CN103333223A - A novel blood-glucose-reducing polypeptide and applications thereof - Google Patents
A novel blood-glucose-reducing polypeptide and applications thereof Download PDFInfo
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- CN103333223A CN103333223A CN2012104770548A CN201210477054A CN103333223A CN 103333223 A CN103333223 A CN 103333223A CN 2012104770548 A CN2012104770548 A CN 2012104770548A CN 201210477054 A CN201210477054 A CN 201210477054A CN 103333223 A CN103333223 A CN 103333223A
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Abstract
The invention relates to a novel blood-glucose-reducing polypeptide and applications thereof. The blood-glucose-reducing polypeptide has good blood-glucose-reducing activity and antioxidant activity. The blood-glucose-reducing polypeptide is prepared by a solid-phase synthesis method and is used for preparing medicines treating diabetes.
Description
Technical field
The present invention relates to a kind of novel Polypeptide-k, with and application in preparation treatment diabetes medicament, this Polypeptide-k has significant hypoglycemic activity and anti-oxidant activity in vivo, can be used for improving generation and the development of diabetes.
Background technology
Along with expanding economy, very big change has taken place in human mode of life, overnutrition, and the physical exertion minimizing is causeed fat and the sickness rate of obesity-related disease such as diabetes increases day by day.According to statistics, present global diabetic subject's number increases to 3.66 hundred million from 1.2 hundred million of nineteen ninety-five, and Chinese diabetic subject presents quick rising tendency, has accounted for 10% of global diabetes number, becomes world's diabetes " first big country ".Therefore, diabetes become the important diseases of current harm humans health already, are after cardiovascular and cerebrovascular diseases, malignant tumour, cause human wounded or disabled, dead the third-largest killer.
More and more studies show that in close relations between diabetes and the oxidative stress.Under hyperglycemia stimulated, the free radical in the diabetes human or animal body and active oxygen generated and increase.The excessive generation of active oxygen is by suppressing the activity of insulin gene promotor, damage beta Cell of islet nuclear and plastosome, reduce special-shaped box PDX-1 (the same source capsule of the pancreas duodenum) expression of gene of pancreas duodenum homology and active with the combination of DNA, the generation of Insulin mRNA (messenger RNA(mRNA)) in the β cell is reduced, thereby cause the biosynthesizing of Regular Insulin to reduce.Oxidative stress also can be modified the intracellular protein of β, and the β cell is produced directly infringement.Therefore oxidative stress plays an important role in the evolution in the generation of diabetes and complication thereof.Anti-oxidant treatment can alleviate oxidative stress, thereby stops or delay the generation of diabetes and complication thereof, development.
And traditional ofhypoglycemic medicine mainly comprises Regular Insulin succagoga (as sulfonylurea) and euglycemic agent (as thiazolidinediones) etc., but these medicines can not stop the development of diabetes and the generation of complication.The diabetic subject must take medicine throughout one's life, and along with the enhancing to drug tolerance, drug effect reduces and finally forfeiture gradually, and medicine itself is also threatening diabetics's health quality to the toxic side effect of human body simultaneously.Therefore increasing people attempts to seek a kind of novel ofhypoglycemic medicine and stops the development of diabetes and the generation of complication.
Summary of the invention
The present invention discloses a kind of novel Polypeptide-k and application thereof first.Experimental result shows that Polypeptide-k of the present invention not only has good hypoglycemic activity in vivo, also has good anti-oxidant activity.Polypeptide-k of the present invention can be used for treatment of diabetes, improves generation and the development of diabetes.
The object of the present invention is to provide a kind of novel Polypeptide-k, its structure is following sequence:
Lys-Thr-Met-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala(SEQ.ID?NO：1)
Lys-Thr-Asn-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala(SEQ.ID?NO：2)
Another object of the present invention is to provide described Polypeptide-k for the preparation of the purposes for the treatment of in the diabetes medicament.
Further purpose of the present invention is to provide a kind of pharmaceutical composition, comprises normally used pharmacology acceptable carrier, solvent, thinner, vehicle and other media in their manufacturing processed in the described pharmacology composition.
The formulation of the present composition can be injection liquid, tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, etc. formulation commonly used on the pharmaceutics.
Tablet for oral use and capsule contain vehicle such as weighting agent, thinner, lubricant, dispersion agent, solubility promoter, sanitas, osmotic pressure regulator, tackiness agent, pregelatinized Starch, cholate/Yelkin TTS mixed micelle systems etc. can be prepared according to the method for knowing in this area.
The dosage of above promoting agent will be different because of prescription.
A further object of the present invention is that effective and described Polypeptide-k or their pharmacology non-toxicity amount can be accepted composition by the people's pharmacology that gives to carry out this kind treatment, and the purposes of Polypeptide-k of the present invention as the treatment diabetes is provided.
Usually, proved favourable amount, for reaching required result, the total amount of the described Polypeptide-k of every kg body weight administration in per 24 hours is 0.001-100mg, the preferred about 0.01-30mg/kg of total amount.If necessary, with the form administration of single dose several times.
Yet, if necessary, also can depart from above-mentioned consumption, namely this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and administration time or the interval of seriousness, preparation and administration.
The objective of the invention is to realize by the following technical solutions:
The invention provides the preparation method of this type of Polypeptide-k, the present invention adopts microwave to promote the efficient synthetic peptide chain that obtains this type of Polypeptide-k rapidly of Fmoc/tBu orthogonally protect solid phase synthesis strategy.
Adopt microwave to promote Fmoc/tBu orthogonally protect solid phase synthesis strategy, earlier syntheticly on solid phase carrier obtain being loaded with first Fmoc and protect amino acid whose resin, ninhydrin method detects sloughs the resin that the Fmoc protecting group obtains being loaded with first amino-acid residue after negative; Enter next coupling circulation again; repeat the step of coupling and deprotection with different protection amino acid according to corresponding peptide order; prolong required aminoacid sequence successively, the synthetic resin that obtains being loaded with corresponding polypeptide cuts down polypeptide with cutting agent at last and obtains the polypeptide crude product from resin.Crude product is purified, and freeze-drying gets the pure product of polypeptide.
The mouse diabetes model that the present invention adopts normal mouse and STZ (streptozotocin) to induce as positive control, is measured the interior hypoglycemic activity of body of polypeptide of the present invention with synthetic in advance listing Polypeptide-k exenatide.
Studies show that more and more the relation between diabetes and the oxidative stress is very close, so the present invention has measured the anti-oxidant activity of the polypeptide described in the claim 1 on the mouse diabetes model that STZ induces.
Below be pharmacological experimental method and the result of the Polypeptide-k that relates among the present invention:
(1) the oral glucose tolerance of normal mouse experiment (OGTT)
Get 6-8 week male mouse of kunming in age (body weight 18-22g), random packet, 8 every group.Fasting be can't help water 16 hours before the experiment, measured basic blood glucose value (30min), the polypeptide (1 μ mol/kg) that synthesizes of abdominal injection the present invention, measure blood glucose value (0min) behind the 30min, 3g/kg glucose is irritated stomach, 30min behind the mensuration oral glucose, 60min, the blood glucose value of 120min.With exenatide (30 μ mol/kg) as positive drug.The results are shown in Table 1.
Table 1.SEQ.ID NO:1, the OGTT experimental result of the normal mouse of SEQ.ID NO:2
| -30min | 0min | 30min | 60min | 120min | |
| Negative control group | 4±0.98 | 4.55±1.14 | 18.72±2.05 | 14.5±2.85 | 6.25±2.13 |
| The exenatide control group | 4.57±0.66 | 4.62±0.44 | 8.02±1.05** | 5.72±1.02** | 4.2±0.24 |
| SEQ.ID NO:1 administration group | 4.6±0.53 | 4.57±0.56 | 12.06±2.25* | 8.13±2.59* | 5.68±1.69 |
| SEQ.ID NO:2 administration group | 4.8±0.45 | 5.13±0.67 | 12.43±2.14* | 8.56±2.32* | 5.32±1.34 |
*P＜0.05,
*P＜0.01 relatively has significant difference with negative control group.
The above results shows that the Polypeptide-k that the present invention synthesizes is being given sugar back 30min, and the blood glucose value of 60min obviously reduces compared to negative control group, has significant difference.And exenatide compares with negative control group and has extremely significant difference.Illustrate that the Polypeptide-k that the present invention synthesizes has good glucose tolerance to normal mouse.
(2) hypoglycemic activity of diabetic mice is measured
Get the 6-8 male mouse of kunming (body weight is 18-22g) in age in week, (0.01mol/L, pH4.5) 50mg/kg injected 3 days abdominal injection streptozotocin (STZ) citrate buffer solution continuously.After the STZ injection 72 hours, the mouse fasting be can't help water 12 hours, measured fasting blood sugar, selected mouse that blood glucose value is higher than 11.1mmol/L as diabetic mice, random packet, 8 every group.The polypeptide (1 μ mol/kg) that the abdominal injection the present invention in continuous 20 days of mouse behind the Cheng Mo synthesizes was surveyed a fasting blood sugar every 5 days, with exenatide (30 μ mol/kg) as positive control.In the time of the 21st day, mouse is plucked eyeball and gets blood and insert in the tube pipe that adds antithrombotics EDTA, and the saccharification blood sugar that the whole blood that obtains uses biochemical instruments to measure in the whole blood is worth (HbAlC) in vain.After getting blood, mouse is put to death, separate its pancreas, preserve islet cells number, area and denaturation degrees in the sections observation mice pancreatic with the formaldehyde solution of putting into 10% after the physiological saline washing of icing.The results are shown in Table 2-4.
Fasting blood sugar level after table 2.SEQ.ID NO:1 and the SEQ.ID NO:2 administration (mmol/L, n=8, mean ± SD)
*P＜0.05,
*P＜0.01 relatively has significant difference with the diabetes control group.
Result in the table 2 shows that the Polypeptide-k successive administration that the present invention synthesizes is after 20 days, and fasting blood sugar obviously reduces compared to the diabetes control group, has significant difference, and is active suitable with exenatide.
Table 3. diabetic mice glycolated hemoglobin value (n=8, mean ± SD)
*P＜0.05,
*P＜0.01 relatively has significant difference with the diabetes control group.
Result in the table 3 shows, compared to the diabetes control group, the HbAlC level of the Polypeptide-k that the present invention synthesizes obviously reduces, and has significant difference, illustrates that Polypeptide-k glucose level in administration three all processes that the present invention synthesizes has obtained good control and improvement.
Table 4. diabetic mice islet cells number, and area and denaturation degrees (n=8, mean ± SD)
The tissue slice result of table 4 shows, after the Polypeptide-k long term administration that the present invention synthesizes, increased pancreas islet number and area compared to the diabetes control group, has weakened the denaturation degrees of the β cell that STZ induces.Illustrate that Polypeptide-k of the present invention has the effect of protection islet cells.
(3) anti-oxidant activity of diabetic mice is measured
In the time of the 21st day, diabetic mice is plucked eyeball and is got blood, insert in the tube pipe, after room temperature is placed 30min, under 4 ℃ of conditions, 3500rpm/10min centrifuging and taking upper serum is measured the anti-oxidant parameter in the serum: GSH (gsh), GSH-PX (Selenoperoxidase), SOD (superoxide-dismutase), MDA (mda).The results are shown in Table 5.
SOD, MDA, GSH in the table 5. diabetic mice serum, and the level of GSH-PX (n=8, mean ± SD)
| SOD(U/mL) | MDA(mmol/mL) | GSH-PX(U/mL) | GSH(mg/mL) | |
| Negative control group | 46.68±1.41 | 8.40±0.41 | 1984.62±139.38 | 10.63±0.80 |
| The diabetes control group | 41.58±2.89 | 12.49±1.35* | 1449.23±49.42## | 8.13±0.13** |
| The exenatide control group | 36.94±2.65 | 7.60±1.48# | 1666.15±58.74 | 11.81±0.18## |
| SEQ.IDNO:1 treatment group | 46.96±4.27 | 7.61±1.39# | 1707.69±52.22 | 12.14±0.42## |
| SEQ.IDNO:2 treatment group | 47.84±3.54 | 8.25±1.65# | 1659.57±42.34 | 12.56±0.68## |
*P＜0.05,
*P＜0.01 relatively has significant difference with negative control group.
#P＜0.05,
##P＜0.01 relatively has significant difference with the diabetes control group.
Result in the table 5 shows, the Polypeptide-k that the present invention synthesizes can strengthen the vigor of the antioxidant enzyme (SOD and GSH-PX) in the body, and reduced the excessive generation of body lipid superoxide (MDA), increased the generation of polyphenoils gsh (GSH).The Polypeptide-k that the present invention synthesizes has good anti-oxidant activity, is better than exenatide.
Above-mentioned all results show that Polypeptide-k that the present invention synthesizes has all demonstrated the function of good glycemic control effect and protection beta Cell of islet on normal mouse and diabetic mice, and the hypoglycemic activity of the synthetic polypeptide of the present invention is roughly suitable with described listing Polypeptide-k exenatide.Compare with traditional ofhypoglycemic medicine, the Polypeptide-k that the present invention synthesizes also has obvious antioxidation activity, can be used for improving generation and the development of diabetes.
By the following examples the present invention is described further.
Embodiment:
Adopt following abbreviation in this specification:
DIEA:N, N '-diisopropylethylamine; DMF: dimethyl formamide; DCM: methylene dichloride; The Fmoc:N-9 fluorenylmethyloxycarbonyl; DIC:N, N '-DIC; DIPEA:N, N '-diisopropylethylamine; The DMAP:4-Dimethylamino pyridine; HBTU: benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester; HOBT:1-hydroxyl-benzotriazole; HPLC: high performance liquid chromatography; ESI-MS: electrospray ionization mass spectrum; Gly: glycine; Ala: L-Ala; Thr: Threonine; Met: methionine(Met); Lys: Methionin; Asn: l-asparagine.
Embodiment 1
The microwave of Lys-Thr-Met-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala (SEQ.ID NO:1) promotes solid phase synthesis.
(1) C-holds being connected of initial amino acid and resin
Take by weighing Wang Resin0.17g (replacement amount 0.6mmol/g), through 7mL DCM swelling 30min, suction filtration removes DCM, rinses well respectively with DMF and DCM.The Fmoc-Ala-OH that takes by weighing (0.3mmol) with DCM dissolving, a spot of DMF hydrotropy, drips DIC (90 μ L) and stirs 30min under the condition of ice bath, occur a large amount of precipitations after reaction finishes.Vacuum is revolved desolventizing, and remaining solid is dissolved among the 3mLDMF, and the resin that swelling is good adds in this mixing solutions, the DMAP that adds catalytic amount again reacts 7min in microwave reactor, microwave power is 25W, temperature of reaction control uses air compressor to produce the pressurized air cooling in 50 ℃.Reaction finishes back elimination reaction solution, with the DMF washing, washs with DCM more earlier.Add the DMAP of 20% aceticanhydride/DCM (V/V) mixing solutions and catalytic amount again, stir 2h under the room temperature condition.After the end socket reaction finishes, the elimination reaction solution, and earlier with DCM washing and vacuum-drying.
(2) the Fmoc protecting group removes
The resin or the resin-polypeptide complex that connect the Fmoc protecting group use 25% piperidines/DMF solution to react 1min in microwave reactor, microwave power is 15W, temperature of reaction control is used the cooling of air compressor pressurized air in 50 ℃, reaction finishes back elimination solution; Add 7mL20% piperidines/DMF (V/V) solution again and react 4min again in microwave reactor, microwave power is 25W, and temperature of reaction is controlled in 75 ℃, uses the cooling of air compressor pressurized air.Reaction finishes back elimination solution, uses the DMF washes clean.Obtain sloughing the polypeptide-resin complexes of Fmoc protecting group.
(3) coupling of resin upper amino acid
The prolongation of peptide chain uses HBTU and HOBt as activator, and DIPEA reacts 10min as activation alkali in microwave reactor, microwave power is 25W, temperature of reaction control is in 50 ℃, and reaction filters reaction solution after finishing, and uses DCM and each 10mL washing resin of DMF 3 times.The resin that takes a morsel, the coupling efficiency of ninhydrin method qualitative detection resin, color reaction is negative, then continues to enter the Fmoc deprotection steps.
(4) prolongation of peptide chain
The steps in sequence that repeats above-mentioned deprotection and coupling is connected corresponding amino acid; each connects after coupled reaction finishes in the peptide circulation; coupling efficiency with ninhydrin method or tetrabromophenol sulfonphthalein method qualitative detection resin; color reaction is negative can to enter next circulation, and color reaction is positive, and then to repeat coupling negative until the qualitative detection result.
(5) cutting of peptide chain
The above-mentioned resin that is connected with polypeptide that obtains is put into reaction flask, and adding cracking agent Reagent R (TFA/ thioanisole/phenol/EDT, 90: 5: 3: 2, V/V) 10mL earlier at 0 ℃ of following jolting 30min, reacts 1h more at normal temperatures.Reaction finishes the back suction filtration, adds a small amount of TFA and DCM washing three times, merging filtrate.Filtrate added in a large amount of ice ether separate out white flocks, frozen centrifugation obtains the crude product of target polypeptides.
(6) purifying of crude product
SEQ.ID NO:1 crude product with obtaining above is dissolved in a spot of water, prepares type reversed-phase HPLC purifying crude product with Tianjin, island.Adopt the anti-phase preparative column of C18 (340mm * 28mm, 5 μ m) in the purifying; Mobile phase A: 0.1%TFA/ water (V/V), Mobile phase B: 0.1%TFA/ methyl alcohol (V/V); Eluent gradient: 20%B-80%B/60min, flow velocity are 6mL/min; The detection wavelength is 214nm.The solution freeze-drying of collecting gets pure product, finally obtains pure product 25.1mg.Theoretical relative molecular mass 1096.39. (ESI-MS, m/z): found[M+H]
+1097.39, [M+2H]
2+549.19, [M+3H]
3+366.46; Calculated[M+H]
+1097.51, [M+2H]
2+549.36, [M+3H]
3+366.54.
Embodiment 2
Lys-Thr-Asn-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala (SEQ.ID NO:2); Theoretical relative molecular mass 1079.29.ESI-MS, m/z:found[M+H]
+1080.29, [M+2H]
2+540.64, [M+3H]
3+360.76; Calculated[M+H]
+1080.31, [M+2H]
2+540.56, [M+3H]
3+360.81.
Embodiment 3
The prescription that contains the injection liquid of promoting agent HY-1
Take by weighing meglumine by recipe quantity, join in the 600mL water for injection, be stirred to whole dissolvings, the pH value of phosphoric acid buffer regulator solution is 7-8, stirs; Take by weighing HY-1 by recipe quantity, be added in the above solution, stir dissolving fully; Add to the full amount of water for injection.Add 0.1% needle-use activated carbon of above-mentioned overall solution volume, stirred 10-30 minute, solution is adopted the carbon removal of 1 micron titanium rod filtration under diminished pressure, with twice smart filters of 0.22 micron filter membrane, get HY-1 solution again.
Claims (4)
1. novel blood sugar lowing polypeptide, its structure is following sequence:
Lys-Thr-Met-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala(SEQ.ID?NO：1)
Lys-Thr-Asn-Met-Lys-Gly-Met-Ala-Gly-Ala-Ala(SEQ.ID?NO：2)。
2. according to the purposes of the novel blood sugar lowing polypeptide described in the claim 1 in the medicine of preparation treatment diabetes.
3. pharmaceutical composition, it comprises each Polypeptide-k or its salt described in the claim 1 of mixing with pharmaceutically acceptable carrier, solvent, thinner, vehicle and other media.
4. the Polypeptide-k described in the claim 1 of and non-toxicity amount effective by the Mammals pharmacology that needs this kind treatment, perhaps the pharmaceutical composition described in the claim 3 provides the purposes of the novel Polypeptide-k of the present invention as the treatment diabetes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108948212A (en) * | 2018-07-25 | 2018-12-07 | 中国药科大学 | Long-actingization oxyntomodulin (OXM) hybrid peptide and the preparation method and application thereof |
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| CN101041693A (en) * | 2007-02-06 | 2007-09-26 | 珠海联邦制药股份有限公司 | Novel blood sugar lowing polypeptide and uses thereof |
| CN101691394A (en) * | 2009-09-17 | 2010-04-07 | 中国药科大学 | Method for solid phase synthesis of bitter gourd MC-JJ6 peptide analogs under microwave irradiation and application of bitter gourd MC-JJ6 peptide analogs |
| CN101691395A (en) * | 2009-09-17 | 2010-04-07 | 中国药科大学 | Method for solid phase synthesis of bitter gourd MC-JJ62 peptide analogs under microwave irradiation and application of bitter gourd MC-JJ62 peptide analogs |
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| CN101041693A (en) * | 2007-02-06 | 2007-09-26 | 珠海联邦制药股份有限公司 | Novel blood sugar lowing polypeptide and uses thereof |
| CN101691394A (en) * | 2009-09-17 | 2010-04-07 | 中国药科大学 | Method for solid phase synthesis of bitter gourd MC-JJ6 peptide analogs under microwave irradiation and application of bitter gourd MC-JJ6 peptide analogs |
| CN101691395A (en) * | 2009-09-17 | 2010-04-07 | 中国药科大学 | Method for solid phase synthesis of bitter gourd MC-JJ62 peptide analogs under microwave irradiation and application of bitter gourd MC-JJ62 peptide analogs |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948212A (en) * | 2018-07-25 | 2018-12-07 | 中国药科大学 | Long-actingization oxyntomodulin (OXM) hybrid peptide and the preparation method and application thereof |
| CN108948212B (en) * | 2018-07-25 | 2021-08-06 | 中国药科大学 | Long-acting Oxyntomodulin (OXM) hybrid peptide and preparation method and application thereof |
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Application publication date: 20131002 |