion sequence of one section of approximately 200 amino acid residue, be called as I domain, its (Yang Huayan that plays a crucial role in identification many protein ligands and non-protein ligands, 2007 academic dissertations, with Atomic Mechanics microscope measurement Mac-1 and ICAM-1 unimolecule interaction force), I domain is the position of Mac-1 parts most with it (comprising ICAM-1) combination.I domain crystal structure is resolved, is the folding of small G-protein sample, is made up of around a β-pleated sheet of central authorities 7 α spirals.Being the adhesion sites (metal ion-dependent adhesion site, MIDAS) that a metal ion relies at the top of domain, is the place, position of I domain binding partner.Have been found that at present I domain crystal has two kinds of conformations to exist, and is called as respectively open to the outside world conformation and " closing " conformation.Recombinant alpha
Μβ
2the M of I domain peptide section after pancreatin enzymolysis
rsee accompanying drawing 1 (Hou Xiaomin, Yuan Cai, Peng Qi etc., integrin alpha
Μβ
2the gene of I domain synthesizes and protein expression, " biotechnology communication ", 2009,20 (1): 8-11).
Integrin alpha
Μβ
2antagonist refer to inhibition integrin alpha
Μβ
2the material of function, generally comprises anti-integrin alpha
Μβ
2antibody, integrin alpha
Μβ
2aminoacid sequence polypeptide and oligopeptide, integrin alpha
Μβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
Μβ
2micromolecular compound antagonist, its structure can be antibody, peptide and micromolecular compound, integrin alpha
Μβ
2antagonist be originally commonly used to study integrin alpha
Μβ
2biological property.
Summary of the invention
The object of the invention is to provide integrin alpha
Μβ
2the application of antagonist in the medicine of preparation treatment platelet counts relevant disease.
Described integrin alpha
Μβ
2antagonist be anti-integrin alpha
Μβ
2antibody, integrin alpha
Μβ
2aminoacid sequence polypeptide and oligopeptide, integrin alpha
Μβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
Μβ
2micromolecular compound antagonist.
According to the present invention, described integrin alpha
Μβ
2aminoacid sequence polypeptide and oligopeptide be based on integrin alpha
Μβ
2each peptide species or the oligopeptide of aminoacid sequence synthesized.
According to the present invention, described α
Μβ
2aminoacid sequence polypeptide and derivant, the analog of oligopeptide be based on integrin alpha
Μβ
2each peptide species of aminoacid sequence synthesized or derivant, the analog of oligopeptide.They on sequence and space structure with α
Μβ
2aminoacid sequence polypeptide and oligopeptide very approach a compounds, due to the similarity of sequence and space structure, it can be brought into play and α in vivo
Μβ
2the effect identical with oligopeptide of aminoacid sequence polypeptide.
According to the present invention, described integrin alpha
Μβ
2micromolecular compound antagonist refer to the integrin alpha of application based on Pharmacophore Model, bioisostere replace, high flux library screening method obtains
Μβ
2micromolecular compound antagonist.
According to the present invention, described anti-integrin alpha
Μβ
2antibody be to there is anti-integrin alpha
Μβ
2the monoclonal antibody of immunoreation feature.
According to the present invention, described platelet counts relevant disease includes but not limited to constitutional or secondary thrombocythemia, constitutional or secondary thrombocytopenia, and every disease being caused by platelet counts is included.
Described thrombocytopenia includes but not limited to immune thrombocytopenia.
Described medicine can be only integrin alpha
Μβ
2antagonist, can be also to contain integrin alpha
Μβ
2the compositions of antagonist.
Described medicine can be prepared into various dosage forms according to common mode, includes but not limited to tablet, capsule, granule, pill, oral liquid, patch.
Described medicine can oral or injection or topical application.
Antiplatelet GPIb α N end antibody can induced platelet activation, apoptosis, can cause platelet to be removed rapidly by macrophage at liver, and the present invention finds anti-integrin alpha
Μβ
2antibody, integrin alpha
Μβ
2aminoacid sequence polypeptide and oligopeptide, integrin alpha
Μβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
Μβ
2micromolecular compound antagonist can significantly suppress the platelet that platelet GPIbα antibody causes and remove, regulation and control platelet counts.
Beneficial effect of the present invention is:
(1) the present invention has opened up integrin alpha
Μβ
2antagonist in the frontier for the preparation for the treatment of platelet counts relevant disease medicine, be antiplatelet GPIb α N end antibody induction platelet activation, apoptosis based on one of platelet counts relevant disease pathogenesis, can cause platelet to be removed rapidly by macrophage at liver, and integrin alpha
Μβ
2antagonist can significantly suppress the platelet that platelet GPIbα N end antibody causes and remove, thereby high specificity, good effect.
(2) integrin alpha
Μβ
2antagonist comprise anti-integrin alpha
Μβ
2antibody, integrin alpha
Μβ
2aminoacid sequence polypeptide and oligopeptide, integrin alpha
Μβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
Μβ
2micromolecular compound antagonist wide material sources, cost is lower, potential applicability in clinical practice is wide.
Brief description of the drawings
Fig. 1 has shown recombinant alpha
Μβ
2the M of I domain peptide section after pancreatin enzymolysis
r.
Fig. 2 has shown that antiplatelet GPIb Alpha antibodies AN51 can assemble by induced platelet.Fig. 2 A. is respectively to the IgG and the AN51 that add 2 μ g/ml in platelet blood plasma (PRP), the variation of recording platelet aggregation with platelet aggregation instrument.Risto represents the platelet aggregation of ristomycin induction; The impact of many kinds of monoclonal antibodies of Fig. 2 B. on platelet aggregation, vertical coordinate represents interior hematoblastic maximum agglutination rate in 15min, wherein only has AN51 induced platelet gathering significantly; Fig. 2 C. adds the IgG of 2 μ g/ml and AN51 to stir after 15min in gathering instrument respectively in PRP, imaging result after object lens amplify 40 times.
Fig. 3 has shown that the platelet aggregation of AN51 induction depends on the GPIb α gathering of antibody induction, does not rely on Fc section.Fig. 3 A.PRP respectively with mouse IgG, the IV.3 incubation 10min at normal temperatures of 10 μ g/ml, add 2 μ g/mlAN51, platelet aggregation instrument records platelet aggregation to be changed; The statistical result of maximum agglutination rate in Fig. 3 B. Fig. 3 A15min; Fig. 3 C. is respectively to the AN51F (ab ') that adds PBS and 2 μ g/ml in PRP
2fragment, platelet aggregation instrument records platelet aggregation to be changed; The statistical result of maximum agglutination rate in Fig. 3 D. Fig. 3 C15min; To the AN51 monomer Fab fragment, dimer (AN51) and the tetramer that add 2 μ g/ml in PRP, (AN51 adds goat-anti mice F (ab ') to Fig. 3 E. respectively
2, AN51+GAM), platelet aggregation instrument records platelet aggregation to be changed; The statistical result of maximum agglutination rate in Fig. 3 F. Fig. 3 E15min.
Fig. 4 has shown AN51 induced platelet apoptosis.Fig. 4 is IgG, the AN51 of μ g/ml and the hematoblastic ratio of apoptosis after washing platelet incubation 1-6 hour A.2; Fig. 4 is the variation of μ g/mlIgG, HIP1 and AN51 and 6 hours blood platelet apoptosis protein expressions of washing platelet incubation B.2.
Fig. 5 has shown that AN51 can cause platelet count in Cavia porcellus body to decline rapidly.Respectively to different Cavia porcellus injection normal mouse IgG, 0.05mg/kg, 0.1mg/kg and 0.2mg/kgAN51, at the appointed time put eye socket blood sampling, platelet Counting by Cavia porcellus forearm vein.
Fig. 6 has shown integrin alpha
Μβ
2antagonist (antibody SZITP) obviously suppressed macrophage (THP-1) and engulfed platelet.The platelet respectively AN51 being stimulated joins in macrophage (THP-1) suspension of the SZITP that contains variable concentrations, and flow cytometer detection platelet is engulfed situation.
Fig. 7 has shown integrin alpha
Μβ
2the polypeptide (SZDT) of sequence obviously suppresses macrophage (THP-1) and engulfs platelet.The platelet respectively AN51 being stimulated joins in macrophage (THP-1) suspension that contains polypeptide (SZDT, 2mM) and control peptide thereof, and flow cytometer detection platelet is engulfed situation.
Detailed description of the invention
Integrin alpha in the present invention
Μβ
2antagonist well-known in the industry, can, according to known conventional method preparation, also can buy by commercial sources to Santa Cruz company, use with conventional method.
Medicine of the present invention can be only integrin alpha
Μβ
2antagonist, can be also to contain integrin alpha
Μβ
2the compositions of antagonist.
Conventionally, medicine can be made to various dosage forms, described medicine can be oral or injection or topical application.
In the present invention, platelet counts relevant disease comprises constitutional or secondary thrombocythemia, constitutional or secondary thrombocytopenia, but is not limited to above-mentioned disease, and every disease being caused by platelet counts is included.
Find before inventor, anti-platelet membrane glycoprotein GPIb-IX-V antibody can cause platelet GPIbα born of the same parents outer end to flock together after being combined with people platelet, make to connect on GPIb α N-end-N-acetyl-GLUCOSAMINE flocks together. simultaneouslyAfter gathering-N-acetyl-GLUCOSAMINE is to liver Macrophage Surface α
Μβ
2the affinity of integrin receptor increases greatly, and platelet is removed by liver macrophage phagocytic.Based on discovery before, the inventor has completed the present invention.
The present invention finds integrin alpha
Μβ
2antagonist can suppress platelet destruction, regulation and control platelet counts.Experiment confirms integrin alpha
Μβ
2one of mechanism of antagonist regulation and control platelet counts remove for the platelet that suppresses antiplatelet GPIb Alpha antibodies and cause.In a preferred embodiment, described platelet counts relevant disease is selected from ITP.Certainly, platelet counts relevant disease does not only include ITP, also comprises constitutional or secondary thrombocythemia, non-immunity thrombocytopenia etc.
Illustrate the present invention with experimental example below, but do not limit in any form the present invention.
Experiment material
Mouse anti human platelet GPIbα N end antibody A N51, anti-human GPIX antibody SZ1 and anti-human GPIIIa antibody SZ21 are obtained by protein G affinity chromatography purification by mouse ascites.Mouse anti human GPIb antibody WM23 is so kind as to give by Du little Ping.Other anti-human GPIb antibody A K2, HIP1, VM16d and SZITP are respectively purchased from Abcam, eBioscience, Thermo Scientifc and Santa Cruz company.Mouse IgG fragmentation test kit is purchased from Thermo Scientific company.Protein G agarose gel is purchased from GE healthcare.Normal mouse IgG buys from Santa Cruz company.Anti-human Fc γ RIIA monoclonal antibody IV.3 is purchased from StemCell company.JC-1, anti-Bak, Bad, Bcl-2, the antibody of Bcl-xl is purchased from green skies biotechnology research institute.Anti-α
Μβ
2antibody SZITP buys from Santa Cruz company, and polypeptide (SZDT) is bought from the biochemical (Shanghai) Co., Ltd. of gill.
Hematoblastic separation and abstersion
Get normal person's fresh venous ACD with 1:7 anticoagulant.300g isolates and is rich in platelet blood plasma (PRP), and PRP is by the centrifugal platelet that obtains of 1500g, after CGS buffer washing 2 times, is resuspended in Tyrode ' the s buffer of improvement to 3 × 10
8/ ml, leaves standstill 1-2h at normal temperatures.For the 3.8% sodium citrate 1:9 anticoagulant for blood of platelet aggregation test, 300g isolates PRP.
Platelet aggregation
The PRP that gets sodium citrate anticoagulant adds respectively normal mouse IgG, many kinds of monoclonal antibodies of antiplatelet GPIb α, ristomycin or AN51F (ab ')
2, with platelet aggregation instrument (Chrono-log) detection platelet aggregation.The monoclonal antibody IV.3 of Effect of Anti Fc γ RIIA to the platelet aggregation test of AN51 induction in, 10 μ g/mlIV.3 first with PRP incubation 5 minutes at normal temperatures, then add AN51 detection of aggregation.
Flow cytometry blood platelet apoptosis
Washing platelet and 2 μ g/mlAN51 difference incubation are after 1-6 hour, JC-1 labelling platelet mitochondrial membrane potential, Flow cytometry platelet mitochondrial membrane potential changes, the platelet that red fluorescence is converted into green fluorescence is defined as apoptosis platelet, and remembers the percentage ratio of apoptosis platelet colony.
SDS-PAGE and Western Blot
Washing platelet and normal mouse IgG, control antibodies HIP1 and AN51 respectively at 37 DEG C incubation after 6 hours, after cracking 30min, add 6 × SDS sample-loading buffer on ice through cell pyrolysis liquid.Albumen carries out Western Blot after being needed on nitrocellulose filter after being separated by SDS-PAGE.Primary antibodie is respectively anti-Bak, Bad, and Bcl-2, the antibody of Bcl-xl, two resist the goat anti-rabbit antibody for HRP labelling, the colour developing of ECL luminescence method.Flow cytometer detection THP-1 cytophagy platelet
The platelet of labelling being crossed to calcein joins in THP-1 cell, and disposes the platelet of not engulfed, the platelet that Flow cytometry is engulfed by THP-1 cell.
Experimental result
1, antiplatelet GPIb α N end antibody A N51 can cause platelet aggregation
The epi-position of monoclonal antibody AN51 is positioned at human blood platelets GPIb α N end 1-35 amino acid residue place, as shown in accompanying drawing 2A and B, can assemble (aggregation rate is 10%-20%) by induced platelet with AN51 and PRP incubation.The antibody of other epi-positions of antiplatelet GPIb α is if the antibody of AK2 (35-59), HIP1 (59-81), VM16d (201-168), WM23 (macroglycopeptide) or anti-other albumen is as SZ1 (GPIX), SZ21 (GPIIIa) induced platelet gathering generation (accompanying drawing 2B) significantly.Micro-imaging result shows that AN51 induced platelet forms little aggregation (accompanying drawing 2C).
2, the platelet aggregation of AN51 induction depends on the GPIb α gathering of antibody induction, does not rely on Fc section
Can be by there is activation and assemble in the Fc section of antiplatelet antibody with Fc γ RIIA receptors bind induced platelet.For study AN51 whether by with Fc γ RIIA zygotic induction platelet aggregation, detected the V.3 impact of the platelet aggregation on AN51 induction of antibody I of antagonism Fc γ RIIA.Accompanying drawing 3A shows that IV.3 does not suppress the gathering of AN51 induction.In addition, do not comprise the AN51F (ab ') of Fc section
2fragment also can be assembled (accompanying drawing 3B) by induced platelet, further illustrates AN51 and causes platelet aggregation not rely on Fc section.
Platelet GPIbα multimerization can be assembled by induced platelet, thereby whether assemble activated blood platelet by induction GPIb α in order to inquire into AN51, detected AN51 monomer Fab fragment, AN51IgG (dimer) and the impact of the anti-AN51 (tetramer) being coupled of goat-anti mice (GAM) two on platelet aggregation.As shown in accompanying drawing 3C, monomer (Fab) can not be assembled by induced platelet; Compared with dimer (AN51), the tetramer (AN51+GAM) can induce larger gathering that (10%vs20%) occurs.
Therefore, the GPIb α that the platelet aggregation of AN51 induction depends on antibody induction assembles, and does not rely on Fc section.
3, AN51 can induced platelet apoptosis
Mitochondrial membrane potential depolarization can be used as one of index of blood platelet apoptosis.Washing platelet, respectively with mouse IgG, the AN51 incubation 1-6 hour at 37 DEG C of 2 μ g/ml, detects apoptosis by the depolarization of detection line mitochondrial membrane potential.Fig. 4 A shows that incubation is after 4 hours, and the ratio of the apoptotic cell that AN51 causes has significant difference compared with IgG, and is time-dependent trend.Detect in addition mouse IgG, control antibodies HIP1 and the AN51 impact on blood platelet apoptosis protein expression.2 μ g/ml antibody and washing platelet incubation cracking platelet after 6 hours, Western Blot result (accompanying drawing 4B) shows, compare with control antibodies HIP1 with IgG, AN51 can cause the up-regulated of pro apoptotic protein Bad and Bak, presses down apoptotic proteins Bcl-2 and Bcl-xl down-regulated expression.Therefore, AN51 can induce the blood platelet apoptosis that mitochondria pathway relies on.
4, AN51 can cause platelet in Cavia porcellus body to be eliminated rapidly
The antibody of anti-GPIb α has hematoblastic effect in the Mice Body of removing.AN51 can be specificly combined with Cavia porcellus GPIb α and cause GPIb α to assemble.Whether can remove platelet in Cavia porcellus body for inquiring into AN51, by the AN51 to Cavia porcellus forearm vein injection 0.05mg/kg, 0.1mg/kg and 0.2mg/kg, before injection of antibodies, after injection of antibodies 5min, 20min, 1hr, 3hr respectively eye socket get blood platelet Counting.Accompanying drawing 5 shows, AN51 can remove platelet after 5 minutes, and is dosage and relies on trend.Guinea pig blood platelet returns to normal level gradually after 3 hours in injection of antibodies.The F of AN51 (ab ')
2fragment also can cause guinea pig blood platelet to reduce rapidly.Injection normal mouse IgG does not affect guinea pig blood platelet number.
5, integrin alpha
Μβ
2antagonist (anti-α
Μβ
2antibody SZITP) obviously suppress macrophage (THP-1) and engulf platelet
AN51 can induce macrophage (THP-1) to engulf platelet.Prepare the platelet that calcein (calcein) has dyed in advance in advance, hematoblastic concentration is 5 × 10
8/ ml, hatches respectively 10 μ g/ml IgG and 10 μ g/mlAN51.The platelet of hatching is joined respectively in THP-1 cell and (adds respectively in advance IgG or the SZITP of 10 μ g/ml, 20 μ g/ml, 40 μ g/ml, 80 μ g/ml), accompanying drawing 6 shows that SZITP can obviously suppress the platelet that THP-1 cytophagy AN51 stimulated, and presents dose dependent.
6, be derived from integrin alpha
Μβ
2the polypeptide of sequence obviously suppresses macrophage (THP-1) and engulfs platelet
AN51 can induce macrophage (THP-1) to engulf platelet.Prepare the platelet that calcein (calcein) has dyed in advance in advance, hematoblastic concentration is 5 × 10
8/ ml, hatches respectively 10 μ g/ml IgG and 10 μ g/mlAN51.The platelet of hatching is joined respectively and adds in advance polypeptide (SZDT, 2mM) and in the THP-1 cell of control peptide (2mM) incubation, accompanying drawing 7 shows that polypeptide (SZDT) obviously suppresses the platelet that THP-1 cytophagy AN51 stimulated.
To sum up, integrin alpha of the present invention
Μβ
2antagonist: anti-integrin alpha
Μβ
2antibody, α
Μβ
2aminoacid sequence polypeptide and oligopeptide, α
Μβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
Μβ
2micromolecular compound antagonist can obviously suppress macrophage (THP-1) and engulf platelet, can suppress platelet destruction, regulation and control platelet counts, therefore can be for the preparation of the medicine for the treatment of platelet counts relevant disease, these diseases comprise: constitutional or secondary thrombocythemia, constitutional or secondary thrombocytopenia etc.
Claims (10)
1. integrin alpha
mβ
2the application of antagonist in preparation treatment platelet counts relevant disease medicine.
2. application according to claim 1, is characterized in that: described integrin alpha
mβ
2antagonist be anti-integrin alpha
mβ
2antibody, integrin alpha
mβ
2aminoacid sequence polypeptide and oligopeptide, integrin alpha
mβ
2aminoacid sequence polypeptide and the derivant of oligopeptide and analog, integrin alpha
mβ
2micromolecular compound antagonist.
3. application according to claim 2, is characterized in that: described anti-integrin alpha
mβ
2antibody be to there is anti-integrin alpha
mβ
2the monoclonal antibody of immunoreation feature.
4. application according to claim 2, is characterized in that: described integrin alpha
mβ
2aminoacid sequence polypeptide and oligopeptide be based on integrin alpha
mβ
2each peptide species or the oligopeptide of aminoacid sequence synthesized.
5. application according to claim 2, is characterized in that: described integrin alpha
mβ
2micromolecular compound antagonist be the integrin alpha of application based on Pharmacophore Model, bioisostere replace, high flux library screening method obtains
mβ
2micromolecular compound antagonist.
6. application according to claim 1, is characterized in that: described platelet counts relevant disease comprises constitutional or secondary thrombocytopenia, constitutional or secondary thrombocythemia.
7. application according to claim 1, is characterized in that: described platelet counts relevant disease is immunologic thrombocytopenic purpura.
8. application according to claim 1, is characterized in that: described medicine is to contain integrin alpha
mβ
2the compositions of antagonist.
9. application according to claim 1, is characterized in that: described medicine is tablet, capsule, granule, pill, oral liquid or patch.
10. application according to claim 9, is characterized in that: described medicine is oral or injection or topical application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104352789A (en) * | 2014-11-13 | 2015-02-18 | 李凯 | Traditional Chinese medicinal preparation for treating secondary thrombocytosis |
| CN108310384A (en) * | 2018-02-05 | 2018-07-24 | 苏州大学 | Application of PI3K inhibitor in preparation of medicines for treating diseases related to platelet number reduction |
| CN109010830A (en) * | 2017-06-08 | 2018-12-18 | 苏州大学 | Application of the blood platelet related inhibitors in preparation treatment decrease of platelet disease drug |
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| CN103610684A (en) * | 2013-11-07 | 2014-03-05 | 苏州大学 | Application of saccharides in preparing medicine for treating platelet quantity related diseases |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104352789A (en) * | 2014-11-13 | 2015-02-18 | 李凯 | Traditional Chinese medicinal preparation for treating secondary thrombocytosis |
| CN109010830A (en) * | 2017-06-08 | 2018-12-18 | 苏州大学 | Application of the blood platelet related inhibitors in preparation treatment decrease of platelet disease drug |
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