CN102702312A - RGDVYIGSK with targeting antithrombotic activity, preparation and applications thereof - Google Patents
RGDVYIGSK with targeting antithrombotic activity, preparation and applications thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses polypeptide RGDVYIGSK with targeting antithrombotic activity, and also discloses a preparation method of the polypeptide RGDVYIGSK and applications of the polypeptide RGDVYIGSK as an antithrombotic agent, belonging to the field of biological medicine. According to the invention, by the conjugation of RGDV and YIGSK, the polypeptide with targeting antithrombotic activity is prepared and obtained. Proved by an animal model test, the RGDVYIGSK has stronger antithrombotic activity.
Description
The application is that the application number of on November 30th, 2006 application is 200610144234.9, and denomination of invention is divided an application for the patent of " polypeptide, its preparation method and application with target antithrombotic activity ".
Technical field
The present invention relates to have the polypeptide RGDVYIGSK of target antithrombotic activity.The preparation method and it that the invention still further relates to it belong to biomedicine field as the application of pharmaceutical preparations having antithrombotic activity.
Background technology
Cell adhesion plays a crucial role in the evolution of cell adhesion property disease (metastasis of cancer, thrombosis, chemistry cause inflammation and osteoporosis).Modulability gp for example laminine, Fibrinogen, RGD peptide, YIGSR and YIGSK etc. can be participated in the cell adhesion process.They and integrin receptor have very strong binding ability.For example in the platelet aggregation process, RGDV has combined crucial effects with activatory platelet surface acceptor GP IIb/IIIa.RGDV combines with the specificity of activatory platelet surface acceptor GP IIb/IIIa, has given RGDV a critical nature, and promptly RGDV can be to the enrichment of the position of platelet activation.Under such prerequisite, put together RGDV and anti-cell adherent YIGSK, just can obtain the target anti-cell and stick polypeptide.
Summary of the invention
One of the object of the invention is that RGDV and YIGSK are puted together, and prepares the polypeptide with target antithrombotic activity.
Two of the object of the invention provides a kind of method for preparing the RGDVYIGSK of antithrombotic acitivity.This method comprises:
1. employing liquid-phase synthesis process is through progressively connecing the protection midbody of synthetic respectively RGDV of peptide and YIGSK;
2. slough the C end protection base of RGDV protection midbody;
3. slough the N end protection base of YIGSK protection midbody;
4. put together the YIGSK protection midbody of the RGDV of C end dissociative protection midbody and N end dissociative, slough the protection base again and obtain RGDVYIGSK.
Wherein, described N end protection base is the blocking group that the N end of polypeptide is used always when protecting, and for example can be tertbutyloxycarbonyl (Boc); Described C end protection base is the blocking group that the C end of polypeptide is used always when protecting, and for example can be benzyloxy (OBzl), methoxyl group (OMe) etc.
Above-described liquid phase synthetic intermediate and the method for protecting are the conventional and technique known of this area.
Animal model test proves that RGDVYIGSK of the present invention has stronger antithrombotic acitivity.
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
The explanation of the shortenings that is occurred among the present invention:
The THF THF
DCC dicyclohexyl imide
The DCU NSC 30023
The OBzl benzyloxy
The Boc tertbutyloxycarbonyl
The OMe methoxyl group
HOBt N-hydroxybenzotriazole
The NMM N-methylmorpholine
Embodiment
The preparation of embodiment 1 HClTyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl
1) preparation of Boc-Ser (Bzl)-Lys (Z)-OBzl
0.59g (2.0mmol) Boc-Ser (Bzl) is dissolved among the anhydrous THF of 6ml, and 0 ℃ adds 0.27g (2.0mmol) N-hydroxybenzotriazole (HOBt) and 0.45g (2.2mmol) dicyclohexyl carbonyl diimine (DCC) down.Stir the anhydrous THF solution that adds 1.084g (2.0mmol) TosLys (Z)-OBzl after 10 minutes.Reaction mixture is regulated pH 8-9 with N-methylmorpholine (NMM), and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the NSC 30023 (DCU) that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 30: 1), obtain 1.216g (94%) target compound.ESI-MS(m/z)648[M+H]
+。
2) preparation of HClSer (Bzl)-Lys (Z)-OBzl
0.648g (1.0mmol) Boc-Ser (Bzl)-Lys (Z)-OBzl is dissolved in 10ml hydrogenchloride-ETHYLE ACETATE (6mol/l) solution; Stirring at room 2 hours; TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)548[M+H]
+。
3) preparation of Boc-Ile-Gly-OMe
With 0.498g (2.0mmol) Boc-IleH
2O is dissolved among the anhydrous THF of 5mL, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir the anhydrous THF solution that adds 0.251g (2.0mmol) HClGly-OMe after 10 minutes.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 60: 1).Obtain 0.567g (94%) target compound.ESI-MS(m/z)303[M+H]
+。
4) preparation of HClIle-Gly-OMe
0.567g (1.87mmol) Boc-Ile-Gly-OMe is dissolved in 15ml hydrogenchloride-ethyl acetate solution (6mol/l); Stirring at room 2 hours; TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)203[M+H]
+。
5) preparation of Boc-Tyr-Ile-Gly-OMe
0.525g (1.87mmol) Boc-Tyr is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.270g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.377g (1.87mmol) HClIle-Gly-OMe.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 60: 1).Obtain 0.808g (93%) target compound.ESI-MS(m/z)466[M+H]
+。
6) preparation of Boc-Tyr-Ile-Gly
0.808g (1.87mmol) Boc-Tyr-Ile-Gly-OMe is dissolved in the 10ml methyl alcohol, and 0 ℃ adds the NaOH aqueous solution (1.5mol/l) down, regulates pH value to 11, stirring reaction 0.5h, and the TLC detection reaction finishes.Add saturated KHSO4 and regulate pH value to 6~7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO
4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, with saturated NaCl come together give a baby a bath on the third day after its birth inferior, anhydrous Na SO
4Dry 3 hours, to filter, filtrate decompression concentrates and removes ETHYLE ACETATE, obtains 0.834g (99%) target compound.ESI-MS(m/z)450[M-H]
-。
7) preparation of Boc-Tyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl
0.857g (1.9mmol) Boc-Tyr-Ile-Gly is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.257g (1.9mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 1.039g (1.9mmol) HClSer (Bzl)-Lys (Z)-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 30: 1).Obtain 1.71g (92%) target compound.ESI-MS(m/z)981[M+H]
+。
8) preparation of HClTyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl
0.98g (1.0mmol) Boc-Tyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl is dissolved in 20ml hydrogenchloride-ethyl acetate solution (6mol/l); Stirring at room 2 hours; TLC detects raw material point and disappears; ETHYLE ACETATE is taken out in decompression, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)881[M+H]
+。
The preparation of embodiment 2 Boc-Arg (Tos)-Gly-Asp (OMe)-Val
1) preparation of Boc-Asp (OMe)-Val-OBzl
0.494g (2.0mmol) Boc-Asp (OMe) is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.758g (2.0mmol) TosVal-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 30: 1).Obtain 0.819g (94%) target compound.ESI-MS(m/z)437[M+H]
+。
2) preparation of HClAsp (OMe)-Val-OBzl
0.819g (1.98mmol) Boc-Asp (OMe)-Val-OBzl is dissolved in 10ml hydrogenchloride-ethyl acetate solution (6mol/l); Stirring at room 2 hours; TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)337[M+H]
+。
3) preparation of Boc-Arg (Tos)-Gly-OMe
0.856g (2.0mmol) Boc-Arg (Tos) is dissolved in the 5ml dry DMF, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous DMF solution of 0.251g (2.0mmol) HClGly-OMe.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 30: 1).Obtain 0.96g (96%) target compound.ESI-MS(m/z)500[M+H]
+。
4) preparation of Boc-Arg (Tos)-Gly
0.96g (1.9mmol) Boc-Arg (Tos)-Gly-OMe is dissolved in the 10ml methyl alcohol, and 0 ℃ adds the NaOH aqueous solution (1.5mol/l) down and regulates pH value to 11, stirring reaction 0.5h, the end of TLC detection reaction.Add saturated KHSO
4Regulate pH value to 6~7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO
4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, with saturated NaCl come together give a baby a bath on the third day after its birth inferior, anhydrous Na SO
4Dry 3 hours, to filter, filtrate decompression concentrates and removes ETHYLE ACETATE, obtains 0.903g (98%) target compound.ESI-MS(m/z)484[M-H]
-。
5) preparation of Boc-Arg (Tos)-Gly-Asp (OMe)-Val-OBzl
0.903g (1.86mmol) Boc-Arg (Tos)-Gly is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.252g (1.86mmol) HOBt and 0.428g (2.08mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.693g (1.86mmol) HClAsp (OMe)-Val-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl
3: CH
3OH, 30: 1).Obtain 1.39g (93%) target compound.ESI-MS(m/z)804[M+H]
+。
6) preparation of Boc-Arg (Tos)-Gly-Asp (OMe)-Val
0.804g (1.0mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Val-OBzl is dissolved in the 10ml methyl alcohol, and 0 ℃ adds the NaOH aqueous solution (1.5mol/l) down and regulates pH value to 11, stirring reaction 0.5h, the end of TLC detection reaction.Add saturated KHSO
4Regulate pH value to 6~7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO
4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, with saturated NaCl come together give a baby a bath on the third day after its birth inferior, anhydrous Na SO
4Dry 3 hours, to filter, filtrate decompression concentrates and removes ETHYLE ACETATE, obtains 0.684g (96%) target compound.ESI-MS(m/z)712[M-H]
-。
The preparation of embodiment 3 RGDVYIGSK
1) preparation of Boc-Arg (Tos)-Gly-Asp (OMe)-Val-Tyr-Ile-Gly-Ser (Bzl)-Lyz (Z)-OBzl
0.713g (1.0mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Val is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.135g (1.0mmol) HOBt and 0.23g (1.09mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.916g (1.0mmol) HClTyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively
3The aqueous solution, 5%KHSO
4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO
4Dry 3 hours.Filtering NaSO
4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHC
l3: CH
3OH, 30: 1).Obtain 1.4g (89%) target compound.
1HNMR(BHSC-300,CDCl
3-d
3)δ=7.76(d,J=5.0Hz,10H),7.87(d,J=7.0Hz,2H),7.34(d,J=7.0Hz,2H),7.19(m,15H),6.95(d,J=7.0Hz,2H),6.65(d,J=7.0Hz,2H),5.7(s,1H),5.34(s,4H),5.17(q,J=6.0Hz,1H),5.0(s,1H),4.92(q,J=6.0Hz,2H),4.63(s,2H),4.52(t,J=6.0Hz,4H),4.09(d,J=6.0Hz,4H),3.87(d,J=5.0Hz,2H),3.67(s,3H),3.05(d,J=6.0Hz,2H),2.96(q,J=6.0Hz,2H),2.7(d,J=7.0Hz,5H),2.5(m,1H),2.35(s,3H),2.0(s,1H),1.7-1.9(q,J=7.0Hz,4H),1.4(s,9H),1.45-1.6(m,4H),0.8-1.3(m,J=8.0Hz,16H)。ESI-MS(m/z)1576[M+H]
+。Ultimate analysis C
78H
105N
13O
20S theoretical value C 59.41, H, 6.71, N11.55. measured value C 60.80, H 6.67, and N 11.38.
2) preparation of RGDSYIGSK
200mg (0.127mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Val-Tyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl is dissolved in the 4mL trifluoracetic acid; Add 1mL trifluoromethanesulfonic acid and 1mL methyl-phenoxide; 0 ℃ of following stirring reaction 1 hour, disposable adding 100mL ether was bled in decompression 5 minutes; The product pressed powder of separating out uses Sephadex G 10 to purify, and obtains 112mg (89%) target compound.
1HNMR(BHSC-300,CDCl
3-d
3)δ=11.0(s,2H),7.80(d,J=5.0Hz,8H),6.95(d,J=7.0Hz,2H),6.68(d,J=7.0Hz,2H),5.7(s,1H),5.0(s,1H),4.92(q,J=6.0Hz,1H),4.86(q,J=6.0Hz,1H),4.62(s,1H),4.51(t,J=6.0Hz,3H),4.09(d,J=6.0Hz,4H),4.03(d,J=7.0Hz,2H),3.56(m,1H),3.05(d,J=6.0Hz,2H),2.73(t,J=6.0Hz,2H),2.68(m,1H),2.65(q,J=6.0Hz,4H),2.5(m,1H),2.0(s,8H),1.79(q,J=7.0Hz,4H),1.55(m,4H),0.8-1.3(m,J=8.0Hz,16H)。ESI-MS(m/z)995[M+H]
+。Ultimate analysis C
43H
71N
13O
14Theoretical value C 51.95, H, and 7.20, N 18.32. measured value C 52.11, H 7.29, and N 18.51.
The antithrombotic acitivity test of Test Example 1 RGDSYIGSK
1) rat operation and apparatus
(male, 220~230g) press 1200mgkg to the SD rat
-1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates RCCA, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, and preparation is in the distal end intubate.
2) intubate
Intubate is the polyethylene rubber tube that silylanization is crossed, and divides three sections, and the stage casing is a polyethylene rubber tube, long 60.0mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, and pipe range 100.0mm, the end that internal diameter 1.0mm, external diameter 2.0mm should manage pull into point pipe (being used to insert rat carotid artery or vein), and external diameter is 1.0mm.Be respectively charged into the long black surgical thread of 6cm in the clean penicillium mould bottle with the number of finishing, weigh; Take out silk thread then, put into the thicker intubate in stage casing of ready intubate according to numbering.
Open rat right side bulldog clamp, fill with heparin-saline solution (50IUkg in will managing through sharp pipe end with syringe
-1), then the arterial end of intubate is inserted the rat right carotid, the heparin of calculated amount is slowly injected in the rat body.
3) administration
Medicine: saline water (3mlkg
-1), the physiological salt soln of the physiological salt soln of Asprin (dosage is 30mg/kg), RGDVYIGSK (dosage is 10 μ mol/kg).
Folder closes rat right carotid artery folder, pulls up the syringe of intubate vein end, has the water-soluble medical fluid injector of medicine of calculated amount to insert the vein end of intubate suction, opens rat right carotid artery folder, and medicine is slowly pushed in the rat body.Folder closes right carotid artery folder, and the vein end in teahouse is inserted the rats with left jugular vein of separator well, opens bulldog clamp, makes blood begin circulation.And pick up counting simultaneously.Can produce thrombus because of blood circulation on the silk thread in this process in the extra heavy pipe of intubate central authorities.
4) thrombus is weighed
Timing is cut off venous incubation after beginning 15 minutes, stops circulation, carefully takes out silk thread with the ophthalmology tweezer, on filter paper, dips in drop of blood gently, puts into the penicillium mould bottle of weighing in advance, accurately weighs and record.Calculate the weight in wet base of thrombus.Each medicine repeats 11 administrations.The wet weight of thrombus
of each group of statistics is also done the t check.
5) result
RGDVYIGSK has good anti-thrombus activity.The result lists table 1 in.
The antithrombotic acitivity of table 1RGDVYIGSK on rat model
N=11; A. compare P<0.001 with saline water.
Claims (3)
1. the polypeptide RGDVYIGSK that has target antithrombotic activity.
2. method for preparing the RGDVYIGSK of claim 1 comprises:
(1) adopts liquid-phase synthesis process, synthesize the protection midbody of RGDV and the protection midbody of YIGSK respectively through progressively connecing peptide;
(2) the C end of sloughing the protection midbody of RGDV is protected base;
(3) the N end of sloughing the protection midbody of YIGSK is protected base;
(4) put together the protection midbody that obtains RGDVYIGSK to the RGDV protection midbody of the YIGSK of N end dissociative protection midbody and C end dissociative;
(5) slough the protection base to the protection midbody of RGDVYIGSK, obtain RGDSYIGSK.
3. the RGDVYIGSK of claim 1 is in the purposes of preparation in the antithrombotic reagent.
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CN106317198A (en) * | 2015-06-24 | 2017-01-11 | 首都医科大学 | GRPAK-The-RGDV, and preparation, activity and application thereof |
CN106336450A (en) * | 2015-07-13 | 2017-01-18 | 首都医科大学 | RGDV-The-GRPAK decapeptide and its preparation method, activity and use |
CN106349333A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | The-K(KAPRG)RGDV hendeca-peptide, as well as preparation, activity and application thereof |
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CN106317199A (en) * | 2015-06-24 | 2017-01-11 | 首都医科大学 | The-GRPAKRGDV decapeptide, and preparation method, activities and application thereof |
CN106317198A (en) * | 2015-06-24 | 2017-01-11 | 首都医科大学 | GRPAK-The-RGDV, and preparation, activity and application thereof |
CN106317199B (en) * | 2015-06-24 | 2019-09-13 | 首都医科大学 | The-GRPAKRGDV decapeptide, preparation, activity and application |
CN106317198B (en) * | 2015-06-24 | 2019-09-17 | 首都医科大学 | GRPAK-The-RGDV, preparation, activity and application |
CN106336450A (en) * | 2015-07-13 | 2017-01-18 | 首都医科大学 | RGDV-The-GRPAK decapeptide and its preparation method, activity and use |
CN106349333A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | The-K(KAPRG)RGDV hendeca-peptide, as well as preparation, activity and application thereof |
CN106336450B (en) * | 2015-07-13 | 2019-09-13 | 首都医科大学 | RGDV-The-GRPAK decapeptide, preparation, activity and application |
CN106349333B (en) * | 2015-07-13 | 2019-09-17 | 首都医科大学 | 11 peptide of The-K (KAPRG) RGDV, preparation, activity and application |
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