CN113354713B - Polypeptide and application thereof in preparation of platelet aggregation resisting medicines - Google Patents
Polypeptide and application thereof in preparation of platelet aggregation resisting medicines Download PDFInfo
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- CN113354713B CN113354713B CN202110664292.9A CN202110664292A CN113354713B CN 113354713 B CN113354713 B CN 113354713B CN 202110664292 A CN202110664292 A CN 202110664292A CN 113354713 B CN113354713 B CN 113354713B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a polypeptide A11 for resisting platelet aggregation, belonging to the technical field of medical biology. The polypeptide A11 of the invention is a sequence of polypeptide consisting of 12 amino acids and having SEQ ID NO. 1, the molecular weight is 1262.24, and the sequence is Ser-Ile-Ser-Ser-Asn-Asn-Ser-Asn-Pro-Val-Glu-Asp. The polypeptide is not limited to inhibiting thrombin-induced platelet aggregation, can be used for exploring the influence of the polypeptide and other platelet activators (collagen, arachidonic acid, ADP, epinephrine, ristocetin and the like) on the effects and related functions of platelets, and can also be used for monitoring the conventional antiplatelet treatment.
Description
Technical Field
The invention belongs to the technical field of medical biology, and relates to a polypeptide, in particular to a polypeptide A11 for resisting platelet aggregation, a preparation method thereof, a pharmaceutical composition comprising the polypeptide A11 as an active ingredient, and an application of the polypeptide A11 in preparation of antiplatelet drugs
Background
The incidence, death rate, disability rate and recurrence rate of the cardiovascular and cerebrovascular disease thrombosis events are high year by year, which not only brings heavy economic burden to patients, but also causes certain damage to the physiology and psychology of the patients, and leads to the reduction of the life quality of the patients. Activation of platelets is a central link in thrombosis, and thus antiplatelet therapy is important in the management of cardiovascular disease. At present, clinical antiplatelet drugs still have bleeding risks, individual differences in curative effects, drug resistance and other defects. Therefore, the search for antiplatelet drugs with higher safety, effectiveness and stronger targeting effect is an important point to be urgently solved in antiplatelet research.
The platelet membrane receptor PAR1 is an important regulator of thrombin interaction with platelets to platelet activation and thrombosis. Proteolysis of the N-terminus of PAR-1 exposes the extracellular thrombin binding site, which binds to thrombin, thereby inducing a clotting response. Inhibition of thrombin-mediated platelet activation is an important target for the development of antiplatelet drugs. For example, the PAR1 competitive antagonist vallaparsone is approved in the united states as an adjunctive antiplatelet agent in patients with acute coronary syndrome, and is also a secondary prophylactic agent for vascular events in patients with myocardial infarction or peripheral arterial disease. However, clinical trials show that while inhibiting platelet aggregation, vorapaxate also increases the risk of cerebral hemorrhage in patients.
At present, no report of the polypeptide A11 for resisting platelet aggregation and the activity thereof exists in the prior art.
Disclosure of Invention
The invention aims to provide a polypeptide A11 for resisting platelet aggregation, a preparation method thereof, a pharmaceutical composition comprising the polypeptide A11 as an active ingredient, and application of the polypeptide A11 in preparation of antiplatelet drugs.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
an anti-platelet aggregation polypeptide A11 is composed of 12 amino acid sequences shown by Ser-Ile-Ser-Ser-Asn-Asn-Ser-Asn-Pro-Val-Glu-Asp, has an amino acid sequence shown by SEQ ID NO. 1 in a sequence table, and has a molecular weight of 1262.24.
The invention also provides application of the anti-platelet aggregation polypeptide A11 in preparation of preparations with platelet aggregation inhibition effect.
And the application of the polypeptide A11 for resisting platelet aggregation in preparing medicaments for resisting platelet aggregation.
And the application of the anti-platelet aggregation polypeptide A11 in preparing medicaments for treating cardiovascular diseases.
According to the application of the polypeptide A11 in preparing the medicines for resisting platelet aggregation or treating cardiovascular diseases, the polypeptide A11 can achieve the effect of resisting platelet aggregation through the remarkable inhibition effect of thrombin-induced human platelet aggregation and thrombin-induced platelet clot retraction.
According to the application of the polypeptide A11 in preparing a medicament for resisting platelet aggregation or treating cardiovascular diseases, the polypeptide A11 can obviously inhibit 0.2U/mL thrombin-induced clot retraction at 1 mM.
According to the application of the polypeptide A11 in preparing the medicines for resisting platelet aggregation or treating cardiovascular diseases, the polypeptide A11 can obviously inhibit platelet aggregation induced by thrombin, and the inhibition efficiency is dose-dependent.
The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of polypeptide A11 for resisting platelet aggregation and a pharmaceutically acceptable carrier.
The polypeptide A11 provided by the invention consists of 12 amino acids, the molecular weight is 1262.24, and the sequence is as follows: Ser-Ile-Ser-Ser-Asn-Asn-Ser-Asn-Pro-Val-Glu-Asp. Experiments show that A11 significantly inhibits thrombin-induced platelet aggregation and clot retraction. Therefore, A11 can be used for the development of antiplatelet drugs. A11 can also be prepared into composition with one or more pharmaceutically acceptable carriers, and can be used for preparing anti-platelet and anti-thrombosis medicines.
When the polypeptide A11 of the present invention is used as a medicine, it can be used as it is or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the present invention, the balance being pharmaceutically acceptable, pharmaceutically acceptable carriers and/or excipients that are non-toxic and inert to humans and animals.
The pharmaceutically acceptable carrier or excipient is one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical formulation auxiliaries. The pharmaceutical composition of the present invention is used in the form of a dose per unit body weight. The medicament can be administered by injection (intravenous injection and intramuscular injection) and oral administration.
Compared with the prior art, the invention has the following advantages:
1. the invention newly invents the polypeptide A11, explores a new medical application of the polypeptide A11, and develops a new application field.
2. The product polypeptide A11 of the invention has the advantages of low price, no toxic or side effect, simple preparation process, convenient use and capability of being made into oral dosage forms, injection dosage forms, tablets and the like.
3. The polypeptide A11 of the invention can obviously inhibit the retraction of blood clots induced by thrombin. Can effectively inhibit platelet aggregation and can be effectively used as an antiplatelet medicament.
4. The product polypeptide A11 of the invention can obviously inhibit platelet aggregation induced by thrombin, and the inhibition efficiency is dose-dependent. Can effectively inhibit platelet aggregation and can be effectively used as an antiplatelet medicament.
Drawings
FIG. 1 is a high performance liquid chromatography purification diagram of a polypeptide provided by the present invention: the peak value C is the purified polypeptide A11.
FIG. 2 is a diagram of the secondary mass spectrometric identification of peak C (polypeptide A11) in FIG. 1.
FIG. 3 is a graph of the effect of polypeptide A11 on thrombin-induced platelet aggregation;
FIG. 4 is a bar graph of the effect of polypeptide A11 on thrombin-induced platelet aggregation;
FIG. 5 is a graph showing the effect of polypeptide A11 on thrombin-induced platelet clot retraction.
Detailed Description
The following describes embodiments of the present invention in more detail with reference to the accompanying drawings and specific examples. However, the present invention is not limited thereto.
Example 1
The polypeptide A11 was synthesized using the method of solid phase polypeptide synthesis according to the method reported in the literature (La Face DM, Couture C, Anderson K, et al. Differential T cell signaling induced by anti-inflammatory peptide-MHC compounds and the associated phenolic reactions. J Immunol. 1997 Mar 1;158 (5): 2057-2064.). The synthesized polypeptide is purified by High Performance Liquid Chromatography (HPLC) to obtain a concentration of 95% or more (figure 1). Subsequent amino acid sequence and molecular weight determinations were made by Mass Spectrometry (MS), which identified the synthesized polypeptide as a11 (fig. 2).
A11 inhibits thrombin-induced human platelet aggregation in vitro.
(1) The platelet-derived healthy volunteers of the experimental people sign blood donation informed consent and give certain nutritional supplement. Collecting venous blood, separating single blood collecting platelet from Kunming blood center, and collecting single blood collecting platelet in Heiyou college of Kunming medical university.
(2) The specific implementation mode is as follows:
step one, DMSO is adopted to dissolve and adjust the concentration of A11 to 400mM and 200 mM.
And step two, washing the platelets. 1mL of human single blood collection platelets which are subjected to constant-temperature shaking storage at 25 ℃ are taken to be placed in a 1.5mL centrifuge tube, EDTA with the final concentration of 5mM and 0.1U/mL of Apyrase (prepared by physiological saline to prevent platelet aggregation in the centrifugation process) are added, and 400g of the mixture is centrifuged for 10 minutes at room temperature; after centrifugation, the supernatant was discarded from human apheresis, and 1mL of Tyrode's Buffer B (137mM NaCl,27mM KCl,1mM MgCl) was added to the cell pellet 2 ，0.42mM NaH 2 PO 4 5.5mM Glucose,5.55mM HEPES, 0.25% bone Serum Albumin, pH 6.5), 5mM EDTA, 0.1U/mL Apyrase, gently blown, 400g at room temperature for another 10 minutes; using Tyrode's Buffer A (137mM NaCl,27mM KCl,1mM MgCl) 2 ,0.42mM NaH 2 PO 4 5.5mM Glucose,5.55mM HEPES, 0.25% bone Serum Albumin, pH 7.4) resuspension of centrifuged platelets, platelet count was adjusted to 150- 9 And L. The platelets were stored at 70rpm with shaking at 25 ℃ and used within 1 hour after washing.
And step three, sucking 400 mu L of washing platelet resuspension and preheating for 5min at 37 ℃. A11 was added to the experimental group at final concentrations of 1mM and 2mM, and an equal volume of DMSO was added to the positive control group (Vehicle), and the incubation was carried out for 20min at 37 ℃. Opening a platelet aggregation instrument, setting parameters as required, putting a magnetic rod into incubated washed platelets, inserting a platelet reaction cup with a magnetic stirring rod into a detection hole of a machine, placing the platelet reaction cup into a test area of the platelet aggregation instrument, adjusting zero, adding thrombin, observing the influence of A11 on platelet aggregation caused by an activator at 37 ℃ and 1200rpm for 5-10 min. And drawing a corresponding bar chart and a corresponding bar chart according to the platelet aggregation curve recorded by the platelet aggregation instrument. Experimental data were statistically analyzed using GraphPadPrism 8.0 software. Group-to-group comparisons were performed using Student's t-test statistical methods. P <0.05 considered the difference to be statistically significant.
As shown in figure 3 of the specification: human washed platelets were incubated with different concentrations of A11 or DMSO at 37 ℃ for 20 minutes, thrombin (0.05U/mL) was added to activate the platelets, and a platelet aggregation curve was plotted and recorded using a platelet aggregometer. The abscissa is the time of the aggregation curve and the ordinate is the real-time aggregation rate of platelets by the platelet aggregometer. A representative platelet aggregation rate curve from the aggregation experiment is presented in fig. 3. At the beginning of the aggregation experiment, the platelet aggregation rate was 0%, thrombin was added immediately, and when the experiment proceeded for about 30 seconds, platelets in the positive control (Vehicle) experiment group began to aggregate. When the aggregation experiment is carried out to about 5 minutes, the aggregation rate of the Vehicle group reaches about 80 percent, the aggregation rate of the 1mM A11 experiment group reaches about 20 percent, and the aggregation rate of the 2mM A11 experiment group reaches about 3 percent. The attached figure 4 of the specification shows: histogram comparing platelet aggregation peaks for Vehicle and the a11(1mM, 2mM) group at different concentrations. Six replicates of Vehicle and a11(1mM, 2mM) at various concentrations, with peak platelet aggregation expressed as mean ± sem, and the differences are statistically significant, where p ≦ 0.001 and p ≦ 0.0001 compared to Vehicle. As can be seen from fig. 3 and 4: a11 can obviously inhibit platelet aggregation induced by thrombin, and the inhibition efficiency is dose-dependent.
Example 2
A11 inhibited platelet clot retraction.
(1) The source of experimental human platelets was the same as in example 1.
(2) The specific implementation mode is as follows:
platelet rich plasma was diluted with Tyrode's Buffer A and quantified at 500X 10 9 L, 200. mu.L of platelet-rich plasma was placed in a siliconized transparent glass tube and incubated at 37 ℃ for 20 minutes. A11 was dissolved in DMSO and adjusted to a concentration of 200 mM. The experimental groups are: a positive Control group (Thrombin 0.2U/mL), a negative Control group (Control) and an A11 experimental group. A11 was added to the test group at a final concentration of 1mM, and DMSO was added to the positive control group and the negative control group at an equal volume to the test group, followed by incubation at 37 ℃ for 20 minutes. After incubation, thrombin was added to the positive control and A11 tubes to a final concentration of 0.2U/mL, mixed well and then photographed every 5 minutes at 37 ℃. And observing the retraction speed of the blood clots of each experimental group and the control group and the size difference of the blood clots. The above test groups were repeated 3 times per group.
As shown in figure 5 of the specification: within 35 minutes of experimental monitoring, the Control group platelet suspension did not produce blood clots and retraction of blood clots without thrombin stimulation. In the positive control group (Thrombin 0.2U/mL), the platelet suspension coagulated into a clot and retracted beginning at the 10 th minute of the experiment and ending at a minimum at 30 minutes. In the 1mM A11 group, the platelet suspension did not clot as a clot, and no significant retraction was seen within 35 minutes of the experiment run. Fig. 5 is a representative picture of a repeat experiment, and similar results are obtained in 3 experiments. Thus, 1mM A11 significantly inhibited 0.2U/mL thrombin-induced clot retraction.
Example 3
Dissolving polypeptide A11 in DMSO, adding water for injection, fine filtering, packaging, and sterilizing to obtain injection.
Example 4
Dissolving polypeptide A11 in DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with sterile filter funnel, performing sterile fine filtration, packaging in ampoule, freeze drying at low temperature, and sealing by aseptic melting to obtain powder for injection.
Example 5
Taking the polypeptide A11, adding excipient according to the weight ratio of the polypeptide A11 to the excipient of 9:1, and preparing into powder.
Example 6
Taking the polypeptide A11, adding an excipient according to the weight ratio of the polypeptide A11 to the excipient of 5:1, granulating and tabletting.
Example 7
Taking the polypeptide A11, and preparing into oral liquid according to conventional oral liquid preparation method.
Example 8:
taking the polypeptide A11, adding excipient according to the weight ratio of the polypeptide A11 to the excipient of 5:1, and making into capsule.
Example 9:
taking the polypeptide A11, adding excipient according to the weight ratio of the polypeptide A11 to the excipient of 3:1, and making into capsule.
The protection scope of the present invention is not limited to the above embodiments, which are only for the purpose of assisting explanation and illustration of the present invention, but not for limiting the protection scope of the present invention, as long as the design is the same as the design of the present invention or the equivalent is within the protection scope of the present invention.
Sequence listing of the invention
The invention name is as follows: polypeptide and application thereof in preparation of platelet aggregation resisting medicines
<110> first subsidiary hospital of Kunming medical university
<120> polypeptide and application thereof in preparation of platelet aggregation resistant drugs
<210> 1
<211> 12
<212> PRT
<213> polypeptide A11
<400> 1
Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp
1 5 10
Claims (5)
1. The polypeptide A11 for resisting platelet aggregation consists of 12 amino acid sequences shown by Ser-Ile-Ser-Ser-Asn-Asn-Asn-Ser-Asn-Pro-Val-Glu-Asp, has an amino acid sequence shown by SEQ ID NO. 1 in a sequence table, and has a molecular weight of 1262.24.
2. The use of the polypeptide a11 for inhibiting platelet aggregation according to claim 1 in the preparation of a medicament for inhibiting platelet aggregation.
3. The use of the anti-platelet aggregation polypeptide a11 according to claim 1 in the preparation of an anti-platelet aggregation medicament.
4. The use of the polypeptide a11 in the preparation of a medicament for resisting platelet aggregation according to claim 3, wherein: the polypeptide A11 can obviously inhibit 0.2U/mL thrombin-induced clot retraction at 1 mM.
5. A pharmaceutical composition, comprising a therapeutically effective amount of the anti-platelet aggregation polypeptide a11 according to claim 1 and a pharmaceutically acceptable carrier.
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| US8563690B2 (en) * | 2008-11-03 | 2013-10-22 | The Board Of Trustees Of The University Of Illinois | Modulation of platelet aggregation |
| CN101514231B (en) * | 2008-12-26 | 2011-04-27 | 重庆大学 | Fusion protein for resisting formation of thrombus targetedly and preparation method and application thereof |
| US20100285583A1 (en) * | 2009-05-08 | 2010-11-11 | Capelluto Daniel G S | Compounds and methods for inhibiting platelet aggregation |
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