CN105175505A - Leptin excitation polypeptide and application thereof - Google Patents
Leptin excitation polypeptide and application thereof Download PDFInfo
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- CN105175505A CN105175505A CN201510563712.9A CN201510563712A CN105175505A CN 105175505 A CN105175505 A CN 105175505A CN 201510563712 A CN201510563712 A CN 201510563712A CN 105175505 A CN105175505 A CN 105175505A
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- leptin
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- atherosclerosis
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Abstract
The invention relates to the field of medicines, in particular to a polypeptide compound for treating or preventing atherosclerosis. Leptin excitation polypeptide is characterized in that the sequence of the leptin excitation polypeptide is TLSKMDQTLAVYQQILTSMP. The leptin excitation polypeptide is prepared by adopting an Fmoc protective solid phase synthesis technology. The leptin excitation polypeptide can be covalently connected to an adjuvant; the adjuvant is bovine serum albumin, human serum albumin or polyethylene glycol. The invention also discloses the application of the leptin excitation polypeptide in treating diseases related to the atherosclerosis. The diseases related to the atherosclerosis comprises angina, myocardial infarction, arrhythmia, cerebral apoplexy, encephalatrophy, resistant hypertension, renal insufficiency and the like. The leptin excitation polypeptide provided by the invention can promote a leptin precursor to be decomposed into active leptin in a targeted manner, promote the secretion of leptin, and achieve the effects of preventing or treating the atherosclerosis.
Description
Technical field:
The present invention relates to pharmaceutical field, be specifically related to the polypeptide compound be used for the treatment of or prevention of arterial is atherosis.
Background technology:
Atherosclerosis (Atherosclerosis) is because fat, thrombus, reticular tissue and calcium carbonate deposit a kind of harmful state caused at blood vessel (mainly artery, but also comprise vein).Be characterized in ductus arteriosus wall thicken hardening, to follow the string and tube chamber reduces.Atherosclerotic symptom depends mainly on the degree of ischemia of vascular lesion and afflicted organ, atherosclerosis of aorta is often asymptomatic, coronary atherosclerosis person, if caliber is narrow reach more than 75%, then can there is stenocardia, myocardial infarction, irregular pulse, even die suddenly.Cerebral arteriosclerosis can cause cerebral ischemia, encephalatrophy, or causes rupture of blood vessel in brain hemorrhage, and atherosclerotic renal artery stenosis often causes enuresis nocturna, intractable hypertension, severe patient to have renal insufficiency.After superior mesenteric atherosclerosis can show as heavy meal, stomachache such as to be had blood in stool at the symptom.Lower limb atherosclerosis causes lumen of vessels Serious Stenosis person can occur intermittent claudication, pulsation of foot dorsal artery disappearance, and severe patient even gangrene can occur.Atherosclerosis is one group and is called the most common, most important one in arteriosclerotic vascular disease.
The atherosclerotic medicine of current prevention and therapy, is mainly for control susceptible factor.As suffered from diabetes, blood sugar should being controlled in time, comprise dietary control.The ofhypoglycemic medicine of diabetes B should be advisable as diamicron etc. not cause hyperinsulinemia; Then should give depressor if any hypertension, make blood pressure be down to proper level, increase if any blood cholesterol, then should control hypercholesterolemia and suitably give fat-reducing medicament.
Leptin (Leptin, LP) is by a kind of protein hormone secreted, and is a kind of hormone secreted by fatty tissue.Its precursor is made up of 167 amino-acid residues, and N-terminal has 21 amino-acid residue signal peptides, and the signal peptide of this precursor is cut off in blood and becomes 146 amino acid, and molecular weight is 16KD, forms Leptin.Leptin has biological effect widely, and wherein more important is act on hypothalamic Metabolism regulation maincenter, plays depress appetite, reduces energy intake, increases energy expenditure, suppresses the effect of lipogenesis.Our experiment shows, adopts leptin agonist can promote the decomposition of leptin precursor, forms activated leptin, depress appetite, suppression lipogenesis, thus effectively suppresses the formation of atherosclerotic plaque.Present stage, do not have the leptin agonist of ripe exploitation to come out, be used for the treatment of atherosclerosis.
Summary of the invention:
The present invention seeks to, for the feature of existing treatment atherosclerosis medicine, to design a kind of polypeptide compound, can effectively treat or prevention of arterial atherosis.
Technical scheme
The exciting polypeptide of leptin, is characterized in that: its sequence is TLSKMDQTLAVYQQILTSMP.Adopt the solid phase synthesis technique preparation of Fmoc protection.Can a covalently bound adjuvant, adjuvant is bovine serum albumin, human serum albumin, or polyoxyethylene glycol.The application of the exciting polypeptide of leptin in treatment atherosclerosis relative disease.Described atherosclerosis relative disease is the pathologies such as stenocardia, myocardial infarction, irregular pulse, cerebral apoplexy, encephalatrophy, intractable hypertension, renal insufficiency.
Beneficial outcomes:
The exciting polypeptide of leptin in the present invention can promote that leptin precursors decompose is for there being active leptin, promotes leptin secretion by target, reaches prevention or treats atherosclerotic effect.Be more preferably the purposes in treatment atherosclerosis relative disease medicine.Described pulse atherosclerosis relative disease comprises the pathologies such as stenocardia, myocardial infarction, irregular pulse, cerebral apoplexy, encephalatrophy, intractable hypertension, renal insufficiency.
Embodiment
Embodiment 1
The chemical synthesis process of polypeptide
The solid phase synthesis technique preparation that polypeptide is protected with Fmoc.Building-up reactions is carried out to N end from C end according to peptide sequence, and Rink medium (can buy in AdvancedChemTech company) has free amino group.In each step connection procedure, amino-acid residue all will activate, and has the HBTU of 4 times of free amino groups on medium in activator mixture, HOBt, DIEA and Fmoc-amino acid.After each amino acid whose ligation, all close the free amino group do not connected, capping 10 minutes with the mixture of a pyridine/acetic acid/N-Methylimidazole (4:1:0.5).After each amino acid whose ligation, next amino acid all will remove the Fmoc-group on medium before connecting, and goes Fmoc-group to use the dimethyl formamide containing 20% piperidines, needs 15 minutes.Finally, after all amino-acid residues are linked in sequence, polypeptide 98% trifluoroacetic acid cuts down from medium, and cutting at room temperature carries out 2 hours.Apply above-mentioned electrochemical conditions can synthesize and obtain polypeptide, sequence is TLSKMDQTLAVYQQILTSMP, and this sequence is brand-new sequence.Or synthesized by the raw work in Shanghai.
Embodiment 2
The exciting polypeptide of leptin is on the impact of the atherosis model of rat aorta
Set up the atherosis model of rat aorta.The C57BL/6J mouse in male 8 week age 40, is divided into 4 groups at random, is respectively: A group is blank group: normal diet is fed; B group is model control group: modeling+high lipid food is fed; C group is drug intervention group: the exciting polypeptide (10mg/kg/d) of modeling+high lipid food+leptin; D is positive drug intervention group: modeling+high lipid food+Rosuvastatin sheet (10mg/kg/d).Continuous 12 weeks.A group mouse feed is normal diet, and B, C, D group mouse high fat high cholesterol diet (containing 15% lard+0.25% cholesterol) is fed, to accelerate the formation of Atherosclerosis Model.After 12 weeks, record Mouse Weight, detect polypeptide to the impact of serum cholesterol: serum total cholesterol (totalcholesterol, TC), triglyceride level (tryglyeride, TG), high density lipoprotein cholesterol (highdensitylipoproteincholesterol, and the level of low density lipoprotein cholesterol (lowdensitylipoproteincholesterol, HDL-C) HDL-C); , detect the atherosis formational situation of mouse aorta: to mouse aorta cardinal principle and the capable oil red O stain of aortic root frozen section, atherosclerotic plaque area is carried out quantitatively.
Result: each group experiment mice experimental session body weight has rising tendency.Along with the change of the time of nursing, the body weight gain compared with normal diet group fast (P<0.05, in table 1) of High-fat diet group.Polypeptide group Mouse Weight increases and normal diet group suitable (P>0.05), body weight comparatively light (P<0.05) compared with model group.Polypeptide group is compared with the model mice group of high fat cholesterol-FED, TG, TC, HDL-C, LDL-C level significantly reduces (P<0.01, in table 2), atherosclerotic plaque area significance reduces (P<0.01, in table 3), all there is statistical significance with model control group comparing difference.
The exciting polypeptide of table 1 leptin is on the impact of the atherosis model mice body weight of rat aorta
* p<0.05, * * p<0.01 is compared with model group
The exciting polypeptide of table 2 leptin is on the impact of the atherosis model mice cholesterol of rat aorta
* p<0.05, * * p<0.01 is compared with model group
The exciting polypeptide of table 3 leptin is on the impact of rat aorta atherosis model mice atherosclerosis area
* p<0.05, * * p<0.01 is compared with model group
Conclusion: the exciting polypeptide of leptin has therapeutic action to rat aorta is atherosis.
SEQUENCELISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120>
the exciting polypeptide of leptin and application thereof
<130>
<160>1
<170>PatentInversion3.5
<210>1
<211>20
<212>PRT
<213> artificial sequence
<400>1
ThrLeuSerLysMetAspGlnThrLeuAlaValTyrGlnGlnIleLeu
151015
ThrSerMetPro
20
Claims (5)
1. the exciting polypeptide of leptin, is characterized in that: its sequence is TLSKMDQTLAVYQQILTSMP.
2. a preparation method for polypeptide described in claim 1, is characterized in that: the solid phase synthesis technique preparation adopting Fmoc protection.
3. the preparation method of polypeptide according to claim 2, is characterized in that: can a covalently bound adjuvant, and adjuvant is bovine serum albumin, human serum albumin, or polyoxyethylene glycol.
4. the application of polypeptide in treatment atherosclerosis relative disease of any one of claim 1-3.
5. purposes according to claim 4, described atherosclerosis relative disease is the pathologies such as stenocardia, myocardial infarction, irregular pulse, cerebral apoplexy, encephalatrophy, intractable hypertension, renal insufficiency.
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| CN201510563712.9A CN105175505A (en) | 2015-09-08 | 2015-09-08 | Leptin excitation polypeptide and application thereof |
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| CN201510563712.9A CN105175505A (en) | 2015-09-08 | 2015-09-08 | Leptin excitation polypeptide and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102499980A (en) * | 2011-12-27 | 2012-06-20 | 中国药科大学 | Application of polypeptides to preparation of medicament for treating or preventing rheumatoid arthritis |
| CN104193807A (en) * | 2014-09-28 | 2014-12-10 | 苏州普罗达生物科技有限公司 | Thrombin-inhibited polypeptide and preparation method and application thereof |
| CN104193809A (en) * | 2014-09-28 | 2014-12-10 | 苏州普罗达生物科技有限公司 | Thrombin inhibition polypeptide as well as preparation method and application thereof |
-
2015
- 2015-09-08 CN CN201510563712.9A patent/CN105175505A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102499980A (en) * | 2011-12-27 | 2012-06-20 | 中国药科大学 | Application of polypeptides to preparation of medicament for treating or preventing rheumatoid arthritis |
| CN104127859A (en) * | 2011-12-27 | 2014-11-05 | 中国药科大学 | Application of polypeptides in preparation of medicament for treating or preventing rheumatoid arthritis |
| CN104193807A (en) * | 2014-09-28 | 2014-12-10 | 苏州普罗达生物科技有限公司 | Thrombin-inhibited polypeptide and preparation method and application thereof |
| CN104193809A (en) * | 2014-09-28 | 2014-12-10 | 苏州普罗达生物科技有限公司 | Thrombin inhibition polypeptide as well as preparation method and application thereof |
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Application publication date: 20151223 |
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