CN110038114A - A kind of purposes of polypeptide in preparation prevention or treatment metabolic syndrome drug - Google Patents
A kind of purposes of polypeptide in preparation prevention or treatment metabolic syndrome drug Download PDFInfo
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Abstract
The present invention relates to biologic medical fields, and in particular to a kind of application of polypeptide (urotensin II, Urotensin II) in preparation treatment and/or prevention of metabolic syndrome/diabetes B/obesity/diabetes complicated disease drug.Polypeptide of the invention has the specific gravity and weight for significantly reducing tissue fat, improves and mitigate insulin resistance, reduces blood glucose effect.Polypeptide effect is novel, is readily synthesized, and dosage is lower, has application and development prospect well.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of polypeptide is comprehensive in preparation prevention, alleviation and/or treatment metabolism
Purposes in simulator sickness/diabetes B/obesity/diabetes complicated disease drug.
Background technique
Metabolic syndrome is a complex set of metabolic disorder disease group, is the pathology shape of a variety of Metabolite abnormal aggregations
State is the risk factor for leading to diabetes cardiovascular and cerebrovascular disease.It has the following characteristics that 1. a variety of metabolic disorders are rolled into one,
Including obesity, hyperglycemia, hypertension, dyslipidemia, these metabolic disorders are the pathology bases of the heart, cerebrovascular disease and diabetes
Plinth.2. there is common pathologic basis, the common causes for thinking them are exactly caused by fat especially central obesity more at present
Insulin resistance and hyperinsulinemia.3. a variety of diseases can be caused cumulative, as hypertension, coronary heart disease, cerebral apoplexy, even certain
A little cancers etc..
Obesity is by the internal superfluous energy chronic metabolic disease that excess accumulation is caused in adipose tissue, is shadow
Ring the material risk factor of cardiovascular and cerebrovascular disease, diabetes and tumour etc..Limitation Energy intaking such as diets, takes slimming drugs；Or
Increase energy consumption and such as tempers strategy because compliance difference or drug side-effect enable obesity patient's weight gain, thus to weight-reducing
It hangs back.Therefore, this fat global health problem how is prevented and treated, finding safely and effectively treatment method becomes
Domestic and international medicine, nutritionist endeavour the hot issue of research.
Diabetes B is the metabolic disease of global prevalence, is the primary risk factor of cardiovascular disease.In global model
In enclosing, about 300,000,000 diabetics, patient numbers are high and still constantly rise, and show in recent years more very.Especially at me
Great variety has occurred in state, with the improvement of people's living standard in our country, dietary structure, living habit, environmental condition etc., with something lost
The illness rate of the closely related carbohydrate metabolism disturbance disease of the factors such as biography, nutrition, metabolism and environment sharply increases, and development trend is still
It is not effectively controlled.The complication such as the heart as caused by metabolic disease, kidney, brain and Ocular Vessels, nerve not only serious shadow
The quality of life of patient is rung, while bringing heavy family and social medical burden.Therefore, diabetes B prevention and treatment is China's mesh
The important scientific problems that front is faced explore the effective measures of prevention and treatment glycometabolism disease, have important scientific value and meaning.
At present clinically, treating fat drug mainly includes appetite inhibitor: CNS inhibition appetite drug adjusts food
The gastrointestinal hormone of desire.It acts on periphery Fatty synthesis and decomposition: acting on gastrointestinal tract and reduce fat absorption (lipase inhibitor
With sodium -2 inhibitor of glucose co-transporters body).Adipose tissue is acted on to reduce Fatty synthesis, release is promoted to decompose.
The drug of diabetes B treatment specifically includes that insulin and the like, sulfonylurea, biguanides, phlorose
Glycosides enzyme inhibitor, thiazolidine diketone derivative, Drugs Promoting Insulin Secretion, Chinese patent drug etc..
It seeks peace the diet products of complication still without Metabolic syndrome can be reduced at present.Polypeptide is that a-amino acid is linked with peptide chain
The compound formed together, and the intermediate product of hydrolysis.Many active peptides are all by inactive precursor, by enzyme
Processing montage be transformed.They have similar structure, retain distinctive bioactivity.Study the structure and function of active peptides
It can, it will help design and development of new active peptides.
Polypeptide of the present invention is a kind of polypeptides matter [Teleost being originally found in bony fish tail portion
caudal neurosecretory system:release of urotensin II from isolated urophyses
[J].Gen Comp Endocrinol,1972,18(3):557-60].1998, [the Cloning of the such as Coulouarn
cDNA encoding the urotensin II precursor in frog and human reveals intense
expression of the urotensin II gene in motoneurons of the spinal cord[J].Proc
Natl Acad Sci U S A.1998 Dec 22；95 (26): 15803-8] human endogenous's property urotensin II is cloned for the first time
(Urotensin II, U II), is a kind of cyclic peptide with 11 amino acid, activated centre is C-terminal connected by disulfide bond and
At cyclic hexapeptide structure.The vasoconstriction effect of U II is the decades of times of Endothelin, is the known strongest object of vasoconstriction effect
Matter [Identification of the natural ligand of an orphan G-protein-coupled
receptor involved in the regulation of vasoconstriction[J].Nat Cell
Biol.1999Oct；1(6):383-5].At present in the world, related polypeptide research discloses special in terms of Cardiovascular regulation
Benefit (United States Patent (USP), the patent No. 4533654, date of patent August in 1985 6 days).In the past the study found that II receptor antagonist of U
Palosuran【The urotensin-II receptor antagonist palosuran improves pancreatic
and renal function in diabetic rats[J].J Pharmacol Exp Ther.2006.316(3):1115-
21] glycolipid metabolism of diabetes can be improved, but exited in the clinical test for diabetic nephropathy because curative effect is undesirable
Clinical test.Sanofi-Aventis company has also carried out other Urotensin II receptor antagonist clinical tests, finally by
It is undesirable in curative effect and exit clinical research.We have discovered that U II itself can improve glycolipid metabolism, explain from another point of view
The bad reason of the effect of its antagonist.Purposes in the present invention about UII in terms of being adjusted to fat and sugar tolerance is adjusted
It is first public.To provide a kind of completely new selection and thinking, anti-fat and diabetes B selection field is widened.
Summary of the invention
The technical problem to be solved by the present invention is to provide the new polypeptide drugs of one kind in preparation prevention, alleviation and/or treatment
Application in metabolic syndrome/diabetes B/obesity/diabetes complicated disease drug.
To solve technical problem of the invention, the invention provides the following technical scheme:
The first aspect of technical solution of the present invention is to provide polypeptide or polypeptide active sequence as follows or containing as follows
Shown in polypeptide or the protein sequence of polypeptide active sequence answering in the drug of preparation treatment and/or prevention of metabolic syndrome
With the polypeptide sequence are as follows: Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, wherein
Cys5And Cys10For disulfide bond connection；The polypeptide active sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10, wherein
Cys5And Cys10For disulfide bond connection.Wherein, the metabolic syndrome includes the protein of human body caused by a variety of causes, rouge
The pathological state of metabolic disorder occurs for fat, carbohydrate.
The second aspect of technical solution of the present invention is to provide polypeptide or polypeptide active sequence as follows or containing as follows
Shown in polypeptide or the protein sequence of polypeptide active sequence in preparation treatment and/or prevention diabetes, obesity, diabetic complication
Drug in application, the polypeptide sequence are as follows: Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-
Cys10-Val11, wherein Cys5And Cys10For disulfide bond connection；The polypeptide active sequence are as follows: Cys5-Phe6-Trp7-Lys8-
Tyr9-Cys10, wherein Cys5And Cys10For disulfide bond connection.Wherein, the diabetes include diabetes B.The fertilizer
Fat includes obesity caused by congenital, posteriority, Drug reason.The diabetic complication refers to the large and small blood of diabetes
Pipe lesion.The diabetic complication includes diabetic nephropathy, diabetes peripheral circulation dysfunction, Diabetes Peripheral nerve
Lesion, diabetic eye diseases, Diabetic myopathy, hyperlipidemia with diabetes.
It is comprehensive to establish fat and insulin-resistant metabolic for the male C57BL/J mouse induced using normal and high fat diet
Sign/diabetes animal model.Detect influence of the polypeptide to the tissue weights such as animal blood glucose, blood insulin, fat and weight.Determine
Work of the polypeptide in preparation prevention, alleviation and/or treatment metabolic syndrome/diabetes B/obesity/diabetic complication product
With.
It is characteristic of the invention that a small amount of medications of polypeptide can reach treatment and preventive effect.Drug is safe and reliable.
The purpose of the present invention is to provide a kind of Glu1‐Thr2‐Pro3‐Asp4‐Cys5‐Phe6‐Trp7‐Lys8‐Tyr9‐
Cys10‐Val11Polypeptide and other Cys containing bioactive sequence5‐Phe6‐Trp7‐Lys8‐Tyr9‐Cys10Polypeptide new application.It is preparing
Metabolic syndrome/diabetes B/obesity/diabetic complication application is alleviated and/or is treated in prevention.
Glu1‐Thr2‐Pro3‐Asp4‐Cys5‐Phe6‐Trp7‐Lys8‐Tyr9‐Cys10‐Val11Polypeptide and other containing activity
Sequence C ys5‐Phe6‐Trp7‐Lys8‐Tyr9‐Cys10Polypeptide, be a kind of polypeptides matter being originally found in bony fish tail portion
[Berlind A.Teleost caudal neurosecretory system:release of urotensin II from
isolated urophyses[J].Gen Comp Endocrinol,1972,18(3):557-60.].1998,
[the Proc Natl Acad Sci U S A.1998Dec 22 such as Coulouarn；95 (26): 15803-8.] people is cloned for the first time
Body endogenous urotensin II (Urotensin II, U II) is a kind of cyclic peptide with 11 amino acid, activated centre C
The cyclic hexapeptide structure that end is formed by connecting by disulfide bond.The vasoconstriction effect of U II is the decades of times of Endothelin, is known receipts
The strongest substance of contracting vascular effect [Identification of the natural ligand of an orphan G-
protein-coupled receptor involved in the regulation of vasoconstriction[J]
.Nat Cell Biol.1999Oct；1(6):383-5.].At present in the world, related polypeptide research is disclosed adjusts in angiocarpy
Save the patent (United States Patent (USP), the patent No. 4533654, date of patent August in 1985 6 days) of aspect.Resistance to fat adjusting and sugar
The purposes that amount adjusts aspect is first public.
The diabetic complication includes the large and small vascular lesion of diabetes: diabetic nephropathy, diabetes peripheral circulation function
It can obstacle, Peripheral neuropathy, diabetic eye diseases, Diabetic myopathy, hyperlipidemia with diabetes.The technology of the present invention
The third aspect of scheme be to provide a kind of pharmaceutical composition preparation treatment and/or prevention of metabolic syndrome, diabetes, obesity,
Application in the drug of diabetic complication, which is characterized in that the pharmaceutical composition contains the as follows of effective dose
Polypeptide or polypeptide active sequence or protein sequence containing polypeptide as follows or polypeptide active sequence and can pharmaceutically connect
The carrier received；The polypeptide sequence are as follows: Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-
Val11, wherein Cys5And Cys10For disulfide bond connection；The polypeptide active sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-
Cys10, wherein Cys5And Cys10For disulfide bond connection.
The pharmaceutical composition can be prepared according to method well known in the art.It can be by by the compounds of this invention and a kind of or more
The pharmaceutically acceptable solid of kind or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.
Content of the compounds of this invention in its pharmaceutical composition is usually 0.1-95 weight %.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization
The daily Suitable dosage ranges for closing object are 0.001-1000 μ g/Kg weight, preferably 0.1-100 μ g/Kg weight.Above-mentioned dosage
With a dosage unit or several dosage unit administrations can be divided into, this depends on the clinical experience of doctor and including with other
The dosage regimen for the treatment of means.The compound of the present invention or composition can be used alone, or with other treatment drug or to the ill medicine
Object, which merges, to be used.When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, it should be adjusted according to the actual situation
Dosage.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route is non-enteric
Road, such as intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, rectum.Administration
Dosage form is liquid dosage form.Liquid dosage form can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o
Type and emulsion), suspension, injection (including liquid drugs injection, powder-injection and infusion), eye drops, nasal drop, lotion and liniment etc.；
The compounds of this invention ordinary preparation can be made and also be made sustained release preparation, controlled release preparation, targeting preparation and various particles to
Medicine system.
Form Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11Polypeptide and other contain
Bioactive sequence Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10Polypeptide amino acid be L-type amino acid and/or D- type amino
Acid.
Advantageous effects
1. the Abnormality of Glycolipid Metabolism that polypeptide of the present invention can improve animal.About polypeptide of the present invention resistance to fat adjusting and sugar
The purposes that amount adjusts aspect is first public.Widen the selection field of antimetabolic syndrome, obesity and diabetes B.
2. at present in the world, about polypeptide of the present invention only disclose in terms of Cardiovascular regulation patent (United States Patent (USP),
The patent No. 4533654, date of patent August in 1985 6 days).The present invention is to report that the polypeptide improves metabolic syndrome, obesity for the first time
And diabetes B.The international and country has no correlative theses and Patent Publication.
3. the application attestation of polypeptide of the present invention has significant mitigation adipose tissue mass, blood glucose is reduced, insulin resistance is improved
Effect.It is developed as drug, there is apparent excellent benefit.
Detailed description of the invention
Definition: Urotensin II (UII) is active peptides (urotensin II)
Fig. 1 active peptides have no significant effect normal C57BL/J mouse weight, and it is comprehensive can to reduce high lipid food inducible metabolism
Simulator sickness/diabetes B/obese mouse weight.Give urotensin II 27.8 μ g/kg (20nmol/kg) in active peptides group abdominal cavity
2 weeks, physiological saline was given in control group abdominal cavity.
Fig. 2 active peptides are to high fat diet inducible metabolism syndrome/diabetes B/obesity mice C57BL/J mouse blood
The influence of sugar.27.8 μ g/kg (20nmol/kg) of urotensin II is given 3 weeks in active peptides group abdominal cavity, and control group abdominal cavity is given
Physiological saline.
Fig. 3 active peptides are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice sugar tolerance
It influences.Active peptides group abdominal cavity gives urotensin II 27.8 μ g/kg (20nmol/kg), and physiology salt is given in control group abdominal cavity
Water.*, P < 0.05**, P < 0.01 is compared with model control group.
Fig. 4 active peptides are resistance to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice insulin
The influence of amount.Active peptides group abdominal cavity gives urotensin II 27.8 μ g/kg (20nmol/kg), and physiology is given in control group abdominal cavity
Salt water.*, P < 0.05**, P < 0.01 is compared with model control group.
Fig. 5 active peptides are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice serum islet
Plain horizontal influence.27.8 μ g/kg (20nmol/kg) of urotensin II is given 3 weeks in active peptides group abdominal cavity, control group abdominal cavity
Give physiological saline.
Influence of Fig. 6 active peptides to intact animal fat weight.Active peptides can reduce normal C57BL/J mouse rouge
Fat weight.27.8 μ g/kg (20nmol/kg) of urotensin II is given 2 weeks in active peptides group abdominal cavity, and life is given in control group abdominal cavity
Manage salt water.Gon: interior fat-sexual gland fat；Sub: subcutaneous fat；BAT: brown fat.*, P < 0.05 is compared with normal group.
Fig. 7 active peptides are to high lipid food inducible metabolism syndrome/diabetes B/obese animal fat weight shadow
It rings.Active peptides can reduce high fat diet C57BL/J mouse adipose tissue weight.Give urotensin II in active peptides group abdominal cavity
27.8 μ g/kg (20nmol/kg) 2 weeks, physiological saline is given in control group abdominal cavity.Gon: interior fat-sexual gland fat；Retro: interior
Dirty fat-retroperitoneal fat；Sub: subcutaneous fat；BAT: brown fat.*, P < 0.05 is compared with high fat diet group.##, P <
0.01 compared with normal group.
Fig. 8 active peptides are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice skeletal muscle solution
The influence of coupling protein UCP3.It is small that active peptides increase normal and high lipid food inducible metabolism syndrome/diabetes B/obesity
The level of murine skeletal muscle uncoupling protein UCP3.Give urotensin II 27.8 μ g/kg (20nmol/ in urotensin group abdominal cavity
Kg), physiological saline is given in control group abdominal cavity.*, P < 0.05 is compared with normal group.
Specific embodiment
Glu is further illustrated below with reference to the present invention1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-
Cys10-Val11Polypeptide and other Cys containing bioactive sequence5-Phe6-Trp7-Lys8-Tyr9-Cys10Polypeptide in preparation prevention, slow
Solution and/or treatment obesity and diabetes B drug and its pharmacological action and purposes in complication product
Following embodiments illustrate the present invention in more detail, are not any limitation of the invention.So being familiar with this
The technical staff in field carries out nonessential modifications and adaptations to embodiment according to foregoing invention content, still falls within of the invention
Protection scope.
The preparation of 1. polypeptide of embodiment
Polypeptide Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11(disulfide bond Cys5-
Cys10) using chemical synthesis (specifically using Solid phase synthesis), HPLC purity is greater than 95%.Polypeptide powder is dissolved in physiology salt
Water is configured to the solution of 1000 μ g/ml, and after packing, -80 DEG C of freezen protectives are spare.With normal saline dilution at corresponding when use
Concentration.
Influence of 2. active peptides of embodiment to intact animal
C57BL/J male mice (Beijing HFK Bio-Technology Co., Ltd.) 10, weight 17-20g, full nutrition
Feed feeding, unlimited drinking water.It gives urotensin 27.8 μ g/kg (20nmol/kg), monitors weight weekly.Once a day, totally 14
It.Before carrying out sugar and insulin tolerance measurement, animal overnight fasting.Measurement basal plasma glucose after give respectively 2g/kg or
0.75U/kg insulin.Blood glucose level is measured in 15,30,60,120 minutes points.After experiment, organ index is measured,
Blood serum designated object.
3. active peptides of embodiment are to high lipid food inducible metabolism syndrome/diabetes B/obese animal influence
By male C57BL/J mouse, weight 17-20g, high lipid food is fed, unlimited drinking water.C57BL/J mouse of the same age
As Normal group, weight 17-20g, whole nutrient feed feeding, unlimited drinking water.Weight is monitored weekly.High fat diet Mice Body
Great fat group mouse is randomly divided into two groups: control group high in fat after normal control 10g, 2 administration group of urotensin.Tail pressurization
Plain administration group intraperitoneal injection gives polypeptide 27.8 μ g/kg (20nmol/kg), and same volume is injected intraperitoneally in control group normal and high in fat
Long-pending physiological saline.Successive administration 3 weeks.Blood glucose, weight are surveyed weekly.Record animal dead situation.After experiment, internal organs are measured
Index, blood serum designated object.
4. active peptides of embodiment are to normal and high lipid food inducible metabolism syndrome/diabetes B/obese animal weight
Influence
Meaning: weight reaction animal energy utilizes balance, is the important indicator and Metabolic syndrome of growing state
The important indicator that sign/diabetes B/obesity mice improves.
Experimental method: animal model and medication are the same as embodiment 2, embodiment 3.It is observed and recorded daily in this experiment dynamic
The ordinary circumstances such as active state, the hair of object, and monitor the weight of animals.
Experimental result: in this experiment, UII has no significant effect intact animal weight.Metabolic syndrome/2 types sugar can be reduced
Urinate disease/obese animal weight.The result is shown in Figure 1.
5. active peptides of embodiment are to high lipid food inducible metabolism syndrome/diabetes B/obese animal blood glucose influence
Meaning: pathoglycemia is the characteristic events of diabetes and metabolic syndrome, while in the case where obesity, can also companion
With the exception of blood glucose.Therefore, blood glucose can reflect metabolic syndrome/diabetes B/obesity disease and progress.
Experimental method: animal model and medication are the same as embodiment 3.Using the surveyed blood glucose value of fasting 4h as fasting blood-glucose.It surveys
Settled day morning 7:00 fasting, 9:00 administration, 11:00 detection.The next morning is administered in random blood sugar, and before non-administration, measurement is random
Blood glucose.
Experimental result: in this experiment, the blood glucose level of model group animal is obviously higher than Normal group.Give UII mono-
Zhou Hou, the empty stomach and random blood glucose level of animal have decline.As a result see Fig. 2.
6. active peptides of embodiment are resistance to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice sugar
The influence of amount
Meaning: glucose tolerance test is the speed and energy that body removes sugar after glucose is injected intraperitoneally for detection limit
Power, to judge animal with the presence or absence of carbohydrate metabolism disturbance.
Experimental method: animal model and medication are the same as embodiment 2, embodiment 3.After animal overnight fasting, every is calculated
Animal uses the amount of glucose.Animal tail portion takes blood, measures animal blood glucose, is 0 point of blood glucose value.Glucose (2g/ is injected intraperitoneally
Kg), measurement 30,60,90 and 120minutes blood glucose value.
Experimental result: UII can improve normal and metabolic syndrome/diabetes B/obese animal impaired glucose tolerance.As a result
See Fig. 3.
7. active peptides of embodiment are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice pancreas islet
The influence of plain tolerance
Meaning: insulin tolerance tests are the speed and energy that body removes sugar after insulin is injected intraperitoneally for detection limit
Power is commonly used in auxiliary judgment animal carbohydrate metabolism disturbance to judge whether there is insulin dysfunction.
Experimental method: animal after 4 hours, calculates the amount that every animal uses insulin on an empty stomach.Animal tail portion takes blood, measurement
Animal blood glucose is 0 point of blood glucose value.It is injected intraperitoneally insulin (0.75U/kg), measurement 15,30,60 and 90minutes blood glucose
Value.Animal model and medication are the same as embodiment 2, embodiment 3.
Experimental result: it is abnormal that UII can improve normal and metabolic syndrome/diabetes B/obese animal insulin tolerance.
As a result see Fig. 4.
8. active peptides of embodiment are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice serum
The influence of insulin level
Meaning: insulin level is increased in metabolic syndrome/diabetes B/obese animal initial period, diabetes decompensation
Phase decline.Animal metabolism syndrome/diabetes B/obesity state can be reacted.
Experimental method: animal model and medication are the same as embodiment 2, embodiment 3.ELISA method is used in insulin detection.
Experimental result: UII has no obvious shadow to normal and metabolic syndrome/diabetes B/obese animal insulin level
It rings.As a result see Fig. 5.
Influence of 9. active peptides of embodiment to intact animal fat weight
Meaning: fat weight is to judge whether there is metabolic syndrome/diabetes B/obese animal important indicator.
Experimental method: animal model and medication are the same as embodiment 2.Different parts adipose tissue is taken, weight in wet base is weighed.
Experimental result: UII can reduce intact animal abdominal cavity fat weight.As a result see Fig. 6.
10. active peptides of embodiment are to high lipid food inducible metabolism syndrome/diabetes B/obesity mice fat weight
Influence
Meaning: fat weight is to judge whether there is metabolic syndrome/diabetes B/obese animal important indicator.
Experimental method: animal model and medication are the same as embodiment 3.Different parts adipose tissue is taken, weight in wet base is weighed.
Experimental result: UII can reduce metabolic syndrome/diabetes B/obese animal internal organ, subcutaneous, brown fat weight
Amount.As a result see Fig. 7.
11. active peptides of embodiment are to normal and high lipid food inducible metabolism syndrome/diabetes B/obesity mice bone
The horizontal influence of bone flesh uncoupling protein UCP3
Meaning: UCP3 is the uncoupling protein of skeletal muscle, and UCP3 expression is increased, indicate skeletal muscle tissue energetic supersession and
Thermogenesis enhancing.
Experimental method: animal model and medication are the same as embodiment 2, embodiment 3.Gene level detection is used
RealtimePCR。
Experimental result: UII can increase normal and metabolic syndrome/diabetes B/obese animal skeletal muscle uncoupling protein
Content illustrates that UII can regulate and control skeletal muscle mitochondrial function, regulates and controls energetic supersession.As a result see Fig. 8.
Claims (9)
1. polypeptide or polypeptide active sequence as follows or the albumen sequence containing polypeptide as follows or polypeptide active sequence
The application being listed in the drug of preparation treatment and/or prevention of metabolic syndrome, the polypeptide sequence are as follows: Glu1-Thr2-Pro3-
Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, wherein Cys5And Cys10For disulfide bond connection；The polypeptide
Bioactive sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10, wherein Cys5And Cys10For disulfide bond connection.
2. application according to claim 1, which is characterized in that the metabolic syndrome includes human body caused by a variety of causes
The pathological state of metabolic disorder occurs for protein, fat, carbohydrate.
3. polypeptide or polypeptide active sequence as follows or the albumen sequence containing polypeptide as follows or polypeptide active sequence
Be listed in preparation treatment and/or prevention diabetes, obesity, diabetic complication drug in application, the polypeptide sequence are as follows:
Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, wherein Cys5And Cys10For disulfide bond company
It connects；The polypeptide active sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10, wherein Cys5And Cys10For disulfide bond company
It connects.
4. application according to claim 3, which is characterized in that the diabetes include diabetes B.
5. application according to claim 3, which is characterized in that the obesity includes that congenital, posteriority, Drug reason are led
The obesity of cause.
6. application according to claim 3, which is characterized in that the diabetic complication refers to the large and small angiosis of diabetes
Become.
7. application according to claim 6, which is characterized in that the diabetic complication includes diabetic nephropathy, diabetes
Peripheral circulation dysfunction, Peripheral neuropathy, diabetic eye diseases, Diabetic myopathy, hyperlipidemia with diabetes.
8. a kind of application of pharmaceutical composition in the drug of preparation treatment and/or prevention of metabolic syndrome, which is characterized in that institute
The pharmaceutical composition stated contains the polypeptide as described below or polypeptide active sequence or containing polypeptide as follows of effective dose
Or the protein sequence and pharmaceutically acceptable carrier of polypeptide active sequence；The polypeptide sequence are as follows: Glu1-Thr2-Pro3-
Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, wherein Cys5And Cys10For disulfide bond connection；The polypeptide
Bioactive sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10, wherein Cys5And Cys10For disulfide bond connection.
9. a kind of pharmaceutical composition preparation treatment and/or prevention diabetes, obesity, diabetic complication drug in answer
With, which is characterized in that the polypeptide as described below or polypeptide active sequence or contain that the pharmaceutical composition contains effective dose
Have it is following shown in polypeptide or the protein sequence and pharmaceutically acceptable carrier of polypeptide active sequence；The polypeptide sequence
Are as follows: Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, wherein Cys5And Cys10For two sulphur
Key connection；The polypeptide active sequence are as follows: Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10, wherein Cys5And Cys10For two sulphur
Key connection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810033338.5A CN110038114B (en) | 2018-01-15 | 2018-01-15 | Application of polypeptide in preparation of medicine for preventing or treating metabolic syndrome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810033338.5A CN110038114B (en) | 2018-01-15 | 2018-01-15 | Application of polypeptide in preparation of medicine for preventing or treating metabolic syndrome |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110038114A true CN110038114A (en) | 2019-07-23 |
| CN110038114B CN110038114B (en) | 2021-12-07 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110755434A (en) * | 2018-07-27 | 2020-02-07 | 中国医学科学院药物研究所 | Application of compound palosuran in prevention and treatment of diseases such as skeletal muscle atrophy |
| WO2023284684A1 (en) * | 2021-07-13 | 2023-01-19 | 南京市妇幼保健院 | Milk-derived polypeptide derivative and applications thereof in preparation of drug, health product and food additive for prevention and treatment of obesity |
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| WO2011007091A1 (en) * | 2009-07-16 | 2011-01-20 | Sanofi-Aventis | Derivatives of 5,6-bisaryl-2-pyridine-carboxamide, preparation thereof, and therapeutic use thereof as urotensin-ii receptor antagonists |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110755434A (en) * | 2018-07-27 | 2020-02-07 | 中国医学科学院药物研究所 | Application of compound palosuran in prevention and treatment of diseases such as skeletal muscle atrophy |
| WO2023284684A1 (en) * | 2021-07-13 | 2023-01-19 | 南京市妇幼保健院 | Milk-derived polypeptide derivative and applications thereof in preparation of drug, health product and food additive for prevention and treatment of obesity |
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| CN110038114B (en) | 2021-12-07 |
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