CN104926923A - Invisible polypeptide with good non-specific protein absorption resistance performance and preparation method thereof - Google Patents
Invisible polypeptide with good non-specific protein absorption resistance performance and preparation method thereof Download PDFInfo
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- CN104926923A CN104926923A CN201510324672.2A CN201510324672A CN104926923A CN 104926923 A CN104926923 A CN 104926923A CN 201510324672 A CN201510324672 A CN 201510324672A CN 104926923 A CN104926923 A CN 104926923A
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Abstract
The invention discloses an invisible polypeptide with a good non-specific protein absorption resistance performance and a preparation method thereof. The structural formula of the invisible polypeptide with the good non-specific protein absorption resistance performance is (please see the formula in the instruction). The invisible polypeptide is formed by condensation polymerization of dipolymer by covalent linkage of gamma-carboxyl of aspartic acid and alpha-amino of lysine, and the problem of biology non-degradability when the equivalent and uniform distribution electric charges needed by non-specific protein absorption materials and methacrylic acid and polyethylene glycol materials serve as drug carriers is solved.
Description
One, technical field
The present invention relates to peptide species and preparation method thereof, specifically a kind of have stealthy polypeptide of good anti-non-specific protein absorption performance and preparation method thereof.
Two, background technology
For biomaterial, the problem still do not solved completely is the non-specific protein absorption of material surface.It causes thrombosis, inflammatory reaction, one of principal element of even biomaterial inefficacy.Polyoxyethylene glycol (PEG) has been widely used in field of biomedical materials, but under the condition contacted with physiological blood for a long time, it is easily oxidized, and is even degraded.It is generally acknowledged, the stability of zwitterionic classes anti-non-specific protein absorption material is more excellent than PEG, wherein most typical is carboxybetaine (CBMA), sulfonic group trimethyl-glycine (SBMA) and Phosphorylcholine (MPC) etc., and they all belong to methyl acrylic ester material.But, when PEG class and methacrylate based polymers are as gene or nano-medicament carrier, when long term administration, due to its biological non-biodegradable, host cell lacks corresponding metabolic mechanism thus causes polymkeric substance in intracellular accumulation, the eubolism of host cell can be disturbed like this, host cell is damaged and even causes host cell dead.Polypeptide class material causes due to its good biocompatibility and biodegradability to be paid close attention to widely.Chen S.F. etc. obtain the polypeptide of the good anti-non-specific protein absorption performance of tool by the method that glutamic acid N-carboxyl inner-acid anhydride (Glu-NCA) and Methionin N-carboxyl inner-acid anhydride (Lys-NCA) mix ring-opening polymerization (ROP).But, be difficult to obtain the equally distributed polypeptide of positive and negative charge because the reactive behavior difference of two kinds of monomers and the monomer purity of different batches are difficult to control.Jiang S.Y. group prepares the oligopeptides containing 4-6 EK unit be made up of electronegative L-glutamic acid (E) and positively charged Methionin (K) by Solid-phase organic synthesis method, which show good anti-non-specific protein absorption performance.But the method depends on amino acid synthesizers, efficiency is low, expend large, and especially for macromolecule polypeptide, preparation efficiency is lower.Chen H. etc. devises the few glycolmethacrylate (OEGMA-lysine) of the Methionin be obtained by reacting by the alpha-amino group of few Ethylene Glycol Methyl acrylate chloride (OEGMA-Cl) and protectiveness Methionin, the superpolymer obtained after polymerization have the excellent anti-non-specific protein absorption performance that provided by OEG and provided by lysine side-chain with the function of Profibrinolysin (plasminogen) specific binding.Although this material shows good anti-non-specific protein absorption performance, its biological non-degradable sex chromosome mosaicism still exists.
Three, summary of the invention
The present invention aims to provide a kind ofly has stealthy polypeptide of good anti-non-specific protein absorption performance and preparation method thereof, can solve the difficult problems such as the biological non-biodegradable of the classical anti-non-specific adsorption protein material of polymethacrylate.So-called stealthy, refer to that material itself can stop protein in the non-specific adsorption on its surface, avoid and to be found by human immune system and to be eliminated, even cause the chance of body rejection, thus it is stealthy to realize human immune system.
The structural formula that the present invention has the stealthy polypeptide of good anti-non-specific protein absorption performance is as follows:
Wherein, n represents the polymerization degree of two kinds of monomers, n=10-30.
The preparation process that the present invention has the stealthy polypeptide of good anti-non-specific protein absorption performance is as follows:
1) condensation
Protectiveness Methionin, protectiveness aspartic acid, condensing agent and racemization inhibitor are dissolved in organic solvent, in nitrogen atmosphere under room temperature confined reaction 48h; After reaction terminates, underpressure distillation removing organic solvent, obtains yellow oil; Yellow oil be dissolved in ethyl acetate, use 10wt.% (mass concentration, lower same) citric acid solution, saturated sodium bicarbonate solution and saturated common salt water washing successively, separatory, collects organic phase; Organic phase revolves steaming desolvation after anhydrous sodium sulfate drying, and silica gel column chromatography is separated (moving phase: dichloromethane/ethyl acetate=3:1 (volume ratio)) and obtains intermediate 1, is white solid, is directly used in next step reaction;
The structural formula of intermediate 1 is as follows:
Wherein, R
1for
R
2for
Because all containing a HCl in commercially available protectiveness Methionin general structure, so need before the reaction to carry out pre-treatment, the amino in Methionin is made to dissociate with triethylamine (TEA) HCl sloughed in structure.
Described protectiveness Methionin is selected from
deng;
Described protectiveness aspartic acid is selected from
deng.
Step 1) described in condensing agent be dicyclohexylcarbodiimide (DCC) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) etc.; Described racemization inhibitor is 1-hydroxy benzo triazole (HOBt) or 1-hydroxyl-7-azo benzotriazole (HOAt) etc.
Step 1) in the mol ratio of protectiveness Methionin, protectiveness aspartic acid, condensing agent and racemization inhibitor be 1:1:2:2.
The volume of described ethyl acetate, 10wt.% citric acid solution, saturated sodium bicarbonate solution, saturated aqueous common salt is respectively the 8-10 of reaction solution volume doubly.
Step 1) described in organic solvent be N, N-diformamide (DMF) or methyl-sulphoxide.
2) Deprotection
Intermediate 1 is joined trifluoroacetic acid (TFA)/CH
2cl
2(V/V=2:1), in, stirring at room temperature reaction 3h, revolves steaming desolvation, residue is dissolved in CH again
2cl
2in, add TEA and adjust pH to 7-8, again revolve steaming desolvation; Filter and drying after washing residue, obtaining intermediate 2, is white solid;
The structural formula of intermediate 2 is as follows:
Wherein, R
1for
3) polycondensation
The ratio of intermediate 2, condensing agent and racemization inhibitor 1:2:2 is in molar ratio joined in organic solvent, in nitrogen atmosphere under room temperature confined reaction 48h, then reaction solution is poured in ether and precipitates polymkeric substance is intermediate 3, not purified be directly used in next step reaction; Step 3) described in organic solvent be DMF or methyl-sulphoxide.
The structural formula of intermediate 3 is as follows:
Wherein, R
1for
Step 3) described in condensing agent be dicyclohexylcarbodiimide (DCC) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) etc.; Described racemization inhibitor is 1-hydroxy benzo triazole (HOBt) or 1-hydroxyl-7-azo benzotriazole (HOAt) etc.
4) Deprotection
By step 3) intermediate 3 that obtains is dissolved in mixing solutions and reacts 6h under room temperature, after reaction terminates by reaction solution impouring ether yellow oil;
Work as R
1for
time, described mixing solutions is the CH of the piperidines of 50wt.%
2cl
2solution;
Work as R
1for
time, described mixing solutions be by the acetic acid solution of the HBr of 33wt.% and TFA by volume 1:1 form.
5) purifying of product
By step 4) yellow oil that obtains is soluble in water, and adjust pH to 7-8 with saturated sodium bicarbonate solution, dialysis, freeze-drying obtains white solid, is target product.Described dialysis refer in redistilled water dialyse 3 days, change water once every 12h.Described freeze-drying refers to freeze-drying under vacuum tightness 13Pa ,-45 DEG C of conditions.
On the basis of existing technology, the present invention designs and prepares a kind of polypeptide by poly aspartic acid band lysine side-chain, due to the anti-protein adsorption performance that it is good, be not easy the immunity and the rejection that cause body, thus achieve the stealthy performance to body immune system; Secondly the polypeptide based on natural amino acid solves the difficult problems such as the biological non-biodegradable of classical polymethacrylate and the anti-non-specific adsorption protein material of PEG class due to its good biodegradable performance.NMR (Nuclear Magnetic Resonance) spectrum (
1hNMR) confirm successfully to obtain target polypeptides; Attenuated total reflectance attenuated total refraction Fourier transform infrared spectroscopy (ATR-FTIR) and enzyme linked immunosorbent assay analysis method (ELISA) is adopted to investigate structure and its anti-non-specific protein absorption performance of this self-assembling polypeptide unimolecular film (SAMs).
Four, accompanying drawing explanation
Fig. 1 is gel permeation chromatography (GPC) figure of target polypeptides.As can be seen from Figure 1 successfully prepare target polypeptides, its weight-average molecular weight (Mw) is about 3.8kDa, and polydispersity coefficient (PDI) is 1.33.
Fig. 2 be target polypeptides nuclear magnetic resonance map (
1hNMR).As can be seen from Figure 2 successfully prepare target polypeptides, and corresponding hydrogen atom is pointed out.
Fig. 3 is attenuated total reflectance attenuated total refraction Fourier transform infrared spectroscopy (ATR-FTIR) figure of the self-assembled monolayer of polypeptide on gold plaque (SAMs).As can be seen from Figure 3 the Liang Ge characteristic absorbance district of secondary acid amides: amide I band (ν
c=O, 1600-1700cm
-1) and acid amides II band (δ
n-H, 1500-1600cm
-1), show to have defined polypeptide SAMs on gold plaque surface.
Fig. 4 is that polypeptide SAMs surface is to the relative nonspecificity protein adsorption amount of human immunoglobulins (anti-IgG) and Fibrinogen (Fg).As can be seen from Figure 4 choose anti-IgG and Fg as model protein, the relative nonspecificity protein adsorption amount of the two is respectively 8.5 ± 3.6% and 12.5 ± 4.8%.
Five, embodiment
1, condensation
δ-(α-benzyl-N
ε-carbobenzoxy-(Cbz)-L-lysyl) the synthesis of-α-tertiary butyl-N-tertbutyloxycarbonyl-L-Aspartic acid (4)
H-Lys (Z)-OBzlHCl (1,6.10g, 15.0mmol) is dissolved in 30mL dry DMF, adds 2.5mL TEA (18.10mmol), under agitation condition, react 20min, filter; Then by BOC-ASP-O
tbu (3,4.34g, 15.0mmol), EDCHCl (5.75g, 30.0mmol), HOBt (4.04g, 30mmol) join in filtrate, after nitrogen protection 30min, and room temperature confined reaction 48h; After reaction terminates, underpressure distillation removes most of DMF, obtains yellow oil; Yellow oil is dissolved in ethyl acetate, use 10wt.% citric acid solution, saturated sodium bicarbonate solution, saturated common salt water washing successively, separatory, organic phase anhydrous sodium sulfate drying, revolve steaming desolvation, silica gel column chromatography is separated (moving phase: dichloromethane/ethyl acetate=3:1, volume ratio) and obtains white solid (4) (7.80g, yield 81.02%).
1HNMR(DMSO-d
6，400MHz)：δ1.21-1.4122H，1.43-1.732H，2.50-2.552H，2.87-2.982H，4.10-4.181H，4.19-4.291H，4.94-5.052H，5.05-5.132H，6.82-6.930.94H，7.18-7.250.92H，7.25-7.3910H，8.24-8.301H
2, the removing of protecting group tertbutyloxycarbonyl (Boc)
δ-(α-benzyl-N
ε-carbobenzoxy-(Cbz)-L-lysyl) synthesis of-L-Aspartic acid (5)
The protecting group tertbutyloxycarbonyl (Boc) of dipeptides adopts TFA/CH
2cl
2(V/V=2:1) remove.4 (8.0g, 12.47mmol) are joined 30mL TFA/CH
2cl
2(V/V=2:1), in, stirring at room temperature reaction 3h, revolves and steams precipitation to dry, residue is dissolved in CH again
2cl
2in, add TEA and adjust pH 7-8, then revolve steaming precipitation to dry; Under agitation condition, be suspended in water by residue and wash 2-3 time, filter, drying obtains white solid (5) (4.60g, yield 76.03%).
1HNMR(DMSO-d
6，400MHz)：δ1.21-1.444H，1.52-1.752H，2.45-2.551H，2.77-2.871H，2.87-2.982H，3.40-3.501H，4.19-4.291H，4.94-5.052H，5.05-5.132H，7.20-7.260.80H，7.27-7.4010H
3, polycondensation
Poly-(δ-(α-benzyl-N
ε-carbobenzoxy-(Cbz)-L-lysyl)-L-Aspartic acid) synthesis of (6)
By 5 (0.2g, 0.4mmol), EDCHCl (0.115g, 0.6mmol), HOBt (0.081g, 0.6mmol) joins in the DMF of 2mL, after nitrogen protection 30min, and room temperature confined reaction 48h; Then reaction solution is poured in a large amount of ether and precipitates to obtain polymkeric substance (6), not purified be directly used in next step reaction.
4, the removing of protecting group carbobenzoxy-(Cbz) (Cbz)
Poly-(N
δ-L-lysyl-L-Aspartic acid) synthesis of (7)
The protecting group carbobenzoxy-(Cbz) (Cbz) of polypeptide adopts 33wt.%HBr/HOAc to remove.Be dissolved in 6 after reacting 6h in the mixing solutions of TFA and 33wt.%HBr/HOAc (V/V=1:1) of 18mL, obtain yellow oil by reaction solution impouring ether.
5, the purifying of product
Yellow oil is water-soluble, and saturated sodium bicarbonate solution adjusts pH to 7-8, and dialysis, freeze-drying obtains white solid (7).Described dialysis refer in redistilled water dialyse 3 days, change water once every 12h.Described freeze-drying refers to freeze-drying under vacuum tightness 13Pa ,-45 DEG C of conditions.Removing completely of protecting group can be confirmed by the completely dissolve at δ 7.27-740 and nuclear-magnetism peak, 4.94-5.13 place.
1HNMR(D
2O，400MHz)：δ1.24-1.422H，1.52-1.824H，2.55-2.872H，2.88-3.002H，4.00-4.151H，4.58-4.671H
The concrete reaction process of each step is as follows:
The n value of target product is 25.
6, the sign of target product
The successful preparation of polypeptide can be confirmed by gel permeation chromatography figure (Fig. 1) and nmr spectrum (Fig. 2).
The ATR-FTIR of the self-assembled monolayer (SAMs) of polypeptide as shown in Figure 3, can know that the characteristic absorbance district amide I band of seeing secondary amide bonds (peptide bond) and acid amides II are with, show to have defined polypeptide SAMs on gold plaque surface; Choose human immunoglobulins (anti-IgG) and Fibrinogen (Fg) as model protein, investigate the anti-non-specific protein absorption performance of this polypeptide SAMs, result as shown in Figure 4.With the protein adsorption amount on tissue culturing polystyrene (TCPS) surface in contrast, be set as 100%, polypeptide SAMs surface is respectively 8.5 ± 3.6% and 12.5 ± 4.8% to anti-IgG and Fg relative nonspecificity protein adsorption amount.
Claims (7)
1. a stealthy polypeptide for anti-non-specific protein absorption, is characterized in that its structural formula is:
Wherein, n represents the polymerization degree of monomer, n=10-30.
2. a stealthy polypeptide production methods for a kind of anti-non-specific protein absorption according to claim 1, is characterized in that comprising the following steps:
1) condensation
Protectiveness Methionin, protectiveness aspartic acid, condensing agent and racemization inhibitor are dissolved in organic solvent, in nitrogen atmosphere under room temperature confined reaction 48h; After reaction terminates, underpressure distillation removing organic solvent, obtains yellow oil; Yellow oil is dissolved in ethyl acetate, uses 10wt.% citric acid solution, saturated sodium bicarbonate solution and saturated common salt water washing successively, separatory, collect organic phase; Organic phase revolves steaming desolvation after anhydrous sodium sulfate drying, and silica gel column chromatography is separated to obtain intermediate 1;
Described protectiveness Methionin is selected from
Described protectiveness aspartic acid is selected from
2) Deprotection
Joined by intermediate 1 in trifluoroacetic acid and the methylene dichloride mixing solutions that 2:1 is formed by volume, stirring at room temperature reaction 3h, revolves steaming desolvation, is dissolved in again in methylene dichloride by residue, adds triethylamine and adjusts pH to 7-8, again revolve steaming desolvation; Filter and drying after washing residue, obtain intermediate 2;
3) polycondensation
The ratio of intermediate 2, condensing agent and racemization inhibitor 1:2:2 is in molar ratio joined in organic solvent, in nitrogen atmosphere under room temperature confined reaction 48h, then reaction solution is poured in ether and precipitates polymkeric substance is intermediate 3;
4) Deprotection
Intermediate 3 is dissolved in mixing solutions and under room temperature, reacts 6h, after reaction terminates, obtain yellow oil by reaction solution impouring ether; Described mixing solutions be by the acetic acid solution of the HBr of 33wt.% and trifluoroacetic acid by volume 1:1 form;
5) purifying of product
By step 4) yellow oil that obtains is soluble in water, and adjust pH to 7-8 with saturated sodium bicarbonate solution, dialysis, freeze-drying obtains white solid, is target product.
3. method according to claim 2, is characterized in that:
Step 1) and step 3) described in condensing agent be dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride;
Step 1) and step 3) described in racemization inhibitor be 1-hydroxy benzo triazole or 1-hydroxyl-7-azo benzotriazole.
4. according to the method in claim 2 or 3, it is characterized in that:
Step 1) in the mol ratio of protectiveness Methionin, protectiveness aspartic acid, condensing agent and racemization inhibitor be 1:1:2:2.
5. method according to claim 2, is characterized in that:
Step 1) in ethyl acetate, 10wt.% citric acid solution, saturated sodium bicarbonate solution, saturated aqueous common salt volume be respectively the 8-10 of reaction solution volume doubly.
6. method according to claim 2, is characterized in that:
Step 1) described in organic solvent be N, N-diformamide or methyl-sulphoxide;
Step 3) described in organic solvent be N, N-diformamide or methyl-sulphoxide.
7. method according to claim 2, is characterized in that:
Step 5) described in dialysis refer in redistilled water dialyse 3 days, change water once every 12h; Described freeze-drying refers to freeze-drying under vacuum tightness 13Pa ,-45 DEG C of conditions.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565824A (en) * | 2016-10-20 | 2017-04-19 | 浙江大学 | Enzyme degradation-controllable anti-nonspecific protein adsorption polypeptide and monomer and preparation method thereof |
| CN109609333A (en) * | 2018-10-12 | 2019-04-12 | 深圳市瀚海基因生物科技有限公司 | A kind of biochip and preparation method thereof |
-
2015
- 2015-06-11 CN CN201510324672.2A patent/CN104926923B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| DONG, CUI-LING等: "The cytocompatibility of polyhydroxyalkanoates coated with a fusion protein of PHA repressor protein (PhaR) and Lys-Gln-Ala-Gly-Asp-Val (KQAGDV) polypeptide", 《BIOMATERIALS》 * |
| 杨庆华: "抗非特异性蛋白质吸附多肽的合成、表征及体外酶降解性能研究", 《中国博士学位论文全文数据库》 * |
| 杨庆华等: "抗非特异性蛋白质吸附多肽的设计、合成与性能表征", 《2013 年全国高分子学术论文报告会》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565824A (en) * | 2016-10-20 | 2017-04-19 | 浙江大学 | Enzyme degradation-controllable anti-nonspecific protein adsorption polypeptide and monomer and preparation method thereof |
| CN109609333A (en) * | 2018-10-12 | 2019-04-12 | 深圳市瀚海基因生物科技有限公司 | A kind of biochip and preparation method thereof |
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