CN113476591A - Application of milk-derived polypeptide derivative in preparation of diabetes prevention and treatment medicines, health-care products and food additives - Google Patents

Application of milk-derived polypeptide derivative in preparation of diabetes prevention and treatment medicines, health-care products and food additives Download PDF

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CN113476591A
CN113476591A CN202110791653.6A CN202110791653A CN113476591A CN 113476591 A CN113476591 A CN 113476591A CN 202110791653 A CN202110791653 A CN 202110791653A CN 113476591 A CN113476591 A CN 113476591A
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milk
derived polypeptide
amino acid
acid sequence
diabetes
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CN113476591B (en
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崔县伟
季晨博
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Nanjing Maternity and Child Healthcare Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

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Abstract

The invention discloses application of milk-derived polypeptide derivatives in preparation of diabetes prevention and treatment medicines, health-care products and food additives. The polypeptide and its derivatives have no side effects, and can be further developed into medicine, health product and food additive for treating diabetes with high safety and no side effects.

Description

Application of milk-derived polypeptide derivative in preparation of diabetes prevention and treatment medicines, health-care products and food additives
Technical Field
The invention relates to the field of polypeptide and metabolism regulation, in particular to application of milk-derived polypeptide derivatives in preparation of medicines, health-care products and food additives for preventing and treating diabetes.
Background
Diabetes is a chronic metabolic disease characterized primarily by hyperglycemia. Diabetes can cause damage and dysfunction of multiple organs, seriously endanger the physical health and the quality of life of patients, and in addition, the long treatment process causes heavy economic burden to the patients. According to the international diabetes union, the number of diabetics in the whole world is increased from 3.82 to 5.92 billion from 2013 to 2035; the number of Chinese diabetics will increase from 9840 to 14270 thousands, leaping first in the world. Therefore, the search for healthy and effective diabetes treatment drugs is an urgent social problem to be solved urgently.
Although the current clinically applied hypoglycemic drugs can achieve a certain hypoglycemic effect, adverse reactions such as gastrointestinal reactions, hypoglycemia, weight gain and the like exist, so that the requirements of all patients cannot be met. Although insulin injection can effectively reduce blood sugar, patients are easy to have symptoms of hypoglycemia and weight gain, and clinical use of the insulin injection is limited to a certain extent. In recent years, due to the appearance of glucagon-like peptide-1 (GLP-1) analogues, exenatide, liraglutide and the like, a new way is provided for clinical treatment of type 2 diabetes. In view of the fact that polypeptides have a good molecular basis as drugs, such as low molecular weight, good specificity, and being not easily accumulated in the body, the development of polypeptide drugs has become a focus of attention. In consideration of the fact that the polypeptides are various in types and activities and easy to modify and reform, the search for new polypeptides with the hypoglycemic effect is of great significance.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide application of a separated milk-derived polypeptide sequence in preparing a medicine for preventing and treating obesity and/or diabetic complications or a health-care product or food additive for preventing diabetes and/or diabetic complications; the invention also aims to provide application of the milk-derived polypeptide derivative containing the milk-derived polypeptide sequence and a transmembrane amino acid sequence in preparing a medicament for preventing and treating obesity and/or diabetes complications or a health-care product or food additive for preventing diabetes and/or diabetes complications.
The technical scheme is as follows: in order to achieve the above object, the isolated milk-derived polypeptide of the present invention comprises the amino acid sequence shown in SEQ ID NO.1, wherein the sequence is Val-Lys-Glu-Ala-Met-Ala-Pro-Lys, and is derived from cow milk beta-casein 113-120 amino acid, and thus can be obtained by amplification and expression through biotechnology or by chemical synthesis (e.g., solid phase/liquid phase synthesis).
On the basis of the separated milk-derived polypeptide, the invention also provides application of a milk-derived polypeptide derivative containing the peptide chain. The milk-derived polypeptide derivative comprises an active amino acid sequence shown as SEQ ID NO.1 and a transmembrane amino acid sequence, wherein the transmembrane amino acid sequence is positioned at the N end of the active amino acid sequence.
Preferably, the transmembrane amino acid sequence comprises at least one section of oligomeric arginine sequence, and the proportion of arginine in the transmembrane amino acid sequence is not less than 40%.
More preferably, the N end of the active amino acid sequence is connected with the oligomeric amino acid segment of glutamine and proline in sequence. The membrane penetrating amino acid sequence formed by the oligomeric amino acids can be effectively connected with an active sequence, is efficiently transported to penetrate through a cell membrane and cannot cause other reactions. Wherein, the oligomeric amino acid segment is a short peptide consisting of at least 2 adjacent and same amino acids.
In a most preferred embodiment of the invention, the polypeptide derivative is selected from the following amino acid sequences:
SEQ ID NO.2: GRKKRRQRRRVKEAMAPK，
SEQ ID NO.3: CYGRKKRRQRRRVKEAMAPK，
SEQ ID NO.4: GRKKRRQRRRPPQVKEAMAPK，
SEQ ID NO.5: GRKKRRQRRRPPQQVKEAMAPK。
the polypeptide sequences shown in SEQ ID NO.1-SEQ ID NO.5 can be modified as necessary, including but not limited to protection/deprotection of specific groups, acylation, alkylation, amidation, esterification of C-terminal and/or N-terminal and/or side chains, and other specific coupling or chelating modifications. In general, the modification may be carried out by adding a carboxyl group to the N-terminal and a hydroxyl group or an amino group to the C-terminal.
The separated milk-derived polypeptide or milk-derived polypeptide derivative can be used for preparing medicines for preventing and treating diabetes and/or diabetic complications, and can be used for preparing health-care products or food additives for preventing diabetes and/or diabetic complications. Can be combined with pharmaceutically acceptable carriers or excipients in the preparation process. Wherein the concentration of the separated milk-derived polypeptide or milk-derived polypeptide derivative exerting bioactivity is 1mg/Kg-20 mg/Kg; more preferably, the concentration is 5mg/Kg-10mg/Kg, and the biological activity is more remarkable.
Furthermore, the diabetes mellitus is type II diabetes mellitus, refers to continuous rise of blood sugar level caused by insufficient insulin secretion or insulin resistance, and is a chronic metabolic disease commonly seen in adults.
Further, the diabetic syndrome according to the present invention is selected from the group consisting of, but not limited to, hyperlipidemia, hyperinsulinemia, insulin resistance syndrome and glucose intolerance.
The separated milk-derived polypeptides and milk-derived polypeptide derivatives can obviously reduce the fasting blood sugar, triglyceride and insulin levels in fasting blood sugar, blood fat and insulin level tests of a db/db diabetes mouse model; in an insulin sensitivity test, a blood glucose curve after insulin is injected into an abdominal cavity shows that the insulin sensitivity can be obviously enhanced; in the glucose tolerance test, the blood glucose curve after intraperitoneal injection of glucose shows that the glucose tolerance can be obviously improved.
Therefore, the separated milk-derived polypeptide and the milk-derived polypeptide derivative provided by the invention can be used for preparing medicines for preventing and treating diabetes, especially II-type diabetes. Meanwhile, the traditional Chinese medicine composition also has remarkable treatment effects on diabetes complications, such as improvement of hyperlipidemia, enhancement of insulin sensitivity, improvement of glucose intolerance and the like. In addition, the experimental process finds that the polypeptide and the derivative thereof have no obvious side effect and can be developed into diabetes treatment medicines, health care products and food additives with high safety and no side effect. In addition, the advantages of high unit activity, low molecular weight, easy modification and synthesis and the like of the polypeptide undoubtedly enable the milk-derived polypeptide and the milk-derived polypeptide derivative to have strong application potential.
Drawings
FIG. 1 is a graph showing the effect of milk-derived polypeptide derivatives on fasting plasma glucose in db/db diabetic mice according to example 2 of the present invention;
FIG. 2 is a graph showing the effect of milk-derived polypeptide derivatives on blood lipid levels in db/db diabetic model mice in example 2 of the present invention;
FIG. 3 is a graph of the effect of milk-derived polypeptide derivatives on insulin levels in db/db diabetic model mice according to example 2 of the present invention;
FIG. 4 is a graph showing the effect of milk-derived polypeptide derivatives on insulin sensitivity in db/db diabetic model mice according to example 3 of the present invention;
FIG. 5 is a statistical comparison of peak areas under the curves of FIG. 4;
FIG. 6 is a graph showing the effect of milk-derived polypeptide derivatives on glucose tolerance in db/db diabetic model mice according to example 4 of the present invention;
FIG. 7 is a statistical comparison of peak areas under the curves of FIG. 6.
Detailed Description
The invention is further described with reference to the following figures and detailed description.
Example 1
Unless otherwise specified, the peptide chains in the following examples of the present invention were obtained by chemical synthesis by Shanghai peptide biology, Inc., with a purity of > 98%.
The present example provides the following polypeptide sequences:
SEQ ID NO.1：Val-Lys-Glu-Ala-Met-Ala-Pro-Lys。
SEQ ID NO. 2: GRKKRRQRRRVKEAMAPK, respectively; molecular formula C93H175N41O22S, average molecular weight 2251.7 g/mol, average isoelectric pH 12.471.
SEQ ID NO. 3: CYGRKKRRQRRRVKEAMAPK, respectively; molecular formula C108H197N45O26S, average molecular weight 2574.06 g/mol, average isoelectric pH 12.471.
SEQ ID NO. 4: GRKKRRQRRRPPQVKEAMAPK, respectively; molecular formula C105H189N43O25S2Average molecular weight 2518.02 g/mol, average isoelectric pH 11.911.
SEQ IDNo. 5: GRKKRRQRRRPPQQVKEAMAPK, respectively; molecular formula C113H205N47O28S, average molecular weight 2702.19 g/mol, average isoelectric pH 12.471.
Any one or more of the combination of the sequences SEQ ID NO.1-SEQ ID NO.5 is used as an active ingredient, and other pharmaceutically acceptable carriers or excipients are added to prepare corresponding medicaments, health-care products and food additives.
The skilled person can make necessary modifications including, but not limited to, protection/deprotection of specific groups, acylation, alkylation, amidation, esterification of the C-and/or N-terminal and/or side chain, and other specific coupling or chelating modifications without departing from the scope of the present invention. Preferably, the modification is carried out by adding a carboxyl group to the N-terminal and a hydroxyl group or an amino group to the C-terminal.
Example 2 Effect of milk-derived Polypeptides and derivatives on fasting plasma glucose, blood lipid, and insulin levels in db/db diabetic model mice
1. Experimental methods
The diabetes model db/db mouse is characterized in that Leptin signal pathway disorder is caused by Leptin receptor point mutation, so that the dbdb mouse has symptoms of obesity, insulin resistance, hyperglycemia, fatty liver and the like. Obvious obesity and fasting blood sugar increase can be generated 6 weeks after the birth of db/db mice, the water intake and urine output are increased, the best effect is realized at 8-12 weeks of db/db mice, and complications such as diabetic nephropathy can be generated. Selecting a db/db diabetic mouse with the age of 8 weeks as an experimental object (purchased from Jiangsu Jiejiaokang Biotechnology Co., Ltd.), preparing 5mg/Kg and 10mg/Kg milk-derived polypeptide derivative solutions of SEQ ID NO.5, taking solvent physiological saline (Vehicle) as a control, and administering the mouse by an intraperitoneal injection method for 4 weeks continuously and twice a week; the change of fasting blood glucose of mice is detected by adopting a Roche glucometer, and the change of blood fat and insulin level is detected by adopting a commercialized kit of plerian and Millipop.
2. Results of the experiment
As can be seen from FIGS. 1-3, after 4 weeks of continuous treatment with the milk-derived polypeptide derivative of SEQ ID No.5, the fasting blood glucose level of mice is significantly reduced, the blood lipid level and the insulin level are also significantly improved, the concentration of 10mg/Kg can be significantly improved, and the treatment effect of 10mg/Kg is better. Hyperglycemia and hyperinsulinemia are typical clinical features of diabetics and are also the leading cause of their complications.
Example 3 Effect of milk-derived Polypeptides and derivatives on insulin sensitivity in db/db diabetic model mice
1. Experimental methods
Using a db/db diabetic mouse as a research object for 6-8 weeks, setting 5mg/Kg and 10mg/Kg of milk-derived polypeptide derivative solutions of SEQ ID NO.5, using solvent normal saline (Vehicle) as a control, and adopting an intraperitoneal injection method to administer the mouse, wherein the injection is continuously performed for 4 weeks, and twice per week; after fasting for 12 hours, injecting insulin in an intraperitoneal injection mode according to the standard of 2.0U/kg of mouse body weight; blood was taken from tail veins 0 min, 15 min, 30 min, 60 min, 90 min and 120 min after injection, and blood glucose changes of mice were measured using a glucometer to evaluate insulin sensitivity of mice.
2. Results of the experiment
As can be seen from FIGS. 4 and 5, the mice in the 5mg/Kg intervention group exhibited a tendency of enhanced insulin sensitivity compared to the control group, while the mice in the 10mg/Kg polypeptide drug intervention group exhibited a significant enhancement in insulin sensitivity, indicating that the milk-derived polypeptide derivative can significantly improve insulin sensitivity of diabetic mice. Insulin resistance is the pathophysiological basis and root cause for the development of type II diabetes.
Example 4 Effect of milk-derived Polypeptides and derivatives on glucose tolerance in db/db diabetic model mice
1. Experimental methods
Using a db/db diabetic mouse as a research object for 6-8 weeks, setting 5mg/Kg and 10mg/Kg of milk-derived polypeptide derivative solutions of SEQ ID NO.5, using solvent normal saline (Vehicle) as a control, and adopting an intraperitoneal injection method to administer the mouse, wherein the injection is continuously performed for 4 weeks, and twice per week; after fasting for 6 hours, injecting glucose in an intraperitoneal injection mode according to the standard of 1 g/kg of mouse body weight; blood was taken from tail veins at 0 min, 15 min, 30 min, 60 min, 90 min and 120 min after injection, and blood glucose changes of mice were measured using a glucometer to evaluate glucose tolerance of mice.
2. Results of the experiment
As can be seen from fig. 6 and 7, the milk-derived polypeptide derivative of the present invention significantly improved glucose tolerance in diabetic mice as compared to the control group, and the effect was better at 10mg/Kg, indicating that there was a dose-dependent relationship.
Sequence listing
<110> Nanjing City health care hospital for women and children
<120> application of milk-derived polypeptide derivative in preparation of diabetes prevention and treatment drugs, health products and food additives
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
Val Lys Glu Ala Met Ala Pro Lys
1 5
<210> 2
<211> 18
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Val Lys Glu Ala Met Ala
1 5 10 15
Pro Lys
<210> 3
<211> 20
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
Cys Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Val Lys Glu Ala
1 5 10 15
Met Ala Pro Lys
20
<210> 4
<211> 21
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 4
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Val Lys Glu
1 5 10 15
Ala Met Ala Pro Lys
20
<210> 5
<211> 22
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 5
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Gln Val Lys
1 5 10 15
Glu Ala Met Ala Pro Lys
20

Claims (8)

1. An application of a separated milk-derived polypeptide in preparing a medicament for preventing and treating diabetes and/or diabetic complications, wherein the milk-derived polypeptide comprises an amino acid sequence shown as SEQ ID NO. 1.
2. Use of an isolated milk-derived polypeptide comprising an amino acid sequence as set forth in SEQ ID No.1 for the preparation of a health product or dietary supplement for the prevention of diabetes and/or diabetic complications.
3. An application of a milk-derived polypeptide derivative in preparing a medicament for preventing and treating diabetes and/or diabetic complications is disclosed, wherein the milk-derived polypeptide derivative comprises an active amino acid sequence shown as SEQ ID NO.1 and a transmembrane amino acid sequence, and the transmembrane amino acid sequence is positioned at the N end of the active amino acid sequence.
4. The application of a milk-derived polypeptide derivative in preparing a health-care product or a food additive for preventing diabetes and/or diabetic complications comprises an active amino acid sequence shown as SEQ ID NO.1 and a transmembrane amino acid sequence, wherein the transmembrane amino acid sequence is positioned at the N end of the active amino acid sequence.
5. The use of a milk-derived polypeptide derivative according to claim 3 or 4 for the manufacture of a medicament for the prevention and treatment of diabetes and/or diabetic complications, wherein: the membrane-penetrating amino acid sequence of the milk-derived polypeptide derivative comprises at least one section of oligomeric arginine sequence, and the proportion of arginine in the membrane-penetrating amino acid sequence is not less than 40%.
6. The use of a milk-derived polypeptide derivative according to claim 5 for the preparation of a medicament for the prevention and treatment of diabetes and/or diabetic complications, wherein: the polypeptide derivative is any one amino acid sequence of SEQ ID NO. 2-SEQ ID NO. 5.
7. Use according to any one of claims 1 to 4, characterized in that the diabetic complications comprise hyperlipidemia, hyperinsulinemia, insulin resistance syndrome and glucose intolerance.
8. Use according to claim 7, characterized in that: the concentration of the separated milk-derived polypeptide or milk-derived polypeptide derivative exerting the biological activity is 1mg/Kg-20 mg/Kg.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006031117A1 (en) * 2004-09-17 2006-03-23 Agrotechnology And Food Innovations B.V. Lipoxygenase inhibitor peptides and their use
CN109384836A (en) * 2017-08-10 2019-02-26 华中科技大学 Prevent and treat polypeptide, preparation method and the application of diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006031117A1 (en) * 2004-09-17 2006-03-23 Agrotechnology And Food Innovations B.V. Lipoxygenase inhibitor peptides and their use
CN109384836A (en) * 2017-08-10 2019-02-26 华中科技大学 Prevent and treat polypeptide, preparation method and the application of diabetes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANTHONY FARDET: "In vitro and in vivo antioxidant potential of milks, yoghurts, fermented milks and cheeses: a narrative review of evidence", 《NUTRITION RESEARCH REVIEWS》 *
陈婷等: "乳源性多肽Casein41的抑菌活性及其作用机制", 《第十三届江浙沪儿科学术会议暨2016年浙江省医学会儿科学学术年会论文汇编》 *

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