CN102180948A - Short peptide having kidney protection function as well as preparation method and application thereof - Google Patents
Short peptide having kidney protection function as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a short peptide having a kidney protection function as well as a preparation method and application thereof. The short peptide having the kidney protection function is characterized in that the amino acid sequence of the short peptide is QEQLERALNSS. The preparation method is characterized by comprising the following steps: successively coupling Ser, Asn, Leu, Ala, Arg, Glu, Leu, Gln, Glu and Gln on serine which is based on resin as a vector; after cracking, and settling with ice ether so as to obtain coarse peptide; and purifying with a high performance liquid chromatography (HPLC) so as to obtain the product. The invention also discloses application of the short peptide having the kidney protection function in the aspects of preparing formulations for treating renal ischemia-reperfusion injury along with acute tubular necrosis, local renal tissue inflammation and renal tubular epithelium cell apoptosis which are caused by the renal ischemia-reperfusion injury. The invention provides a novel clinic medicament for preventing and treating the renal ischemia-reperfusion injury, thereby bringing good news for patients suffering renal transplant.
Description
Technical field
The present invention relates to a kind of small peptide and its production and application with kidney provide protection, its sequence and structure derive from erythropoietin (erythropoietin, EPO) the polypeptide surface section of B spiral (Helix B surface peptide, HBSP).
Background technology
The kidney hypoxic-ischemic causes energy metabolism deficiency, ATP excessively to exhaust, refilling process produces a large amount of oxyradicals again, and both all can cause the renal cells accent to be died, and renal function is badly damaged.Simultaneously, in the ischemic process, a large amount of inflammatory cells are raised to matter between uriniferous tubules, discharge various inflammatory mediators, not only cause the nephridial tissue coup injury, can cause that also kidney vascular endothelial cell damage and immunogenicity strengthen, and further cause the immunity blood vessel injury.The reason that causes renal ischemic reperfusion injury clinically mainly contains cardiovascular disorder, Sepsis, wound and surgical operation etc.And increase gradually along with kidney transfer operation recently, the delayed renal graft function recovery and the chronic graft ephrosis that cause because of ischemical reperfusion injury have had a strong impact on surgical effect and patient's prognosis.Though experiment and the clinical study to renal ischemic reperfusion injury deepens continuously in recent years, and developed the medicine of multiple kidney provide protection, its general curative effect is all imprecise.
Erythropoietin (EPO) is widely used in correcting the renal anemia of uremic patient clinically.Recent study shows, EPO is after renal tissue part and receptors bind, can suppress caspase (caspase) by many barss approach and activate, keep mitochondrial membrane potential, promote glycolysis-and adenosine triphosphate (ATP) to synthesize, thereby reduce the renal cells apoptosis.In addition, EPO also can reduce inflammatory factor and receptor expression such as interleukin-11 (IL-1), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), macrophage chemoattractant protein-1 (MCP-1) and the Toll sample acceptor of ischemical reperfusion injury metanephros tissue local-4(TLR-4), significantly suppress matter inflammatory cell infiltration between the ischemic metanephric tubule, and by the reaction of NF-kB pathway downward modulation local inflammation.Though EPO demonstrates good nephridial tissue provide protection, it also has in clinical treatment increases blood viscosity, promote thrombosis, promote tumour to form and cause untoward reaction such as hypertension.And the effect of the organization protection of EPO is dose-dependently, and the dosage threshold value will cause the probability that untoward reaction takes place to increase greatly apparently higher than the normal dose of the short red effect of performance.Therefore, can the untoward reaction that how not only keeps organization protection's effect of EPO but also avoid short red effect to bring have become its key that be applied to clinical kidney protection treatment.
Summary of the invention
The purpose of this invention is to provide a kind of small peptide with kidney provide protection and its production and application, described small peptide can keep organization protection's effect of EPO can avoid urging the untoward reaction that red effect brings again.
In order to achieve the above object, the invention provides a kind of small peptide, it is characterized in that aminoacid sequence is QEQLERALNSS with kidney provide protection.This sequence and structure derive from EPO B helical surface peptide section (Helix B surface peptide, HBSP).
The invention also discloses above-mentioned preparation method with small peptide of kidney provide protection, it is characterized in that, concrete steps are: coupling Ser, Asn, Leu, Ala, Arg, Glu, Leu, Gln, Glu and Gln successively on the Serine that with the resin is carrier, after the cracking, obtain thick peptide with the sedimentation of ice ether; Obtain product through the HPLC purifying.Small peptide of the present invention also can adopt conventional amino acid coupling method synthetic.
The invention also discloses the above-mentioned application of small peptide in the preparation of preparation treatment renal ischemic reperfusion injury with kidney provide protection.
The invention also discloses the above-mentioned application of small peptide in the preparation of the acute tubular necrosis that preparation treatment renal ischemic reperfusion injury causes with kidney provide protection.
The invention also discloses the above-mentioned application of small peptide in the preparation of the nephridial tissue local inflammation that preparation treatment renal ischemic reperfusion injury causes with kidney provide protection.
The invention also discloses the above-mentioned application of small peptide in the preparation of the renal cells apoptosis that preparation treatment renal ischemic reperfusion injury causes with kidney provide protection.
The invention also discloses the above-mentioned application of small peptide in preparation organ transplantation protection liquid with kidney provide protection.
The advantage of the small peptide HBSP of the present invention's preparation is:
1, provides a kind of novel clinical medicine of prevent and treat renal ischemic reperfusion injury, for the renal transplant patient brings glad tidings;
2, can be used as a kind of composition that liquid is preserved in organ transplantation;
3, studies confirm that almost and have no side effect;
4, be small peptide class medicine, the biological activity height, security is good;
5, it is easy to be converted into clinical medicine, further application prospect light.
Preparation process of the present invention is reliable and stable, technology maturation, and easy handling, preparation efficiency is higher.
Description of drawings
Fig. 1 be EPO with (EPOR)
2Bonded space conformation figure;
Fig. 2 is a HBSP sequence synoptic diagram;
Fig. 3 detects collection of illustrative plates for HPLC;
Fig. 4 is molecular weight identification figure;
Fig. 5 is that postoperative 48h serum creatinine and urea nitrogen levels are measured figure;
Fig. 6 is renal tissue section HE dyeing and damage pathological score (200x) figure;
Fig. 7 is a renal tissue TUNEL colored graph;
Fig. 8 is a TUNEL positive cell percentage diagram;
Fig. 9 is that the local Monocytes of nephridial tissue is soaked into figure;
Figure 10 is the short red effect comparison diagram of HBSP and EPO.
Embodiment
Specify the present invention below in conjunction with embodiment.
Embodiment 1: erythropoietin B helical surface peptide (Helix B surface peptide, preparation HBSP):
HBSP is a kind of small peptide with kidney provide protection; its sequence and structure derive from the (erythropoietin of erythropoietin; EPO) (Helix B surface peptide, HBSP), concrete aminoacid sequence is QEQLERALNSS to B helical surface peptide section.As shown in Figure 1, for EPO with (EPOR)
2Bonded space conformation figure, 4 subunit spirals (Helix A-D) of EPO form the ball-like structure of a compression by hydrophobic interaction, 1 and 2 (square frame of broken lines) of dotted line sign are the joint portion of EPO and high-affinity receptor, and hydrophilic Helix B is positioned at EPO spherule top (circular dashed line frame).As shown in Figure 2, be HBSP sequence synoptic diagram, form HBSP from 11 amino-acid residues of water-wetted surface extraction of Helix B spiral.The L-glutamic acid that is positioned at the N end can spontaneous cyclisation form Pyrrolidonecarboxylic acid, forms peptide chain shown in the pHBSP(top).
The preparation method of HBSP:
1, synthetic:
(1) selects Ser-WangResin(Serine king resin, Tianjin Nankai Hecheng S﹠T Co., Ltd. for use); Benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU, heavenly steed fine chemicals company limited); HOBT(1-hydroxybenzotriazole, 1-Hydroxybenzotrizole, heavenly steed fine chemicals company limited), DIEA(N, N-diisopropylethylamine, N, N-Diisoproylethylamine, Aladdin reagent (Shanghai) Co., Ltd.)
(2) amino acid whose coupling:
With 0.1mmol replacement amount is after the Ser-WangResin of 0.38mmol/g takes off fmoc, add HBTU solution that 0.3mmol concentration is 0.1mmol/L, HOBT that 0.3mmol concentration is 0.1mmol/L, DIEA solution that 0.6mmol concentration is 0.2mmol/L and Fmoc-Ser (tBu)-OH of 0.3 mmol, reaction 1.5min, the indenes inspection is transparent, DMF washing 3 times, methanol wash 1 time, DMF washing 1 time;
The above-mentioned Fmoc(fluorenylmethyloxycarbonyl that takes off) step is for 20% DBLK(, six hydrogen piperidines, and prompt chemical reagent company limited, DMF solvent are moistened in Shanghai) solution washes twice, 5 min for the first time, 7 min for the second time, DMF washing 3 times, methanol wash 1 time, washed with dichloromethane 1 time.
(3) repeat the amino acid linked reaction, above-mentioned Fmoc-Ser (tBu)-OH is replaced with Fmoc-Asn (Trt)-OH(Asn(Asparagine l-asparagine successively)), Fmoc-Leu-OH (Leu(Leucine leucine)), Fmoc-Ala-OH (Ala(Alanin L-Ala)), Fmoc-Arg (Pbf)-OH (Arg(Arginine arginine)), Fmoc-Glu (OtBu)-OH (Glu(Glutamicacid L-glutamic acid)), Fmoc-Leu-OH, Fmoc-Gln (Trt)-OH (Gln(Glutarnine glutamine)), Fmoc-Glu (OtBu)-OH, Fmoc-Gln (Trt)-OH carries out coupling, obtains Fmoc-QEQLERALNSS-WangResin;
(4) Fmoc-QEQLERALNSS-WangResin is removed after the Fmoc,, wash 2 times, each 5min, dry adsorbent with methyl alcohol with DMF washing 5 times;
(5) use classical lysate (weight ratio is the mixture of trifluoroacetic acid, tri isopropyl silane and the water of 94:3:3) 2ml cracking 2h, add ice ether 100ml sedimentation and obtain thick peptide.
2, purifying:
Moving phase: A uses the 0.1vol% trifluoroacetic acid aqueous solution mutually, and B uses the acetonitrile solution of 100 vol % mutually.
Employing Varian preparative high performance liquid chromatography instrument (model PrepStar-218, Varian Inc, California, USA).
Analyze chromatographic column (model AC01, Beijing innovation is logical permanent): C18 30 * 250mm 100A 10 μ m.
The purifying gradient: B changes to 35 vol % from 15 vol % in 20min, and the liquid chromatographic detection instrument (model UltiMate3000, Dionex Corporation, California, USA) wavelength set is at 230nm.
Lyophilize: connect down main peak solution through high pressure lipuid chromatography (HPLC) (HPLC) purifying, with the acetonitrile in the solution through Rotary Evaporators (model V855, BUCHI Labortechnik AG in Flawil, Switzerland) remove, last freeze drier (model LGJ-12, Beijing development in science and technology company limited of Song Yuan Huaxing), behind the 48h, obtain the white powder product.
Purity detecting: behind the HPLC purifying, can see that the area under curve (Rel.Area) of the main peak under the 6.17min is that product purity reaches 98.12%, as shown in Figure 3, for HPLC detects collection of illustrative plates.
3, identify:
Carry out molecular weight detection, instrument MSQ Plus Mass Spectrometer(Dionex Corporation, California, USA), source ESI(electron spray ionisation, electrospray ionization), taper hole voltage+75v, applied sample amount 5ul, range 100～2000Da.The HBSP theoretical molecular is 1274.4, and 637.8 for the peak with 2 electric charges in the molecular weight, consistent with theoretical molecular, as shown in Figure 4, is molecular weight identification figure.
Embodiment 2:HBSP to rats with renal ischemic reperfusion injury (ischemia reperfusion, IR) metanephros function effect:
A. set up the rats with renal ischemic reperfusion injury model: with 0.12g/kg dosage intraperitoneal injection of ketamine solution (available from last marine mountain hospital laboratory animal experimental center, specification: 2ml:0.1g), be fixed on the flat board after the anesthesia, enter the abdominal cavity along the midline incision stomach wall, expose the right side kidney and the kidney base of a fruit careful the separation, give not damaged blood vessel clip folder and close the kidney base of a fruit, handle the left kidney and the kidney base of a fruit with method.Kidney base of a fruit blood vessel blocking 45min, the black explanation folder of kidney color purpling closes successfully, unclamps behind the blood vessel clip kidney and piebald shape occurs and change the explanation blood perfusion and recover.Sham operated rats is only given and is separated the bilateral kidney and the kidney base of a fruit, will not press from both sides and close.
B. the HBSP treatment is organized in kidney blood perfusion recovery back 1min, 6h, 12h and is given pre-configured 8nmol/ml HBSP normal saline solution by 8nmol/kg dosage abdominal cavity respectively, and all the other respectively organize the corresponding equivalent physiological saline that gives.
C. postoperative 48h gets and respectively organizes the rat serum sample, and the centrifugal 5min of 1400g gets serum and gives automatic clinical chemistry analyzer and detect and respectively to organize serum creatinine and urea nitrogen levels.
D. postoperative 48h gets and respectively organizes the kidney sample and place 10% formalin fixing respectively, or preserves in liquid nitrogen and be equipped with subsequent disposal.
As shown in Figure 5, be that postoperative 48h serum creatinine and urea nitrogen levels measure figure, experimental result shows that IR group renal function obviously reduces, and compares with sham operated rats, and serum creatinine and urea nitrogen levels raise about 16 times and 9 times respectively, difference have statistical significance (
P＜0.05).Use the HBSP treatment and can obviously improve the renal function level, compare serum creatinine with the IR group and blood urea nitrogen has reduced by 60.2% and 50.8% respectively, difference have remarkable statistical significance (
P＜0.05).
The influence of the renal tubular necrosis that embodiment 3:HBSP causes rats with renal ischemic reperfusion injury:
A. will test the capable paraffin embedding of kidney of rats tissue sample of gained in 1 and make section, with conventional HE method dyeing.
B. nephridial tissue pathological change degree is respectively organized in observation under the light microscopic, parallel injury of renal tubular pathological grading (the normal kidney of 0=; The 1=microlesion is involved＜5% cortex and priopticon; The 2=minor injury involves cortex and the priopticon of 5%-25%; The 3=moderate lesion is involved cortex and the priopticon of 25%-75%; The 4=severe injury involves〉75% cortex and priopticon).
As shown in Figure 6, for renal tissue section HE dyeing and damage pathological score (200x) figure (with the Vehicle group relatively,
* P＜0.05), experimental result shows, IR group rat shows that tangible tubulopathy is rational to be changed, and obscurity boundary is unclear, swelling, vacuolar degeneration and necrosis etc., and the change of HBSP treatment group kidney of rats tubule pathologic obviously alleviates, and the injury of renal tubular pathological score is starkly lower than the IR group.
The renal tubular epithelial cell apoptosis that embodiment 4:HBSP causes rats with renal ischemic reperfusion injury:
A. will test the capable paraffin embedding of kidney of rats tissue sample of gained in 1 and make section, dye with conventional TUNLE immunohistochemical staining method.
B. microscopically is observed the parallel apoptotic index classification of renal cells apoptosis situation.
As shown in Figure 7, be renal tissue TUNEL colored graph, as shown in Figure 8, for TUNEL positive cell percentage diagram (with Vehicle group relatively,
* P＜0.05), experimental result shows that HBSP treatment group kidney of rats tissue T UNLE stained positive cell is starkly lower than the IR group, prompting HBSP can obviously reduce the renal cells apoptosis, the protection nephridial tissue.
The influence of the nephridial tissue local inflammation that embodiment 5:HBSP causes rats with renal ischemic reperfusion injury:
A. will test the capable paraffin embedding of kidney of rats tissue sample of gained in 1 and make section,, with conventional HE method dyeing.Observe monocyte infiltration situation in the rat HE stained.
B. the immunohistochemical methods antibody staining is analyzed the expression of nephridial tissue MCP-1 and the level of corresponding acceptor CCR-2: paraffin section is handled the back routinely and wash 5min in the phosphate buffered saline buffer of (pH=7.4), be configured to sheep blood serum solution (solvent is the PBS of pH=7.4) the processing section 20min of volumetric concentration 10% with the normal sheep serum (grinding territory (Shanghai) chemical reagent company limited) of 10ml, deproteinize solution inclines, drip anti-MCP-1 (rabbit anti-mouse antibody, Santa Cruz Biotechnology, California, U.S.A., article No. SC-28879, weaker concn 1:500) and anti-CCR-2 antibody (rabbit anti-mouse antibody, Abcam, Cambridge, UK, article No. ab21667, weaker concn 1:500), 4 ℃ of overnight incubation, PBS(pH=7.4) washing, add ELIAS secondary antibody (goat anti-rabbit antibody, Beijing Bo Aosen Bioisystech Co., Ltd, article No. bse-0295G, weaker concn 1:5000), incubated at room 30min, PBS(pH=7.4) washing is in (Fuzhou Maixin biotechnology Development Co., Ltd of horseradish peroxidase system, article No. DAB-3032) carry out color reaction in, microscopically is observed immune labeled after the mounting.
As shown in Figure 9, be that the local Monocytes of nephridial tissue soaks into figure, the IR group than sham operated rats MCP-1/CCR2 express showed increased (
P＜0.01), HBSP group than IR group MCP-1/CCR2 express obviously and reduce (
P＜0.01), experimental result shows that HBSP can obviously reduce the nephridial tissue monocyte infiltration, and HBSP treatment group kidney MCP-1/CCR-2 expression is starkly lower than the IR group.
Embodiment 6:EPO and HBSP are short red, and effect is compared:
As shown in figure 10, for the short red effect comparison diagram of HBSP and EPO (
* P＜0.05), experimental result shows that EPO administration group red blood cell count(RBC) obviously increases, and HBSP administration group and physiological saline group red corpuscle do not have obvious rising, prove that HBSP there is no short red effect.
＜110〉Zhongshan Hospital Attached to Fudan Univ
＜120〉has the preparation of the small peptide of kidney provide protection
<160>?1
<210>?1
<211>?11
<212>?PRT
＜213〉artificial sequence
<220>
＜223〉according to the disclosed linear polypeptide sequence that derives from erythropoietin B spiral of document
<300>
<301>?Brines?M,?Patel?NS,?Villa?P,?Brines?C,?Mennini?T,?De?Paola?M,?Erbayraktar?Z,?Erbayraktar?S,?Sepodes?B,?Thiemermann?C,?Ghezzi?P,?Yamin?M,?Hand?CC,?Xie?QW,?Coleman?T,?Cerami?A
<302>?Nonerythropoietic,?tissue-protective?peptides?derived?from?the?tertiary?structure?of?erythropoietin
<303>?Proc?Natl?Acad?Sci?U?S?A
<304>?105
<305>?0027-8424
<306>?10925-10930
<307>?20080805
<308>?18676614
<309>?20080925
<400>?1
Gln?Glu?Gln?Leu?Glu?Arg?Ala?Leu?Asn?Ser?Ser
1 5 10
Claims (7)
1. the small peptide with kidney provide protection is characterized in that, its aminoacid sequence is QEQLERALNSS.
2. the described preparation method of claim 1 with small peptide of kidney provide protection, it is characterized in that, concrete steps are: coupling Ser, Asn, Leu, Ala, Arg, Glu, Leu, Gln, Glu and Gln successively on the Serine that with the resin is carrier, after the cracking, obtain thick peptide with the sedimentation of ice ether; Obtain product through the HPLC purifying.
3. the described application of small peptide in the preparation of preparation treatment renal ischemic reperfusion injury of claim 1 with kidney provide protection.
4. the described application of small peptide in the preparation of the acute tubular necrosis that preparation treatment renal ischemic reperfusion injury causes of claim 1 with kidney provide protection.
5. the described application of small peptide in the preparation of the nephridial tissue local inflammation that preparation treatment renal ischemic reperfusion injury causes of claim 1 with kidney provide protection.
6. the described application of small peptide in the preparation of the renal cells apoptosis that preparation treatment renal ischemic reperfusion injury causes of claim 1 with kidney provide protection.
7. the described application of small peptide in preparation organ transplantation protection liquid of claim 1 with kidney provide protection.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212111A (en) * | 2011-05-05 | 2011-10-12 | 中国人民解放军第三军医大学 | Micromolecule polypeptide and micromolecule polypeptide liposome as well as applications thereof |
| CN102432671A (en) * | 2011-11-30 | 2012-05-02 | 复旦大学附属中山医院 | Targeting polypeptide SPSCVLP capable of inhibiting growth and transfer of liver cancer and application thereof |
| CN103275186A (en) * | 2013-06-07 | 2013-09-04 | 复旦大学附属中山医院 | Polypeptide having kidney protection effect, and application thereof |
| CN106075392A (en) * | 2016-07-18 | 2016-11-09 | 滨州医学院 | Erythropoietin derivatives application in hearing protection |
| CN112741895A (en) * | 2021-01-19 | 2021-05-04 | 中国人民解放军陆军军医大学 | Application of EPO analog in preparing medicament for treating sepsis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101378772A (en) * | 2005-08-05 | 2009-03-04 | 阿拉伊姆药品公司 | Tissue protective peptides and uses thereof |
-
2011
- 2011-03-03 CN CN2011100507775A patent/CN102180948A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101378772A (en) * | 2005-08-05 | 2009-03-04 | 阿拉伊姆药品公司 | Tissue protective peptides and uses thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212111A (en) * | 2011-05-05 | 2011-10-12 | 中国人民解放军第三军医大学 | Micromolecule polypeptide and micromolecule polypeptide liposome as well as applications thereof |
| CN102212111B (en) * | 2011-05-05 | 2014-04-30 | 中国人民解放军第三军医大学 | Micromolecule polypeptide and micromolecule polypeptide liposome as well as applications thereof |
| CN102432671A (en) * | 2011-11-30 | 2012-05-02 | 复旦大学附属中山医院 | Targeting polypeptide SPSCVLP capable of inhibiting growth and transfer of liver cancer and application thereof |
| CN103275186A (en) * | 2013-06-07 | 2013-09-04 | 复旦大学附属中山医院 | Polypeptide having kidney protection effect, and application thereof |
| CN103275186B (en) * | 2013-06-07 | 2015-07-01 | 复旦大学附属中山医院 | Polypeptide having kidney protection effect, and application thereof |
| CN106075392A (en) * | 2016-07-18 | 2016-11-09 | 滨州医学院 | Erythropoietin derivatives application in hearing protection |
| CN112741895A (en) * | 2021-01-19 | 2021-05-04 | 中国人民解放军陆军军医大学 | Application of EPO analog in preparing medicament for treating sepsis |
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Application publication date: 20110914 |