CN108503693B - Polypeptide KM17 for promoting platelet aggregation - Google Patents
Polypeptide KM17 for promoting platelet aggregation Download PDFInfo
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- CN108503693B CN108503693B CN201710558285.4A CN201710558285A CN108503693B CN 108503693 B CN108503693 B CN 108503693B CN 201710558285 A CN201710558285 A CN 201710558285A CN 108503693 B CN108503693 B CN 108503693B
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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Abstract
A polypeptide KM17 for promoting platelet aggregation. The invention belongs to the technical field of medical biology, and particularly relates to a novel polypeptide with a platelet aggregation promoting effect. The polypeptide KM17 is composed of 19 amino acids, has the sequence of the polypeptide of SEQ ID NO. 1, has the molecular weight of 2168.41Da, and has the sequence of Leu-Val-Asn-Glu-Glu-Ala-Thr-Gly-Gln-Phe-His-Val-Tyr-Pro-Glu-Leu-Pro-Lys-Pro. The polypeptide has obvious promotion effect on platelet aggregation induced by ADP, can be used for exploring the effect of the polypeptide and other platelet activators on platelets and the influence of related functions, can be used for monitoring the existing antiplatelet treatment, and can be applied to the preparation of medicines for promoting platelet aggregation, stopping bleeding, treating cardiovascular diseases and the like.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to a novel polypeptide with a platelet aggregation promoting effect.
Background
Cardiovascular and cerebrovascular diseases mainly comprise common diseases such as acute myocardial infarction, cerebral infarction, pulmonary infarction, ischemic heart disease, cerebral apoplexy and the like, seriously threaten the health and the life of human beings and are the first cause of death of residents in China [1 ]. Platelet activation is an important initiation factor in the process of occurrence and development of cardiovascular and cerebrovascular diseases, and platelet activation, adhesion and aggregation to thrombosis are a series of cascade reactions, which not only play a key role in the physiological hemostasis process, but also participate in pathological processes such as thrombosis, tissue repair and the like [2,3 ]. Platelet aggregation plays a central role in thrombus formation. The inducers of platelet aggregation mainly include: collagen, arachidonic acid, ADP, thrombin, etc.
1. Collagen-induced platelet activation
When collagen is exposed by damage to vascular endothelial cells or plaque rupture, platelet membrane protein binding to the exposed collagen or activated vWF is a key step in initiating thrombosis. The surface of the platelet is provided with two specific sequences of membrane protein GPVI and integrin-alpha 2 beta 1 for recognizing collagen, thereby firmly binding the collagen. Among them, GPVI is a collagen signal transduction receptor involved in integrin- α 2 β 1-regulated signal transduction and platelet activation and aggregation after platelet adhesion [4-7 ]. Under the combined action of collagen and two membrane proteins, the activation pathway of integrin alphaIIb beta 3 is finally activated, which causes platelet aggregation and release [8,9 ].
2. Arachidonic acid-induced platelet activation
Increased levels of intracellular Ca2+ in platelets can cause activation of phospholipase A2, which in turn frees arachidonic acid from phospholipid membranes. Arachidonic acid synthesizes thromboxane A2(TXA2) under the action of cyclooxygenase-1, and after TXA2 is combined with TXA2 receptor on platelet membrane [10], the arachidonic acid is combined with specific G protein-coupled receptors Gq and G13 to activate platelets. TXA2 is not only a strong agonist of platelet activation and vascular smooth muscle contraction, it can also amplify platelet activation signals caused by low doses of thrombin and ADP, among others. TXA2 activates PLC β downstream of it upon binding to the receptor, causing activation of IP3, DAG, G13 and the signaling pathways associated with these proteins [11], ultimately causing platelet deformation and release of intra-platelet granules [12 ].
3. ADP-induced platelet activation
ADP is a major component of dense granule release in activated platelets, and plays a very important role in platelet activation and aggregation processes. ADP receptors are mainly P2Y1, P2Y12 and P2X 1. Wherein P2Y1 is a G protein coupled transmembrane receptor, after ADP is combined with P2Y1 receptor, P2Y1 receptor is coupled with Gq protein to activate phospholipase C, thereby leading Ca2+ to flow into the cell from the extracellular direction, and the increase of the intracellular Ca2+ concentration activates protein kinase C to cause platelet deformation and aggregation [13 ]. P2Y12 is a G protein-coupled receptor [14], and is important not only for ADP-induced irreversible platelet aggregation, but also for ADP-mediated generation of TXA 2. The P2X1 protein receptor is a ligand-gated ion channel, is mainly responsible for the rapid calcium influx caused by ADP, and has weak action in platelet aggregation [15 ].
4. Thrombin-induced platelet activation
Thrombin is the most potent platelet agonist, which activates platelets by binding to platelet membrane surface Protease Activated Receptors (PARs). Human platelets express PAR-1 and PAR-4[16], either of which is activated to cause platelet aggregation and particle release [17 ]. Research shows that PAR-1 is sensitive to low-concentration thrombin, and PAR-4 triggers the activation and aggregation of platelets only in a high-concentration thrombin environment; and thrombin cleaves PAR-4 20 to 70 times slower than PAR-1, and thus PAR-1 is the most important receptor for thrombin to cause platelet activation [18,19 ]. Studies have shown that PAR-1 is coupled to Gq, G13, Gi/z and PAR-4 is coupled to Gq, G13 only, linking the coagulation signal to the intracellular signaling pathway, resulting in activation of PLC β, PI3K and Ras-like Rho kinase, leading to hydrolysis of IP3, calcium mobilization and activation of PKC [17,20 ].
However, the existing antiplatelet drugs not only have side effects such as bleeding tendency (cerebral hemorrhage, massive hemorrhage of digestive tract) and the like [21], but also have resistance or low response phenomena in clinical application, and adverse ischemic events still occur; meanwhile, the drugs have single action mechanism and have certain limitation on antiplatelet action: such as aspirin, irreversibly blocks COX-1 synthesis, thereby inhibiting platelet activation, aggregation [10,22 ]; clopidogrel irreversibly inhibits ADP binding to its receptor P2Y12, inhibiting ADP-induced platelet aggregation [23 ]; ticagrelor reversibly interacts with the ADP-P2Y12 receptor, also inhibiting ADP-induced platelet aggregation [24 ]; vorapaxar and Atopaxar are PAR-1 inhibitors now in clinical trials that inhibit thrombin-induced platelet aggregation [25,26 ]; the abciximab, tirofiban and eptifibatide are all GP IIb/IIIa receptor antagonists [27 ]. Clinically, in order to increase the curative effect and reduce the side effect, antiplatelet drugs with different action mechanisms are used in combination. Therefore, it is of great significance to search for a safer and more reliable novel antiplatelet drug.
Disclosure of Invention
The invention aims to provide a novel polypeptide with the function of promoting platelet aggregation, which has obvious promotion function on platelet aggregation induced by ADP, can be used for exploring the influence of the polypeptide and other platelet activators on the platelet and related functions, can be used for monitoring the existing antiplatelet treatment, and can be applied to the preparation of medicines for promoting platelet aggregation, stopping bleeding, treating cardiovascular diseases and the like.
The technical scheme adopted for realizing the above purpose of the invention is as follows: the polypeptide KM17 is composed of 19 amino acids, has the sequence of the polypeptide of SEQ ID NO. 1, has the molecular weight of 2168.41Da, and has the sequence of Leu-Val-Asn-Glu-Glu-Ala-Thr-Gly-Gln-Phe-His-Val-Tyr-Pro-Glu-Leu-Pro-Lys-Pro. After the polypeptide is synthesized, the high performance liquid chromatography and mass spectrometry technology verify that the synthesized substrate is a complete amino acid sequence.
The polypeptide provided by the invention has the activity of promoting ADP-induced platelet aggregation through testing: under the action of ADP alone, the average aggregation rate of induced platelets is 32%; the mean platelet aggregation rate induced by the combined action of 100 μ M KM17 and ADP was 53%, and the aggregation promoting rate was 66%. In the range of 25-100. mu.M, the platelet aggregation rate gradually increased with the increase in KM17 concentration, showing a dose-dependent relationship. The polypeptide is not limited to promotion of platelet aggregation induced by ADP, can be used for exploring the influence of the polypeptide and other platelet activators (adrenalin, ristocetin and the like) on the effects and related functions of platelets, and can also be used for monitoring the conventional antiplatelet treatment.
The polypeptide provided by the invention can be applied to preparations with the function of promoting platelet aggregation.
The polypeptide provided by the invention can be applied to the preparation of medicines for promoting platelet aggregation, stopping bleeding and treating cardiovascular diseases.
The polypeptide provided by the invention is a medicament for promoting platelet aggregation, stopping bleeding and treating cardiovascular diseases, wherein the polypeptide is an active ingredient and contains one or more pharmaceutically acceptable carriers.
The polypeptide provided by the invention can be applied to the preparation of a scar forming agent or a dermatological emulsion.
The biological properties of the polypeptides provided by the invention can foresee many applications thereof.
The polypeptide provided by the invention can be used for hemorrhagic diseases: evaluating platelet aggregation function, evaluating the effectiveness of existing hemostatic treatments (hemostatic bandages, hemostatic adhesives, etc.).
The polypeptide provided by the invention can be used for evaluating thrombotic diseases: evaluating platelet aggregation function, and evaluating the effectiveness of an antiplatelet therapy (e.g., aspirin, clopidogrel, ticagrelor, etc.) on current or future therapies.
The invention can be used as a scar forming agent or a dermatological emulsion: healing of certain wound scarring or dermatological diseases requires in situ migration, adhesion, aggregation and activation of platelets.
The invention relates to a polypeptide KM17 consisting of 19 amino acids, which is used for determining the effect on platelet aggregation activity through an in vitro human platelet aggregation experiment. Experiments prove that the polypeptide has obvious promotion effect on platelet aggregation induced by ADP. The novel polypeptide KM17 sequence related to the invention has not been reported so far.
Drawings
The following drawings are included to illustrate specific embodiments of the invention and are not intended to limit the scope of the invention as defined by the claims.
FIG. 1 is a high performance liquid chromatography purification diagram of a polypeptide provided by the present invention: the peak value C was KM 17.
FIG. 2 is a secondary mass spectrum of peak C (i.e., KM 17).
FIG. 3 is a graph showing the effect of KM17 on platelet aggregation induced by thrombin, ADP, collagen and arachidonic acid, as measured by optical turbidimetry. After incubation of platelet-rich plasma with different concentrations of KM17 for 30 minutes at 37 deg.C, ADP (A), arachidonic acid (B), collagen (C), thrombin (D) inducer was added and the platelet aggregation curves (mean, n.gtoreq.4) were recorded.
FIG. 4 is a bar graph showing the effect of KM17 on thrombin, ADP, collagen and arachidonic acid-induced platelet aggregation, as measured by optical turbidimetry. The influence of different concentrations of KM17 on platelet aggregation induced by thrombin, ADP, collagen and arachidonic acid (mean. + -. standard error, n is not less than 4). (P < 0.05), (P < 0.01).
Detailed Description
Example (b): the polypeptide KM17 provided by the invention promotes ADP-induced human platelet aggregation in vitro.
The effect of KM17 on collagen, arachidonic acid, thrombin, ADP-induced platelet aggregation was evaluated by optical turbidimetric assay.
Platelets were collected from healthy volunteers provided from our hospital blood bank with signed consent.
(1) Diluting the polypeptide with deionized water containing 15% DMSO to adjust the final concentration of the polypeptide to 10 mM; an equal volume of 15% DMSO polypeptide-free deionized water was added to the control experiment.
(2) Taking 100 μ l of the apheresis platelets, diluting the platelets with 300 μ l of modified Tyrode's buffer (137mM NaCl,27mM KCl,1mM MgCl2,0.42mM NaH2PO4,5.5mM Glucose,5.55mM HEPES, 0.25% Bovine Serumalbumin, pH 7.4) to obtain platelet-rich plasma, wherein the number of platelets is adjusted to 2.5X 108 platelets/mL; separately, 100. mu.l of the collected platelet was diluted with 300. mu.l of Tyrode's buffer solution and centrifuged at 10000rpm for 10 minutes to obtain a supernatant as platelet poor plasma.
(3) After 400. mu.l of the platelet resuspension was aspirated and preheated at 37 ℃ for 5min, KM17 (0. mu.M, 10. mu.M, 50. mu.M, 100. mu.M) was added to the platelet resuspension solution at different concentrations and incubated at 37 ℃ for 30 min. Opening a platelet aggregation instrument, setting parameters as required, placing a magnetic rod in the incubated platelet-rich plasma, inserting a platelet reaction cup with a magnetic stirring rod into a detection hole of a machine, placing the platelet reaction cup in a test area of the platelet aggregation instrument, adjusting zero, adding thrombin, ADP, collagen and an arachidonic acid inducer, observing the influence of KM17 on platelet aggregation caused by different activators at 37 ℃ and 1200rpm for 5-10 min. Each KM17 concentration group was repeated at least four times and averaged. Recording the platelet aggregation profiles and plotting the corresponding bar graphs on the basis of the platelet aggregation rates (FIG. 3, FIG. 4)
(4) Experimental data were processed with SPSS 21.0 statistical software. Results are expressed as mean ± sem. Performing homogeneous variance test for multiple groups, performing one-way ANOVA for homogeneous variance, and performing LSD (least-significant difference) for pairwise comparison; if the variance is not uniform, the Tamhane' sT2 test is carried out, and the t test is adopted for pairwise comparison. P < 0.05 the difference was considered statistically significant.
Through platelet aggregation experiments, the polypeptide KM17 can obviously promote ADP-induced human platelet aggregation, and has no obvious influence on platelet aggregation caused by collagen, thrombin, arachidonic acid and the like. Wherein, the average aggregation rate of induced platelets is 32% under the single action of ADP; the mean aggregation rate of the induced platelets under the combined action of 100 mu M KM17 and ADP is 53% and the accelerated aggregation rate is 66% (calculation method of accelerated aggregation rate: [ (X-Y)/Y ] X100%, X represents the mean aggregation of the platelets in 100 mu M KM17 group, and Y represents the mean aggregation rate of the platelets in the blank control group). In the range of 25-100nM, the platelet aggregation rate gradually increased with increasing KM17 concentration, showing a dose-dependent relationship.
Reference documents:
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2.George JN(2000)Platelets.Lancet 355:1531-1539。
3.Jurk K,Kehrel BE(2010)[Pathophysiology and biochemistry of platelets].Internist(Berl)51:1086,1088-1092,1094。
4.Coller BS,Beer JH,Scudder LE,Steinberg MH(1989)Collagen-platelet interactions:evidence for a direct interaction of collagen with plateletGPIa/IIa and an indirect interaction with platelet GPIIb/IIIa mediated byadhesive proteins.Blood 74:182-192。
5.Moroi M,Jung SM(2004)Platelet glycoprotein VI:its structure and function.Thromb Res114:221-233。
6.Puett D,Wasserman BK,Ford JD,Cunningham LW(1973)Collagen-mediated platelet aggregation.Effects of collagen modification involving the proteinand carbohydrate moieties.J Clin Invest 52:2495-2506。
7.Tsuji M,Ezumi Y,Arai M,Takayama H(1997)A novel association of Fc receptor gamma-chain with glycoprotein VI and their co-expression as acollagen receptor in human platelets.J Biol Chem 272:23528-23531。
8.Li Z,Delaney MK,O'Brien KA,Du X(2010)Signaling during platelet adhesion and activation.ArteriosclerThromb Vasc Biol 30:2341-2349。
9.Zahid M,Mangin P,Loyau S,Hechler B,Billiald P,et al.(2012)The future of glycoprotein VI as an antithrombotic target.J Thromb Haemost 10:2418-2427。
10.Halvorsen S,Andreotti F,ten Berg JM,Cattaneo M,Coccheri S,et al.(2014)Aspirin therapy in primary cardiovascular disease prevention:a positionpaper of the European Society of Cardiology working group on thrombosis.J AmColl Cardiol 64:319-327。
11.Chakraborty R,Pydi SP,Gleim S,Bhullar RP,Hwa J,et al.(2013)New insights into structural determinants for prostanoid thromboxane A2receptor-and prostacyclin receptor-G protein coupling.Mol Cell Biol 33:184-193。
12.Bhavaraju K,Lakhani PR,Dorsam RT,Jin J,HitchcockIS,et al.(2011)G(12/13)signaling pathways substitute for integrin alphaIIbbeta3-signaling forthromboxane generation in platelets.PLoS One 6:e16586。
13.Cattaneo M(2005)The P2 receptors and congenital platelet function defects.Semin Thromb Hemost31:168-173。
14.Jin J,Kunapuli SP(1998)Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation.Proc NatlAcad Sci U S A 95:8070-8074。
15.Vial C,Hechler B,Leon C,Cazenave JP,Gachet C(1997)Presence of P2X1purinoceptors in human platelets and megakaryoblastic cell lines.ThrombHaemost78:1500-1504。
16.Coughlin SR(1999)How the protease thrombin talks to cells.Proc Natl Acad Sci U S A 96:11023-11027。
17.Hua Y,Keep RF,Gu Y,Xi G(2009)Thrombin and brain recovery after intracerebral hemorrhage.Stroke 40:S88-89。
18.Martorell L,Martinez-Gonzalez J,Rodriguez C,Gentile M,Calvayrac O,et al.(2008)Thrombin and protease-activated receptors(PARs)inatherothrombosis.Thromb Haemost 99:305-315。
19.Carrim N,Arthur JF,Hamilton JR,Gardiner EE,Andrews RK,et al.(2015)Thrombin-induced reactive oxygen species generation in platelets:A novel rolefor protease-activated receptor 4 and GPIbalpha.Redox Biol 6:640-647。
20.Sambrano GR,Weiss EJ,Zheng YW,Huang W,Coughlin SR(2001)Role of thrombin signalling in platelets in haemostasis and thrombosis.Nature 413:74-78。
21.Geisler T,Gawaz M,Steinhubl SR,Bhatt DL,Storey RF,et al.(2010)Current strategies in antiplatelet therapy--does identification of risk andadjustment of therapy contribute to more effective,personalized medicine incardiovascular disease Pharmacol Ther 127:95-107。
22.Tantry US,Mahla E,Gurbel PA(2009)Aspirin resistance.Prog Cardiovasc Dis 52:141-152.
23.Ray S(2014)Clopidogrel resistance:the way forward.Indian Heart J 66:530-534。
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SEQUENCE LISTING
<110> first Hospital affiliated to Kunming medical university
<120> a platelet aggregation-promoting polypeptide KM17
<140>
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 19
<212> PRT
<213> Artificial sequence
<400> 1
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu
1 5 10 15
Pro Lys Pro
Claims (3)
1. A platelet aggregation-promoting polypeptide KM17, characterized by: the polypeptide KM17 is composed of 19 amino acids, has the sequence of the polypeptide of SEQ ID NO. 1, has the molecular weight of 2168.41Da, and has the sequence of Leu-Val-Asn-Glu-Glu-Ala-Thr-Gly-Gln-Phe-His-Val-Tyr-Pro-Glu-Leu-Pro-Lys-Pro.
2. Use of the platelet aggregation-promoting polypeptide KM17 according to claim 1 in the preparation of a preparation having an ADP-induced platelet aggregation-promoting and hemostatic effect.
3. Use according to claim 2, characterized in that: the polypeptide is an active ingredient and contains one or more pharmaceutically acceptable carriers.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101014357A (en) * | 2004-07-07 | 2007-08-08 | 麦迪库瑞国际公司 | Combination therapies employing platelet aggregation drugs |
| CN102224167A (en) * | 2008-09-24 | 2011-10-19 | 第戎大学医疗中心 | Recombinant proteins having haemostatic activity and capable of inducing platelet aggregation |
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- 2017-07-10 CN CN201710558285.4A patent/CN108503693B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101014357A (en) * | 2004-07-07 | 2007-08-08 | 麦迪库瑞国际公司 | Combination therapies employing platelet aggregation drugs |
| CN102224167A (en) * | 2008-09-24 | 2011-10-19 | 第戎大学医疗中心 | Recombinant proteins having haemostatic activity and capable of inducing platelet aggregation |
Non-Patent Citations (2)
| Title |
|---|
| CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo;Cyndi Wong 等;《BLOOD》;20090219;第113卷(第8期);第1818-1828页 * |
| Molecular cloning of a gene belonging to the carcinoembryonic antigen gene family and discussion of a domain model;JOHN A. THOMPSON 等;《Proc. Natl. Acad. Sci. USA》;19870501;第84卷(第9期);第2965-2969页 * |
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