CN106279400A - Design of P8 incretin peptide and application thereof - Google Patents
Design of P8 incretin peptide and application thereof Download PDFInfo
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K14/605—Glucagons
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Abstract
Devise a kind of new hypoglycemic fat-regulating peptide P8, by increasing capacitance it is possible to increase the half-life, play the effect of its GLP1R agonist, the effect hypoglycemic fat-regulating of GLP1 class islets of langerhans can be played simultaneously.P8 peptide can suppress the feed of STZ diabetic mice, reduces fasting glucose, reduces triglyceride and free fatty acid levels, keeps islets of langerhans form, increases beta Cell of islet area, improves the C peptide level of blood, plays its hypoglycemic fat-regulating effect.P11 peptide can reduce the blood glucose of db/db diabetic mice, improves insulin tolerance.
Description
Art
The present invention relates to pharmacy and medical science association area, particularly to diabetes (including 1 type and type 2 diabetes mellitus) and also
Send out prevention and the treatment of disease；Specifically, the present invention relates to a kind of new type of peptides and its purposes, and contain this new type of peptides and spread out
The biological pharmaceutical preparation with analog, can be used for preventing and treat people's diabetes and complication thereof.
Background
Diabetes are a kind of metabolism disorder syndromes being characterized with chronic hyperglycemia, it is now recognized that the phase of h and E
Interaction is main inducing, but its pathogeny is not yet completely clearly.Diabetes can be divided into 4 types: type 1 diabetes, 2 type glycosurias
Disease, gestational diabetes and other types diabetes.Type 1 diabetes (Type 1 diabetes mellitus, T1DM) is one
Planting autoimmune disease, owing to making beta Cell of islet damage the forfeiture of autoantibody toleration, body cannot produce enough
Insulin, insulin definitely lacks, and causes blood glucose to raise, therefore patient once falls ill and needs lifelong insulin injection.Type 2 diabetes mellitus
(Type 2 diabetes mellitus, T2DM), is referred to as again non-insulin-dependent diabetes mellitus, low because of β cell function
Under, insulin lacks and insulin resistant relatively.In recent years, the prevalence of type 2 diabetes mellitus is gradually increased, according to World Health Organization (WHO)
Prediction, the year two thousand thirty, will there be 300,000,000 type 2 diabetes mellitus patients in the whole world.At present, for the most oral fall of medicine of type 2 diabetes mellitus
Sugar medicine and insulin.Although such medicine can effectively reduce blood glucose, and improves patients symptomatic, but still there is hypoglycemia and body weight
The defects such as increase.Additionally, along with the prolongation of diabetic duration, such medicine all can not stop the deterioration of patient's β cell.
Glucagon-like-peptide-1 (glucagon-like peptide-1, GLP-1) is to be compiled by glucagon protogene
Code, modifies 30 the amino acid whose incretins (incretin) obtained by processing.Mainly closed by the L cell of small intestinal mucosa
Becoming and secrete, the α cell at islets of langerhans also has expression.GLP-1 has two kinds of biologically active forms, GLP-1 (7-37) and GLP-1
(7-36) amide, mainly with the activity form existence of GLP-1 (7-36) amide in blood circulation, both have common biology
Activity.
The less stable of natural human GLP-1, is easily degraded by DPP IV (DPPIV), and is quickly removed by kidney,
Its half-life t1/2≤2min.GLP-1 cuts away N-terminal His-Ala through DPPIV, generates GLP-1 (9-36) amino polypeptide,
Just research is thought, GLP-1 (9-36) amino polypeptide does not have biologic activity, and also has GLP-1 receptor (GLP-1R)
Certain antagonism, found that GLP-1 (9-36) amino polypeptide had the effect of para-insulin in recent years.
The physiological action of GLP-1 mainly includes three parts, and one is by being combined with GLP-1R, plays physiological effect,
Including: 1. glucose dependency insulin secretion accelerating；2. glucagon suppression secretion；3. postpone gastric emptying, reduce appetite, subtract
Few diet, controls body weight；4. suppression β apoptosis, promotes β cell proliferation and differentiation.Two are, GLP-1 degrades through DPPIV,
Generate GLP-1 (9-36) amino polypeptide, it is possible to suppression liver glyconeogenesis enzyme and the expression of fatty acid synthase, suppress glyconeogenesis regulating liver-QI
Dirty lipogenesis, plays para-insulin effect.Three is that GLP-1 (9-36) amino polypeptide is through endopeptidase (NEP 24.11)
Cutting into GLP-1 (32-36) amino 5 peptide, increase energy expenditure on obese type mice, suppression body weight increases.
Summary of the invention
Goal of the invention:
It is an object of the invention to design a new incretin peptide, effectively treat and prevent diabetes and complication thereof.
Technical scheme:
This hypoglycemic fat-regulating peptide P8 transforms according to the wild type of GLP-1, and the aminoacid of the 2nd is replaced to Gly by Ala,
Add Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser at the end of GLP-1, extend its half-life, it is possible to reduce by 1 type glycosuria
The sick blood glucose with type 2 diabetes mellitus mice.Sequence is as follows:
GLP-1:HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
P8:HEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
The application in treatment or prevention type i diabetes medicine of the P8 peptide.
The application in treatment or prevention type ii diabetes medicine of the P8 peptide.
Beneficial effect:
Clinical confirmation, GLP-1 analog can significantly reduce the blood glucose of type ii diabetes patient, suppression feed, reduce
Glycolated hemoglobins etc., meanwhile, GLP-1 and the like can reduce the blood glucose of type i diabetes patient, reduces HbAle egg
In vain, but individual there is the unfavorable factor lost weight in some.In the present invention, the aminoacid of the 2nd of GLP-1 the is replaced by Ala
Change Gly into, add Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser at the end of GLP-1, serve reduction type i diabetes
Effect with type ii diabetes mouse blood sugar.
It is an advantage of the current invention that to be replaced by aminoacid and the little peptide of end interpolation, construct a kind of incretin peptide.Experiment knot
Fruit proves that P8 peptide can play sugar dependency promoting insulin secretion (IPTGG) effectively, reduces STZ diabetic mice
Blood glucose, the feed of suppression STZ diabetic mice, keep good islets of langerhans form (HE dyeing), increase STZ diabetes mould
The islet area (immunostaining, and cumulative area) of type mice, increases the C peptide level of STZ diabetic mice, and its blood sugar lowering is made
With being substantially better than Exenatide and GLP-1, P8 peptide can be effectively reduced the fasting glucose of db/db mice, and effect is substantially better than
GLP-1。
Accompanying drawing explanation
The dependent promoting insulin secretion of the sugar (IPTGG) of Fig. 1 P8；
Fig. 2 P8 adds up the impact of feed to STZ diabetic mice；
Fig. 3 P8 impact on STZ diabetic mice blood glucose；
Fig. 4 P8 is on STZ diabetic mice triglyceride and the impact of free fatty
Fig. 5 P8 impact on STZ diabetic mice islets of langerhans form (HE dyeing)
Fig. 6 P8 impact on STZ diabetic mice islet area
Fig. 7 P8 impact on the C peptide level of STZ diabetic mice
Fig. 8 P8 impact on the blood glucose of db/db diabetic mice
Fig. 9 P8 impact on the insulin tolerance of db/db diabetic mice
Detailed description of the invention
Below in conjunction with some examples, invention is described in further details.Should be understood that these embodiments are intended merely to citing
The present invention is described, rather than limits the scope of the present invention by any way.
The dependent promoting insulin secretion of sugar of embodiment 1:P8
1, sugared dependent promoting insulin secretion (IPTGG)
(purchased from Yangzhou University's fullsized relatively medical center, credit number: SCXK's male c57 mice of 40 8 week old (revives)
2012-0004).It is randomly divided into 4 groups, often group 10, respectively solvent control group (negative control group), the Exendin-4 group (positive
Matched group), GLP-1 group (positive controls), P8 group (experimental group).Abdominal cavity carbohydrate tolerance process is as follows: c57 mice empty stomach 12 is little
Time, survey fasting glucose, respectively injection peptide or solvent, 30 minutes injectable dextrose monohydrates (1.5g/kg), the most respectively at injection sugar
Latter 15,30,60,120 minutes detection blood glucose, and area under difference calculated curve.Result P8 has the rush pancreas of glucose dependency
Island element secretory function, is respectively provided with significant difference with group of solvents and GLP-1 group, as Exendin-4 group effect.Result such as figure
Shown in 1.
The pharmacodynamic evaluation one of embodiment 2:P8
1, STZ diabetic mice modeling, and packet
(purchased from Yangzhou University's fullsized relatively medical center, credit number: SCXK's male c57 mice of 80 6 week old (revives)
2012-0004), adaptability is raised 1 week.Empty stomach 12 hours before experiment, by the dosage lumbar injection STZ solution (pH=of 50mg/kg
The citrate buffer solution of 5.2), injection 5 days, detect fasting glucose in after injection 1 week, 2 weeks respectively continuously, and blood glucose value all exceedes
11.0mmol/L, for modeling success.One-tenth mould mice being randomly divided into 4 groups, often group 12, respectively solvent control group is (negative right
According to group), Exendin-4 group (positive controls), GLP-1 group (positive controls), P8 group (experimental group).Dosage is
25nmol/kg, every day 2 times, solvent is normal saline, subcutaneous injection 0.1ml, and set time point is administered, AM 9:00-10:00,
PM 8:00-9:00.Negative control group, subcutaneous injection 0.1ml normal saline.
2, STZ diabetic mice is added up the impact of feed
From the beginning of administration, often organize to record respectively and initially add appetite, every the surplus appetite of detection in 1 day or 2 days, and continue to add new
Mus grain, and record, the like, it was administered by 5 weeks and terminates, total food-intake of record mice, and draw accumulative feed curve, result
Feed as accumulative in Fig. 2, P8 group is considerably less than group of solvents, GLP-1 group and Exendin-4, has the effect of identical suppression feed.
3, the impact on STZ diabetic mice blood glucose
Mice 8 hours on an empty stomach, AM 8:00 starts fasting, PM 4:00, and tail vein detection fasting glucose, detection blood glucose is examined
Survey instrument (Omron blood glucose meter HEA-231 type), as being administered 0 week blood glucose.It is being administered 1,2,3,4,5 weeks the most respectively, detection sky
Abdomen blood glucose, fasting time and detection time, result such as Fig. 3, it is little that P8 group can significantly reduce STZ diabetes model with 0 week method
The fasting glucose of Mus, hence it is evident that be better than GLP-1 group and Exendin-4 group, by the 5th week, compares with model group, p≤0.01, has aobvious
Write sex differernce.
4, on STZ diabetic mice triglyceride and the impact of free fatty
After being administered 5 weeks, eye socket takes blood, stands and collects serum, and test kit detects triglyceride (TG) and free-fat respectively
Acid (FFA) level, result such as Fig. 4.Result shows, serum triglyceride level, and P8 group compares with model group, p≤0.001, tool
Having pole significant difference, Exendin-4 group to compare with model group, p≤0.01, GLP-1 compares with model group, no significant difference
Property；Serum free fatty acid levels, P8 group compares with model group and has significant difference, p≤0.01, GLP-1 group, Exendin-
4 groups are compared with model group, without dominant work difference.Result illustrates, P8 can substantially reduce STZ diabetic mice after processing
Triglyceride and free fatty acid levels, be better than GLP-1 group, Exendin-4 group.
5, the impact on STZ diabetic mice islets of langerhans form (HE dyeing)
After being administered 5 weeks, put to death mice, take pancreas, fix with formalin, after HE dyes, observe islets of langerhans form, result
Such as Fig. 6.Model group islet damage is serious, is hardly visible complete Pancreas Islet Structure, GLP-1 group, Exendin-4 group and P8 group pancreas
Island form be improved significantly, it can be observed that cell color is shallow, the arrangement Pancreas Islet Structure in a strand.Illustrate GLP-1 group,
Exendin-4 group and P8 group all can improve islets of langerhans form.
6, the impact on STZ diabetic mice islet area
After being administered 5 weeks, putting to death mice, take pancreas, formalin is fixed, and immunostaining (insulin, ki67), result is such as
Fig. 7.Immunostaining picture shows, model group beta Cell of islet seldom (STZ wound inducement beta cell is dead), and GLP-1 group,
Exendin-4 group and P8 group beta Cell of islet increase, and illustrate that P8 group can substantially increase beta Cell of islet amount, increase beta Cell of islet
Area.
7, the impact on the C peptide level of STZ diabetic mice
After being administered 5 weeks, eye socket takes blood, stands and collects serum, test kit detection C peptide level, result such as Fig. 8.Result shows,
There is significant difference, p≤0.05 in P8 group and model group, GLP-1 group, Exendin-4 group compare with model group, no significant difference,
Illustrate that P8 can substantially reduce the C peptide level of STZ diabetic mice after processing, be better than GLP-1 group, Exendin-4 group.
The pharmacodynamic evaluation two of embodiment 3:P8
1, the impact on db/db diabetic mice blood glucose
The male db/db mice (purchased from Nanjing University, credit number: SCXK (Soviet Union) 2015-00001) of 24 6 week old, suitable
Answering property is raised 1 week., started to check that blood glucose, AM 8:00 start fasting, AM 12:00, tail vein detection blood glucose, detection from the 7th week
With blood-sugar detecting instrument (Omron blood glucose meter HEA-231 type).When the 9th week, start to be administered, and detect blood glucose, when the 10th week, with mould
Type group, GLP-1 group compare, and blood glucose significantly reduces, respectively p≤0.001 and p≤0.05, and persistently maintain relatively low blood glucose water
Flat, there is significant difference with model group, blood sugar lowering is substantially better than GLP-1 group, remains basically stable with Exendin-4 group.
2, the impact on db/db diabetic mice insulin tolerance
16th week, mice 8 hours on an empty stomach, AM 8:00 started fasting, PM 4:00, tail vein detection fasting glucose, detection
With blood-sugar detecting instrument (Omron blood glucose meter HEA-231 type), detect fasting glucose, as 0 blood glucose of insulin tolerance, press
The injected sc insulin of 1IU/kg, the most respectively 15,30,60,90,120 minutes detection blood after insulin injection
Area under sugar, and difference calculated curve.Result P8 significantly improves insulin tolerance, is respectively provided with significantly with group of solvents and GLP-1 group
Sex differernce, as Exendin-4 group effect.
Claims (5)
1. a novel blood sugar lowering is adjusted, it is characterised in that its aminoacid sequence is: HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
SSGAPPPS。
A kind of new type of peptides the most according to claim 1 application in treatment or prevention type i diabetes medicine.
A kind of new type of peptides the most according to claim 1 application in treatment or prevention type 2 diabetes mellitus medicine.
New type of peptides the most according to claim 1 and pharmaceutical carrier or pharmaceutically active substance make compositions in treatment or prevention
Application in type i diabetes medicine.
New type of peptides the most according to claim 1 and pharmaceutical carrier or pharmaceutically active substance make compositions in treatment or prevention
Application in type 2 diabetes mellitus medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610805193.7A CN106279400A (en) | 2016-09-06 | 2016-09-06 | Design of P8 incretin peptide and application thereof |
| PCT/CN2017/098674 WO2018045872A1 (en) | 2016-09-06 | 2017-08-23 | Polypeptide and uses thereof |
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| CN201610805193.7A CN106279400A (en) | 2016-09-06 | 2016-09-06 | Design of P8 incretin peptide and application thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018045872A1 (en) * | 2016-09-06 | 2018-03-15 | 中国药科大学 | Polypeptide and uses thereof |
| WO2018232810A1 (en) * | 2017-06-19 | 2018-12-27 | 中国药科大学 | Long-acting polypeptide for lowering blood glucose and regulating lipid and use thereof |
| CN109200273A (en) * | 2017-07-04 | 2019-01-15 | 中国药科大学 | A kind of polypeptide is used to prepare the purposes of prevention or treatment fatty liver drug |
| CN109280083A (en) * | 2017-07-21 | 2019-01-29 | 苏州瑞德升跃制药技术有限公司 | GLP-1 polypeptide and application thereof with GLP-1 receptor agonist activity |
| CN109395065A (en) * | 2017-08-18 | 2019-03-01 | 中国药科大学 | A kind of polypeptide is used to prepare the purposes of slimming medicine |
| WO2019127630A1 (en) * | 2017-12-28 | 2019-07-04 | 南京零一生物科技有限公司 | Bifunctional polypeptide having hypoglycemic and immunomodulatory effects and use thereof |
| CN111138552A (en) * | 2020-01-15 | 2020-05-12 | 中国药科大学 | Lipid-lowering polypeptide and pharmaceutical application thereof |
| CN111196859A (en) * | 2020-01-22 | 2020-05-26 | 中国药科大学 | Bifunctional polypeptide P30 and application thereof |
| CN112079931A (en) * | 2020-08-17 | 2020-12-15 | 平顶山学院 | Long-acting GLP-1 analogue polypeptide and application thereof in reducing blood sugar and regulating lipid |
| CN117624305A (en) * | 2023-12-04 | 2024-03-01 | 北京旺江生物技术有限公司 | Polypeptide extracted from Momordica Charantia and its application in treating diabetes |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018045872A1 (en) * | 2016-09-06 | 2018-03-15 | 中国药科大学 | Polypeptide and uses thereof |
| WO2018232810A1 (en) * | 2017-06-19 | 2018-12-27 | 中国药科大学 | Long-acting polypeptide for lowering blood glucose and regulating lipid and use thereof |
| CN109134661A (en) * | 2017-06-19 | 2019-01-04 | 中国药科大学 | Long-acting hypoglycemic fat-regulating polypeptide and application thereof |
| CN109134661B (en) * | 2017-06-19 | 2019-10-15 | 中国药科大学 | Long-acting hypoglycemic fat-regulating polypeptide and application thereof |
| CN109200273B (en) * | 2017-07-04 | 2021-02-19 | 中国药科大学 | Application of polypeptide in preparation of medicine for preventing or treating fatty liver disease |
| CN109200273A (en) * | 2017-07-04 | 2019-01-15 | 中国药科大学 | A kind of polypeptide is used to prepare the purposes of prevention or treatment fatty liver drug |
| CN109280083A (en) * | 2017-07-21 | 2019-01-29 | 苏州瑞德升跃制药技术有限公司 | GLP-1 polypeptide and application thereof with GLP-1 receptor agonist activity |
| CN109280083B (en) * | 2017-07-21 | 2023-05-16 | 苏州瑞德升跃制药技术有限公司 | GLP-1 polypeptides having GLP-1 receptor agonist activity and uses thereof |
| CN109395065A (en) * | 2017-08-18 | 2019-03-01 | 中国药科大学 | A kind of polypeptide is used to prepare the purposes of slimming medicine |
| WO2019127630A1 (en) * | 2017-12-28 | 2019-07-04 | 南京零一生物科技有限公司 | Bifunctional polypeptide having hypoglycemic and immunomodulatory effects and use thereof |
| CN111138552A (en) * | 2020-01-15 | 2020-05-12 | 中国药科大学 | Lipid-lowering polypeptide and pharmaceutical application thereof |
| CN111196859A (en) * | 2020-01-22 | 2020-05-26 | 中国药科大学 | Bifunctional polypeptide P30 and application thereof |
| CN112079931A (en) * | 2020-08-17 | 2020-12-15 | 平顶山学院 | Long-acting GLP-1 analogue polypeptide and application thereof in reducing blood sugar and regulating lipid |
| CN117624305A (en) * | 2023-12-04 | 2024-03-01 | 北京旺江生物技术有限公司 | Polypeptide extracted from Momordica Charantia and its application in treating diabetes |
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Application publication date: 20170104 |