WO2020235947A1

WO2020235947A1 - Cacb1-derived peptide, variant of cacb1-derived peptide, and use thereof

Info

Publication number: WO2020235947A1
Application number: PCT/KR2020/006650
Authority: WO
Inventors: 윤동호; 김태완; 오태호
Original assignee: 경북대학교 산학협력단
Priority date: 2019-05-22
Filing date: 2020-05-21
Publication date: 2020-11-26
Also published as: KR20200135213A; KR102425548B1

Abstract

The present invention relates to a Cacb1-derived peptide, a variant of the Cacb1-derived peptide, a composition for the prevention or treatment of hypertension, and a composition for the relaxation of blood vessels, the compositions comprising same. The Cacb1-derived peptide and the variant of the Cacb1-derived peptide according to the present invention have an excellent blood pressure-lowering effect and fewer side effects, and are easy to manufacture and industrialize, and thus can be effectively used in the development of a novel therapeutic agent for hypertension. In addition, the peptide and the variant thereof have a potential vasodilating effect, and thus are expected to be used as candidate materials for a therapeutic agent for diseases that can be treated or ameliorated by vasodilation, such as angina, prostatic hyperplasia, and erectile dysfunction.

Description

Cacb1-derived peptide, Cacb1-derived peptide variant and its use

The present invention relates to a Cacb1-derived peptide, a variant of the Cacb1-derived peptide, and a composition for preventing or treating hypertension comprising the same, and a composition for relaxing blood vessels.

Hypertension is a disease with a high prevalence rate that one out of three adults in most countries suffers from it.According to the 2016 National Health and Nutrition Survey, the prevalence of hypertension in Korea was over 11 million. If not treated, hypertension is often referred to as a “silent killer” because it injures the heart and blood vessels without any symptoms, and leads to stroke, acute myocardial infarction, and death through a process called atherosclerosis.

The hypertension treatment has been developed in earnest since the 1950s, and the coercive action is effective, the safety is proven, and the side effects are relatively minor, so there are five types of coercive agents that are recognized as early drugs for coercion therapy: diuretics, beta Blockers and alpha-beta blockers, calcium antagonists, ACE inhibitors (Angiotensin converting enzyme inhibitors), ARB blockers (Angiotensin receptor blockers). These primary-selective coercive agents are similar in intensity of coercive effect, but when applied individually to patients, they can show a large difference in morbidity, mortality, and occurrence of side effects.

On the other hand, compounds used in the past are easily decomposed in pharmaceutical dosage forms and are not only less stable, but also act on other cells, resulting in loss of strength in the body, vomiting, coughing, headache, loss of appetite, and taste disorders. It is reported to have problems. For example, in the case of thiazide diuretics, it is the oldest antihypertensive drug with sufficiently proven efficacy and safety, and is used as a first choice drug, but gout, hyperuricemia, hypokalemia, hyponatremia, hypercalcemia, dyslipidemia, impaired glucose tolerance, It is known that it can cause erectile dysfunction. In addition, the launch of a new concept of hypertension in the last 10 years is insignificant, and the pharmaceutical market is preparing to launch a combination drug that combines two or more of the existing hypertension drugs.

In the case of hypertension, due to the nature of the disease, long-term use of the drug is required, and if the drug is suddenly stopped, more side effects may occur. Therefore, safety should be ensured without repeated dose toxicity without side effects. Accordingly, there is an urgent need to develop a new hypertension treatment that can replace existing hypertension drugs and apply to patients who have not seen treatment effects with existing hypertension drugs.

Accordingly, the present inventors have tried to develop a new therapeutic agent for hypertension based on a peptide, and as a result, confirmed the blood pressure lowering effect of the peptide derived from Cacb1 and its variants, and completed the present invention.

Accordingly, an object of the present invention is a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1-derived peptide; and a cell-permeable peptide or a half-life extending peptide; a pharmaceutical composition for preventing or treating hypertension comprising a fusion peptide, a composition for relaxing blood vessels, a food composition, and a method for preventing or treating hypertension.

To achieve the above object,

The present invention is a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1 derived peptide; and a cell-permeable peptide or a half-life extending peptide; provides a pharmaceutical composition for preventing or treating hypertension comprising a fusion peptide.

In addition, the present invention a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1 derived peptide; and a cell-permeable peptide or a half-life extending peptide; provides a composition for relaxation of blood vessels comprising a fusion peptide.

b) Cacb1 derived peptide; and a cell-permeable peptide or a half-life extending peptide; provides a food composition for preventing or improving hypertension comprising a fusion peptide.

b) Cacb1 derived peptide; and a cell-permeable peptide or a half-life extending peptide; provides a method for preventing or treating hypertension comprising administering a fusion peptide to an individual.

The Cacb1-derived peptide and the variant of the Cacb1-derived peptide of the present invention have excellent blood pressure lowering effect, have few side effects, and are easy to manufacture and industrialize, and thus can be usefully used in the development of a new therapeutic agent for hypertension. In addition, due to its potential vasodilating effect, it is expected to be used as a therapeutic candidate for diseases that can be treated or ameliorated by vasodilation such as angina pectoris, prostatic hyperplasia, and erectile dysfunction.

1 is a change in blood pressure during intravenous injection of Cacb1 (344-359) peptide (IKITSPKVLQRLIKSR) into a rat animal model, and the control and Cacb1 (344-359) (0.15 mg/kg; 0.2ml, IV) treatment group Blood pressure comparison (A), Cacb1 (344-359) (1 mg/kg; 0.2 ml, IV) is a diagram showing the blood pressure changes in the treatment groups (B, C).

2 is a diagram showing changes in blood pressure when intravenous injection of Cacb1 (389-397) peptide (LDENQLEDA) into an animal model.

Figure 3 is a diagram showing the blood pressure change during injection of Cacb1 (344-359)I344V peptide (VKITSPKVLQRLIKSR) (A) or Cacb1 (344-359)I344V/K357R peptide (VKITSPKVLQRLIRSR) (B) to an animal model.

4 is a diagram showing a change in blood pressure (A) when injected intravenously with Cacb1(344-359)K357R peptide (IKITSPKVLQRLIRSR) in an animal model and a change in blood pressure when injected intramuscularly (B).

Figure 5 is a Cacb1 (344-359) peptide, Cacb1 (389-397) peptide, Cacb1 (344-359) I344V peptide, Cacb1 (344-359) I344V / K357R peptide or Cacb1 (344-359) K357R peptide in an animal model. Changes in systolic blood pressure during intravenous injection (A), blood pressure (B) and hemodynamic indicators (systolic, diastolic, and mean blood pressure) of each individual in an animal model before and after administration of Cacb1 (344-359) peptide (C ; The number in parentheses is a diagram showing the number of animal models used for the average calculation.

Figure 6 is a diagram showing the blood pressure change during injection of Cacb1 (344-359)I344V/T347S peptide (VKISSPKVLQRLIKSR) (A) or Cacb1 (344-357)I344V/T347S/K357R peptide (VKISSPKVLQRLIRSR) (B) to an animal model.

Figure 7 shows changes in blood pressure when injected with Cacb1 (344-357)I344V/I346V/T347S peptide (VKVSSPKVLQRLIKSR) (A) or Cacb1 (344-357)I344V/I346V/T347S/K357R peptide (VKVSSPKVLQRLIRSR) (B) in an animal model. It is a diagram shown.

8 shows Cacb1(344-359), Cacb1(389-397), Cacb1(344-359)I344V/T347S (Cacb2(392-407)), Cacb1(344-357)I344V/T347S/K357R(Cacb2(392) -407)K405R), systolic blood pressure of Cacb1(344-357)I344V/I346V/T347S(Cacb4(333-348)) or Cacb1(344-357)I344V/I346V/T347S/K357R(Cacb3(292-307)) It is a diagram showing the results of measurement of change (A) and hemodynamic indicators (systolic phase, diastolic phase, and mean blood pressure) (B; the number in parentheses is the number of animal models used for average calculation).

9 is a diagram showing the blood pressure change (A) and the results of measuring hemodynamic indicators (systolic phase, diastolic phase and mean blood pressure) by concentration (B) when TAT-Cacb1 (389-397) fusion peptide is injected into an animal model.

Figure 10 shows the blood pressure change (A) and Cacb1 (344-359) K357R, peptide K2-palm peptide (0.5, 1, 2 mg/kg) when injected intravenously with K2-palm peptide (1 mg/kg) in an animal model, or Hemodynamic indicators (systolic phase, diastolic phase, mean blood pressure and heart rate) were measured when K7-palm peptide (2 mg/kg) was injected intravenously (B; the number in parentheses is the number of animal models used for the average calculation) Is a diagram showing.

Figure 11 shows the blood pressure change (A) and Cacb1 (344-359) K357R peptide, Cacb1 (344-359) K357R-EYEKEYE peptide (0.5, 1,) when injected intravenously with K20-palm (2 mg/kg) peptide into an animal model. 2 mg/kg) or K20-palm peptide (2 mg/kg) when injected intravenously, hemodynamic indicators (systolic, diastolic, mean blood pressure and heart rate) were measured (B; numbers in parentheses are used for average calculation) Is a diagram showing the number of animal models).

Hereinafter, the present invention will be described in detail.

In the present invention, the “Cacb1” gene refers to a protein constituting a calcium channel, and among them, a gene encoding a calcium channel β1 subunit, and means a Voltage-dependent L-type calcium channel subunit beta-1 gene, to which the present invention belongs. In the art, the gene is also referred to as CAB1, Cacnb, Cacnlb1, Cchb1, Cchlb1, Calcium channel voltage-dependent subunit beta 1 or voltage-dependent calcium channel beta1 subunit.

In an embodiment of the present invention, a peptide derived from Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1, calcium channel β1 subunit) (protein ID P54283.1 (rat)) was used in the experiment.

In the present invention, the "Cacb1-derived peptide" is used to include both a Cacb1-derived peptide, a Cacb1-derived peptide variant, and a fatty acid-peptide complex in which a fatty acid is additionally bound to a Cacb1-derived peptide variant.

In the present invention, the term "fusion" refers to the integration of two molecules having the same function or structure as or different from each other, which is all physical, chemical or biological to which a cell-permeable peptide or a half-life extending peptide can bind to a Cacb1 derived peptide according to the present invention. Fusion by method is included without limitation.

In the present invention, the term "fusion peptide" is a peptide in which the derived peptide and a functional peptide are fused, and in the present invention, the functional peptide may be a cell-penetrating peptide or a half-life extending peptide, preferably SEQ ID NOs: 11 to 19 and SEQ ID NO. It may be any one selected from the group consisting of 22, and any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11 to 19 and SEQ ID NO: 22 and 70% or more, preferably 80% or more, more preferably 90% Above, most preferably, it may include an amino acid sequence having a sequence homology of 95% or more.

In the present invention, the term “variant” refers to a peptide in which one or more amino acid residues of the peptides derived from Cacb1 are deleted, added, inserted or substituted within the range capable of exerting the blood pressure lowering effect according to the present invention. In the present invention, the Cacb1-derived peptide may consist of an amino acid sequence represented by SEQ ID NO: 1, and the variant of the Cacb1-derived peptide may be one in which one or more amino acid residues are substituted in the amino acid of SEQ ID NO: 1.

Variants of the Cacb1 peptide according to the present invention include substitution of isoleucine (I) of isoleucine (I) of amino acid 344 to valine (V) of amino acid of SEQ ID NO: 1, and arginine of lysine (K) of amino acid 357 (arginine). , R) substitution, substitution of threonine (T) at amino acid 347 to Serine (S) and substitution of isoleucine (I) at amino acid 346 to valine (V) It may include one or more substitutions selected from the group, and preferably may be represented by any one amino acid sequence selected from the group consisting of SEQ ID NOs: 2 to 8, and any one selected from the group consisting of SEQ ID NOs: 2 to 8 It may comprise an amino acid sequence having a sequence homology of at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably at least 95% of the amino acid sequence.

Meanwhile, those skilled in the art may modify some sequences of the peptides according to the present invention or reduce their size, or use a known peptide modification method (terminal modification, cyclic peptide, fatty acid fusion, peptide fusion, etc.) to lower blood pressure. It will be apparent that the size and duration of the bioavailability can be improved, and the bioavailability can be improved.

In an experimental example of the present invention, it was confirmed that a remarkable blood pressure lowering effect was exhibited when the peptide represented by the amino acid sequence of SEQ ID NOs: 1 to 8 was injected into an animal model.

On the other hand, as a result of sequencing, the amino acid sequence of SEQ ID NO: 1 according to the present invention is the same as that of Human β1b (389-404) corresponding to the amino acid sequence of rat Cacb1 (344-359) (SEQ ID NO: 25), and SEQ ID NO: 5 The amino acid sequence of is the same as the amino acid sequence (SEQ ID NO: 26) of Human β2a (341-356) or Human β2b (342-357) corresponding to the rat Cacb2 (392-407) amino acid sequence, and the amino acid sequence of SEQ ID NO: 8 is The amino acid sequence (SEQ ID NO: 27) of Human β3 (292-307) corresponding to Rat Cacb3 (292-307) is the same, and the amino acid sequence of SEQ ID NO: 7 is Human β4 (287) corresponding to Rat Cacb4 (333-348). -302) was confirmed to be the same as the amino acid sequence (SEQ ID NO: 28). Therefore, it is apparent to those skilled in the art that the peptide according to the present invention can be used without limitation, without limitation, a peptide derived from the protein Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1, calcium channel β1 subunit) constituting a rat or human calcium channel. something to do.

The "fatty acid-peptide complex" of the present invention may be a form in which a fatty acid is additionally bound to a peptide variant derived from Cacb1. In the present invention, the peptide variant derived from Cacb1 is represented by any one selected from the group consisting of SEQ ID NOs: 1 to 8 It may be an amino acid sequence, more preferably an amino acid sequence represented by SEQ ID NO: 4, and 70% or more, preferably 80% or more, more preferably 90% or more, most preferably an amino acid sequence represented by SEQ ID NO: 4 Preferably, it may include an amino acid sequence having 95% or more sequence homology. In addition, in the present invention, the fatty acids are Myristic acid, Stearic acid, Linoleic acid, Palmitic acid, Oleic acid, and lauric acid. It may be one or more selected from the group consisting of (Lauric acid), more preferably palmitic acid (Palmitic acid). The fatty acid may be bound to any position of the peptide variant peptide derived from Cacb1, preferably to lysine among amino acids. In one embodiment, the fatty acid-peptide complex according to the present invention may be any one selected from the group consisting of SEQ ID NOs: 20 and 21, and 70% or more with any one amino acid sequence selected from the group consisting of SEQ ID NOs: 20 and 21 , Preferably 80% or more, more preferably 90% or more, and most preferably 95% or more of an amino acid sequence having sequence homology.

In the present invention, the term "Cell Penetrating Peptides (CPP)" is a short cell membrane-permeable peptide of about 10 to 30, and most of them are protein-transduction domains (PTDs) or membrane-transduction sequences (Membrane -Translocating Sequence, MTS) is also called PTD or MTS. The cell-permeable peptide can efficiently transport the fusion protein into the cell even when it is linked to another peptide or protein. In the present invention, the cell-permeable peptide is a previously known cell-permeable peptide capable of penetrating the cell membrane, for example, pep-1 peptide (KETWWETWWTEWSQPKKKRKV), low molecular protamine (LMWP, VSRRRRRRGGRRRR), TAT. Peptide (TAT peptide, YGRKKRRQRRR), Penetratin (RQIKIWFQNRRMKWKK), Antennapedia (ANTP), D-arginine oligopeptide (R8 or higher) or L-arginine oligopeptide (L-arginine oligopeptide) , R8 or more), but is not limited thereto, and preferably may be a TAT peptide represented by the amino acid sequence of SEQ ID NO: 10.

In the present invention, the term'half-life extension peptide' is used to mean both a half-life extension peptide and a peptide in which a fatty acid is bonded to a half-life extension peptide, and more preferably, it may be a peptide in which a fatty acid is bonded to a half-life extension peptide. The half-life extending peptide is a peptide having a characteristic capable of extending the half-life when linked to other peptides and proteins, and may be a peptide consisting of about 2 to 12 amino acids, preferably a peptide consisting of 5 to 10 amino acids. May be, more preferably a peptide consisting of 7 peptides, more preferably a peptide consisting of an amino acid sequence represented by SEQ ID NO: 24, and 70% or more, preferably 80% of the amino acid sequence represented by SEQ ID NO: 24 It may include an amino acid sequence having sequence homology above, more preferably 90% or more, and most preferably 95% or more.

In addition, a fatty acid may be additionally bound to the half-life extending peptide, and the fatty acids include myristic acid, stearic acid, linoleic acid, palmitic acid, and oleic acid ( Oleic acid) and lauric acid (Lauric acid) may be one or more selected from the group consisting of, more preferably, palmitic acid (Palmitic acid). The peptide to which a fatty acid is bound to the half-life extending peptide may be a peptide consisting of an amino acid sequence represented by SEQ ID NO: 23, and 70% or more, preferably 80% or more, more preferably 90% or more, of the amino acid sequence represented by SEQ ID NO: 23 , Most preferably, it may comprise an amino acid sequence having 95% or more sequence homology. The fatty acid may be bound to any position of amino acids of the half-life extending peptide, and preferably, may be bound to lysine among the amino acids of the half-life extending peptide, but is not limited thereto.

In the present invention, the Cacb1-derived peptide may be a peptide represented by the amino acid sequence of SEQ ID NO: 1, a variant thereof, or a peptide represented by the amino acid sequence of SEQ ID NO: 9, and the variant is amino acid 344 in the amino acid sequence of SEQ ID NO: 1 Substitution of phosphorus isoleucine (I) to valine (V), substitution of lysine (K), amino acid 357 to arginine (R), and threonine (T), amino acid 347 Serine (S) and amino acid 346 isoleucine (isoleucine, I) may include one or more substitutions selected from the group consisting of valine (V) substitution, preferably SEQ ID NO: 2 It may be represented by any one amino acid sequence selected from the group consisting of SEQ ID NOs: 2 to 8, and 70% or more, preferably 80% or more, more preferably It may comprise an amino acid sequence having at least 90%, most preferably at least 95% sequence homology.

In the present invention, the fusion peptide is a fusion of a peptide derived from Cacb1 according to the present invention and a cell-permeable peptide or a half-life extending peptide, preferably represented by any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11 to 23. Can be.

On the other hand, in an experimental example of the present invention, it was confirmed that when a cell-permeable peptide was fused to a Cacb1-derived peptide, which did not show a blood pressure-lowering effect when administered alone, a remarkable blood pressure-lowering effect was shown. Cacb1 by fusion with a cell-permeable peptide It can increase the blood pressure lowering effect of the derived peptide.

In addition, in an experimental example of the present invention, it was confirmed that the duration of the blood pressure lowering effect significantly increased when a fatty acid was bound to a Cacb1 derived peptide that showed a blood pressure lowering effect of about 5 minutes when administered alone or a half-life extending peptide was fused. Fatty acid or half-life extending peptides can increase the duration of blood pressure drop of Cacb1 derived peptides.

The pharmaceutical composition comprising the peptide according to the present invention as an active ingredient is not limited thereto, but may include one or more of a pharmaceutical diluent selected from saline, buffered saline, dextrose, water, glycerol, and ethanol.

The composition according to the present invention can be applied differently depending on the purpose of administration and disease. The amount of the active ingredient to be actually administered depends on various related factors, namely the disease to be treated, the degree of the patient's condition, whether or not co-administered with other drugs, the age of the patient, the weight, the food, the administration time, the route of administration, and the administration ratio of the composition. It must be decided in consideration of (ratio). The dosage and route of administration of the composition may be adjusted according to the form and severity of the disease, and may be administered once a day or dividedly administered 1 to 3 times, but is not limited thereto.

The composition according to the present invention can be administered orally or parenterally. Parenteral administration refers to administration of drugs through routes of administration other than oral, that is, rectal, intravenous, peritoneal and muscle, arterial, transdermal, nasal, inhalation, ocular, and subcutaneous.

The composition may be formulated in any form such as oral dosage form, injectable solution or topical preparation. Formulation is preferably prepared to be suitable for oral and injectable administration (true solution, suspension or emulsion), and most is prepared in oral form such as tablets, capsules, soft capsules, aqueous drugs, pills, granules, etc. desirable.

In the above formulation, the peptide of the present invention may be filled into a soft capsule without an excipient, and may be mixed with a carrier or diluted into a suitable formulation. Examples of suitable carriers include starch, water, saline, Ringer's solution, dextrose, and the like.

The composition can be applied directly to animals including humans. The animal is a group of organisms corresponding to plants, which mainly consumes organic matter as nutrients, and refers to that the digestion, excretion and respiratory organs are differentiated, and may preferably be a vertebrate, more preferably a mammal. The mammal may be a human, a dog, a cat, a mouse, a pig, a cow or a goat, and preferably a human.

The pharmaceutical composition according to the present invention may contain, as an active ingredient, a peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23, and other formulations, methods of use, and purposes of use. Additional ingredients, that is, pharmaceutically acceptable or nutritionally acceptable carriers, excipients, diluents, or auxiliary ingredients may be further included.

In more detail, the pharmaceutical composition may include nutrients, vitamins, electrolytes, flavoring agents, coloring agents, heavy agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, It may further contain stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the carrier, excipient, or diluent may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose. Selected from the group consisting of rose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline. Although it may be one or more, it is not limited thereto, and all of a conventional carrier, excipient, or diluent may be used. The components may be added independently or in combination with a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23 as active ingredients.

The pharmaceutical composition comprises from 0.001% to 99.9% by weight, preferably from 0.1% to 99% by weight of a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23 based on the total weight of the composition. , More preferably 1% to 50% by weight may be included.

In addition, the pharmaceutical composition may further contain conventional fillers, extenders, binders, disintegrants, surfactants, anti-aggregating agents, lubricants, wetting agents, fragrances, emulsifiers or preservatives, etc., when formulated into pharmaceuticals, orally or parenterally All can be used.

Specifically, solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid formulations include at least one excipient, such as starch, calcium carbonate, and water in the active ingredient. It can be prepared by mixing sucrose, lactose, gelatin, or the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. have.

In addition, the formulation of the pharmaceutical composition according to the present invention may be in a preferred form depending on the method of use, and in particular, after administration to a mammal, a method known in the art is used to provide rapid, sustained or delayed release of the active ingredient. It can be adopted and formulated. Examples of specific formulations include warning agents, granules, lotions, liniment, limonade, powder, syrup, eye ointment, liquid, aerosol, EXTRACTS, elixir, ointment, fluid extract, emulsion, Suspensions, preparations, needles, eye drops, tablets, suppositories, injections, spirits, capsules, creams, pills, soft or hard gelatin capsules, and the like.

The dosage of the pharmaceutical composition according to the present invention may be appropriately selected by those skilled in the art in consideration of the administration method, the age, sex and weight of the user, and the severity of the disease. For example, the pharmaceutical composition of the present invention is 0.000001 mg/kg/day to 1000 mg/kg/ based on a peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23. It can be administered daily. Administration may be administered once a day, or may be divided several times. The above dosage does not in any way limit the scope of the present invention.

In addition, the pharmaceutical composition according to the present invention, in addition to the peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23, which are active ingredients, compounds having a known hypertension treatment effect, especially used as food It may further contain a natural substance-derived material, and may be included in each of 5 parts by weight to 100 parts by weight based on 100 parts by weight of the active ingredient.

The composition may be provided in the form of a pharmaceutical composition.

The composition according to the present invention can be used for the prevention or treatment of diseases that can be ultimately treated or ameliorated by vasodilation or vasodilation as it exerts a vasodilating or dilating effect. Hypertensive complications, heart failure, atherosclerosis, angina pectoris, myocardial infarction, cerebral infarction, stroke, cerebral hemorrhage, cardiovascular diseases including peripheral blood circulation disorders, prostatic hyperplasia or erectile dysfunction, etc., but are not limited thereto. According to recent studies, it has been reported that erectile dysfunction and prostatic hyperplasia are not one single disease, but are closely related to other vascular diseases, especially cardiovascular diseases, and in these diseases, vascular dilatation disorders or structural abnormalities of blood vessels are found. Many patients with erectile dysfunction have various vascular diseases such as high blood pressure and peripheral arterial disease. According to an embodiment of the present invention, the fusion peptide in which the Cacb1-derived peptide or the cell-permeable peptide or the half-life-prolonging peptide and the Cacb1-derived peptide according to the present invention are fused exhibits a remarkable blood pressure lowering effect, and its potential vasodilating or dilating effect It will be apparent to those skilled in the art that can be ultimately used for the prevention or treatment of cardiovascular disease, prostatic hyperplasia or erectile dysfunction.

In the present invention, the term "prevention" refers to any action that inhibits or delays progression of a disease that can be treated or ameliorated by vasodilation including hypertension by administration of the pharmaceutical composition according to the present invention.

In the present invention, the term "treatment" refers to all actions in which a disease that can be treated or ameliorated by vasodilation, including hypertension, is improved or beneficially altered by administration of the pharmaceutical composition according to the present invention.

There is no particular limitation on the type of food, but it is preferably a health functional food. Examples of foods to which the above substances can be added include various foods, beverages, gum, candy, tea, vitamin complexes, and functional foods, which are special nutritional foods (e.g., formula, infant food, etc.), processed meat products, Fish products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements, seasoning foods (eg, soy sauce, miso, red pepper paste, mixed sauce, etc.), sauces, confectionery (eg, snacks), dairy products (eg, Fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickles, etc.), beverages (eg, fruit, vegetable drinks, soy milk, fermented drinks, ice cream, etc.), natural seasonings (eg, ramen soup, etc.) ), vitamin complexes, alcoholic beverages, alcoholic beverages, and other health supplements, but are not limited thereto. The food, beverage or food additive may be prepared by a conventional manufacturing method.

The peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23 of the present invention may be added to food as it is or may be used with other foods or food ingredients, and may be appropriately used according to a conventional method. have. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the peptide in the health food can be added in an amount of 0.01 to 15% by weight, preferably 0.1 to 5% by weight of the total food weight, and in a health beverage composition, 0.01 to 5.0 g, preferably 0.01 to It can be added in a proportion of 1.0 g. However, in the case of long-term intake for the purpose of health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

The health functional beverage composition according to the present invention is not particularly limited in other ingredients, except for containing peptides as essential ingredients in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients, such as in a conventional beverage. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like, and polysaccharides such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumachin, stevia extract, etc.), and synthetic flavoring agents (saccharin, aspartan, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 0.1 to 2.0 g, preferably about 0.1 to 1.0 g per 100 of the composition of the present invention.

The health functional food of the present invention is prepared by adding an antibiotic peptide composed of the amino acid sequence of the present invention during the manufacturing process of the food as a base material, or by adding the amino acid sequence of the present invention after the production of the base food. It can be easily obtained by applying a step of adding the constituent peptide. At this time, taste and odor correction agents may be added as necessary.

In a food composition for the purpose of preventing or improving hypertension, the amount of the peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23 is 0.00001% to 50% by weight of the total food weight. It may be included, but is not limited thereto.

The subject may be a mammal including a human. The subject may have, or may be, a subject with high blood pressure.

The peptide consisting of any one amino acid sequence selected from SEQ ID NOs: 1 to 8 and SEQ ID NOs: 11 to 23 of the present invention may be administered into the individual, and the administration method may be oral or parenteral administration. The method of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal route, but It is not limited.

In the present specification, terms and definitions used in the composition for relaxing blood vessels, the food composition for preventing or improving hypertension, and the method for preventing or treating hypertension are the same as the pharmaceutical composition for preventing or treating hypertension, so in consideration of duplication and complexity Description has been omitted.

Terms not otherwise defined in the specification have the meanings commonly used in the art to which the present invention belongs.

Hereinafter, the present invention will be described in detail by examples and experimental examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.

실시예 1. 본 발명에 따른 Cacb1 변이체의 준비Example 1. Preparation of Cacb1 variant according to the present invention

A peptide derived from Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1, calcium channel β1 subunit) (protein ID P54283.1 (rat)), a protein constituting the calcium channel, specifically the amino acid sequence of Cacb1 protein 344 Peptide IKITSPKVLQRLIKSR (hereinafter referred to as “Cacb1(344-359)”) and variants thereof consisting of No. 359 (based on rat) were used in the experiment. All peptides were purchased from Peptron Co., Ltd. (Daejeon, Korea), and the synthesis was performed through the synthesis of solid-phase peptides by the Fmoc chemistry method. Specifically, each amino acid was synthesized using an automatic synthesizer by synthesizing each amino acid one by one in resin according to a predetermined sequence, and the synthesized crude peptide was purified using reverse phase HPLC and dried with a freeze dryer. Used. The molecular weight of Cacb1 (344-359) is 1879 Da, and it has a relatively well soluble water solubility in water (solubility in water 10 mg/ml), so it was dissolved in 0.9% NaCl (physiological saline, Saline) and used in the experiment.

The amino acid sequences of all the peptides used in the present invention are shown in Table 1 below.

*Cacb1(344-359) I344V/T347S (SEQ ID NO: 5) is the same as the amino acid sequence of the existing Cacb2(392-407) [protein ID Q8VGC3.2(rat)]. #Cacb1(344-359) I344V/I346V/T347S (SEQ ID NO: 7) is the same as the amino acid sequence of the existing Cacb4(333-348) [protein ID D4A055.2(rat)]. $Cacb1(344-359) I344V/I346V/T347S/K357R (SEQ ID NO: 8) is the same as the amino acid sequence of the existing Cacb3(292-307) [protein ID P54287.1(rat)].

In addition, the peptide sequence derived from human Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1, calcium channel β1 subunit) (protein ID: AAB58781.1 (human)) corresponding to the rat reference amino acid sequence of Table 1 It is shown in Table 2 below.

* SEQ ID NO: 25 is the same as the amino acid sequence of Cacb1 (344-359) (SEQ ID NO: 1); SEQ ID NO: 26 is the same as the amino acid sequence of Cacb1(344-359)I344V/T347S (SEQ ID NO: 5); SEQ ID NO: 27 is the same as the amino acid sequence of Cacb1 (344-359) I344V/I346V/T347S/K357R (SEQ ID NO: 8); SEQ ID NO: 28 is identical to the amino acid sequence of Cacb1 (344-359) I344V/I346V/T347S (SEQ ID NO: 7).

실시예 2. 랫트 동물모델의 대퇴동맥 및 정맥 카테터 삽입술Example 2. Femoral artery and venous catheterization of rat animal model

All experiments were conducted with the approval of the Laboratory Animal Ethics Committee of Kyungpook National University. As experimental animals, male and female rats (Sprague-Dawley rats) of about 330 to 430 g were used, and a catheter was inserted into the femoral artery and vein to measure arterial blood pressure and inject the peptide solution according to the present invention. .

First, the rat is anesthetized by supplying isoflurane (2%) with oxygen (1~1.5%), intraperitoneal urethane (1g/kg) injection and isoflurane (0.8~) through a laryngeal mask. 1%) to maintain anesthesia by injection. In order to expose the femoral nervous system bundle, the femoral skin was incised, and the femoral sheath was removed by incision along the long axis between the femoral artery and vein. Thereafter, the femoral artery was pulled in the lateral direction and the femoral vein was pulled inward, and two silk sutures (4-0 silk) were inserted under the artery located just below the femoral heart artery (arteria profunda femoris), one loosely ligated. Then, pulled toward the body, the other was firmly ligated toward the leg at the furthest point possible. Similarly, two silk sutures (4-0 silk) were inserted under the vein located under the vena profunda femoris, and the silk threads were loosely ligated for subsequent proximal and distal ligation. Then, a microincision was made at about 2 mm in the distal ligation site of each femoral artery or femoral vein, and a catheter (PE50 tube) prefilled with a saline solution containing 300 U/L heparin was inserted with a 1 mL syringe. When the catheter was initially inserted, the proximal ligation was loosened and the catheter was completely inserted (>1cm), and then the proximal ligation was completed with a triple knot around the artery and catheter or around the vein and catheter to fix the catheter to the blood vessel. The blood inside the inserted catheter was checked, and the heparin-treated saline solution was flushed to confirm catheter patency.

실시예 3. 실험 동물에서 동맥 혈압의 측정Example 3. Measurement of arterial blood pressure in experimental animals

The catheter, inserted through the femoral artery, was connected to the PowerLab Data acquisition system (ADInstruments, Dunedin, Zew Zealand) and connected to a pressure transducer placed flush with the rat's heart. Arterial blood pressure was analyzed by LabChart (version 7, ADInstruments). The systolic pressure was identified as a peak, and the diastolic pressure was identified as a valley between the maximum and maximum, and the mean arterial pressure was 1/ of the difference between the systolic blood pressure and the diastolic blood pressure. It was calculated by adding 3. Heart rate was determined as the number of cycles per minute. In the figure, the blood pressure change amount (Δ) was calculated by subtracting the blood pressure after injection from the blood pressure before injection of the peptide solution. Statistical analysis was performed by Student T-test (*p <0.05, **p <0.01), and analysis values were expressed as mean±standard error (SEM). The results are shown in Table 3 below.

실험예 1. Cacb1 유래 펩타이드의 혈압 하강효과 확인Experimental Example 1. Confirmation of blood pressure lowering effect of Cacb1 derived peptide

In order to select a peptide candidate that induces a decrease in blood pressure when administered to an animal model, the blood pressure lowering effect of two peptides having a length of 9 or 16 amino acids derived from Cacb1 protein was confirmed.

1-1. Cacb1(344-359) 펩타이드의 혈압 하강효과 확인1-1. Confirmation of blood pressure lowering effect of Cacb1(344-359) peptide

The result of dissolving Cacb1 (344-359) peptide (IKITSPKVLQRLIKSR, SEQ ID NO: 1) prepared in Example 1 in 0.9% NaCl and injecting it into the femoral vein of an adult rat is shown in FIG. 1. As shown in Fig. 1A, it was confirmed that the systolic blood pressure and diastolic blood pressure recorded from the femoral artery were significantly reduced at a dose of 0.15 mg/kg or more. In addition, as shown in B of FIG. 1, when the dose was treated with 1 mg/kg, it was confirmed that a larger and more sustained blood pressure lowering effect appeared, and as shown in FIG. 1C, blood pressure changes were analyzed in seconds. As a result, it was confirmed that systolic and diastolic blood pressure decreased (2, about 60/30 mmHg) after administration than before (1, about 130/90 mmHg) before administration of Cacb (344-359) peptide, and then recovered (3, about 130 mmHg). /90 mmHg).

1-2. Cacb(389-397) 펩타이드의 혈압 하강효과 확인1-2. Confirmation of blood pressure lowering effect of Cacb(389-397) peptide

The result of dissolving the peptide LDENQLEDA (hereinafter referred to as “Cacb1(389-397)”) (SEQ ID NO: 9) consisting of amino acid sequences 389 to 397 (rat based) derived from the same Cacb1 protein in physiological saline and administering it to the femoral vein Is shown in Figure 2. As shown in Fig. 2, it was confirmed that the Cacb(389-397) peptide did not affect blood pressure at the dose of 0.5 mg/kg.

Through the above results, it was confirmed that among the peptides derived from Cacb1, in particular, the blood pressure decreased depending on the administration of the Cacb1 (344-359) peptide, and the blood pressure lowering effect of the variant of the Cacb1 (344-359) peptide was confirmed in subsequent experiments. I wanted to.

실험예 2. 본 발명에 따른 Cacb1 펩타이드의 변이체의 혈압 하강효과 확인Experimental Example 2. Checking the blood pressure lowering effect of the variant of Cacb1 peptide according to the present invention 2-1. Cacb1(344-359)I344V, Cacb1(344-359)I344V/K357R, Cacb1(344-359)K357R의 효과 분석2-1. Analysis of the effects of Cacb1(344-359)I344V, Cacb1(344-359)I344V/K357R, and Cacb1(344-359)K357R

VKITSPKVLQRLIKSR (hereinafter referred to as “Cacb1(344-359)I344V) in which isoleucine (I), amino acid 344 was substituted with valine, V in the Cacb1 (344-359) peptide whose blood pressure lowering effect was confirmed in Experimental Example 1 ”) (SEQ ID NO: 2), a peptide VKITSPKVLQRLIRSR (hereinafter “Cacb1(344-359)I344V/K357R”) in which lysine (K), which is amino acid 357, is substituted with arginine (R)) ( SEQ ID NO: 3), the blood pressure lowering effect of peptide IKITSPKVLQRLIRSR (“Cacb1(344-359)K357R”) (SEQ ID NO: 4) in which only amino acid lysine (K) at amino acid 357 was substituted with arginine (R) was confirmed, and the results are shown. It is shown in 3 and 4. In particular, an experiment of injecting intramuscular injections other than intravenous injection was additionally performed and the results were confirmed.

3A and 3B, Cacb1(344-359)I344V, Cacb1(344-359)I344V/K357R were dissolved in physiological saline and administered to the femoral vein at a dose of 0.3 to 0.5 mg/kg or more. It was confirmed that it had a blood pressure lowering effect.

As shown in Fig. 4A, it was confirmed that Cacb1(344-359)K357R also showed a remarkable blood pressure lowering effect. In particular, it was confirmed that Cacb1(344-359)K357R showed a drop in arterial blood pressure at a dose of 1.8 mg/kg even when injected into the femoral muscle of a rat (Intramuscular injection) (FIG. 4B).

The experimental results up to Experimental Example 1, Experimental Example 2, and 2-1 are summarized in FIG. 5. As shown in Fig. 5A and B, it was confirmed that Cacb1 (344-359) excluding the Cacb (389-397) peptide and its mutant peptides exhibited a significant blood pressure lowering effect, and as shown in Fig. 5C, 0.5 As a result of measuring hemodynamic indicators when administered at a dose of mg/k, significant differences between Cacb1 (389-397) peptide and Cacb1 (344-359) and its mutant peptides were found in systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Confirmed.

2-2. Cacb1(344-359)I344V/T347S, Cacb1(344-357)I344V/T347S/K357R의 효과 분석2-2. Analysis of the effects of Cacb1(344-359)I344V/T347S, Cacb1(344-357)I344V/T347S/K357R

The peptide VKISSPKVLQRLIKSR in which isoleucine (I) at No. 344 was substituted with valine (V) and threonine at No. 347 (Threonine, T) was substituted with Serine (S) in the Cacb1 (344-359) peptide whose blood pressure lowering effect was confirmed in Experimental Example 1 (“Cacb1(344-359)I344V/T347S” or “Cacb2(392-407)”) (SEQ ID NO: 5) and a peptide VKISSPKVLQRLIRSR (“Cacb1()) in which the 357 th lysine (K) is substituted with arginine (R). The blood pressure lowering effect of 344-357)I344V/T347S/K357R" or "Cacb2(392-407)K405R) (SEQ ID NO: 6) was confirmed, and the results are shown in FIG. 6.

As shown in Fig. 6A, when the Cacb1(344-359)I344V/T347S (or Cacb2(392-407)) peptide is administered into the femoral vein of an animal model, a change in arterial blood pressure at a dose of 0.5 mg/kg Although not given, it was confirmed that the administration of 0.77 mg/kg caused a significant decrease in blood pressure. In the case of the Cacb1(344-357)I344V/T347S/K357R peptide, it was confirmed that a significant blood pressure lowering effect was exhibited even at a dose of 0.5 mg/kg, as shown in FIG. 6B.

2-3. Cacb1(344-357)I344V/I346V/T347S, Cacb1(344-357)I344V/I346V/T347S/K357R의 효과 분석2-3. Analysis of the effects of Cacb1(344-357)I344V/I346V/T347S, Cacb1(344-357)I344V/I346V/T347S/K357R

In the Cacb1 (344-359) peptide, the blood pressure lowering effect was confirmed in Experimental Example 1, isoleucine (I) at No. 344 and No. 346 with valine (V), and threonine at No. 347 (Threonine, T) with serine (S) Peptide VKVSSPKVLQRLIKSR (“Cacb1(344-357)I344V/I346V/T347S” or “cacb4(333-348)”) (SEQ ID NO: 7) and a peptide in which the 357th lysine (K) is substituted with arginine (R) The blood pressure lowering effect of VKVSSPKVLQRLIRSR (“Cacb1(344-357)I344V/I346V/T347S/K357R” or “Cacb3(292-307)”) (SEQ ID NO: 8) was confirmed, and the results are shown in FIG. 7.

As shown in FIG. 7, it was confirmed that both Cacb1(344-359)I344V/T347S and Cacb1(344-357)I344V/I346V/T347S/K357R showed a significant blood pressure lowering effect when administered into the femoral vein of an animal model.

Through the above results, it was confirmed that the Cacb1 peptide and variants thereof according to the present invention prepared in Example 1, except for Cacb1 (389-397), can exhibit a distinct blood pressure lowering effect. This is summarized in Figure 8.

실험예 3. Cacb1(389-397)에 TAT 서열을 연결한 펩타이드의 혈압 하강효과 확인Experimental Example 3. Checking the blood pressure lowering effect of the peptide connecting the TAT sequence to Cacb1 (389-397)

A cell-permeable peptide TAT sequence (YGRKKRRQRRR) (SEQ ID NO: 10) was added to the amino acid sequence of the Cacb1 (389-397) peptide, which was confirmed to have no blood pressure lowering effect in Experimental Example 1-2 (hereinafter, “TAT-Cacb ( 389-397)) (SEQ ID NO: 19), and the blood pressure lowering effect of the YGRKKRRQRRR-LDENQLEDA peptide was confirmed. The results are shown in FIG. 9.

As shown in FIG. 9, as a result of administering TAT-Cacb (389-397) into the femoral vein of an animal model, it was found that unlike the case where Cacb (389-397) was administered alone, it showed a remarkable blood pressure lowering effect in a concentration-dependent manner. Confirmed.

실험예 4. Cacb1(344-359)K357R에 팔미트산(palmitic acid)을 추가한 펩타이드의 혈압 하강효과 및 지속 시간 확인Experimental Example 4. Confirmation of blood pressure lowering effect and duration of peptides with palmitic acid added to Cacb1(344-359)K357R

In Experimental Example 2-1, palmitic acid was bound to the lysine located at the second of the amino acid sequence of Cacb1 (344-359) K357R peptide, which was confirmed to have the blood pressure lowering effect (hereinafter referred to as “K2-palm”) (SEQ ID NO: 20) Alternatively, palmitic acid was bound to the seventh lysine (hereinafter, referred to as “K7-palm”) (SEQ ID NO: 21), and the blood pressure lowering effect and duration of the peptides were confirmed. The effect was compared with Cacb1 (344-359)K357R (0.5mg/kg) and the results are shown in FIG. 10.

As shown in FIG. 10, when K2-palm was administered into the femoral vein of an animal model, a significant blood pressure lowering effect was induced at a dose of 1 mg/kg, and it was confirmed that the effect lasted for 2 hours or more. In addition, when K7-palm was administered at a dose of 2 mg/kg, a blood pressure lowering effect similar to that of K357R was obtained, and it was confirmed that the effect lasted for 1 hour or more. These results show that the addition of palmitic acid can increase the duration of the blood pressure lowering effect.

실험예 5. Cacb1(344-359)K357R에 EYEKEYE 펩타이드를 융합한 펩타이드의 혈압 하강 효과 및 지속 시간 확인Experimental Example 5. Confirmation of blood pressure lowering effect and duration of peptide fused with EYEKEYE peptide to Cacb1(344-359)K357R

In Experimental Example 2-1, the EYEKEYE sequence (SEQ ID NO: 24), which is a half-life extending peptide, was added to the amino acid sequence of the Cacb1 (344-359)K357R peptide, which confirmed the blood pressure lowering effect (hereinafter, "Cacb1 (244-259)K357R-EYEKEYE" (SEQ ID NO: 22) or EYEK (pamitoyl)EYE sequence, a half-life extension peptide bound to a fatty acid (hereinafter referred to as “K20-palm”) (SEQ ID NO: 23), and the effect and duration of the blood pressure lowering of the peptides Was confirmed.

As shown in FIG. 11, when Cacb1(344-359)K357R-EYEKEYE was administered into the femoral vein of an animal model, a blood pressure lowering effect similar to that of K357R was observed at a dose of 2 mg/kg. In addition, when K20-palm was administered into the femoral vein of an animal model, a significant blood pressure lowering effect was induced at a dose of 2 mg/kg, and it was confirmed that the effect lasted 1 to 2 hours. These results show that the duration of the blood pressure lowering effect can be increased by the addition of a fatty acid-conjugated half-life extending peptide.

Through the above results, the Cacb1 peptide and the variant of the Cacb1 peptide according to the present invention have excellent blood pressure lowering effect, and have a bio-friendly and high specificity due to the nature of the peptide, showing excellent pharmacological effects while having fewer side effects compared to other hypertension treatments. It was confirmed that it can be usefully used in the development of a new hypertension treatment. In addition, it is expected to be used as a therapeutic agent for diseases that can be treated or ameliorated by vasodilation such as angina pectoris, prostatic hyperplasia, and erectile dysfunction due to its potential vasodilation or dilation effect.

Although the present invention has been described as the above-mentioned preferred embodiment, it is possible to make various modifications or variations without departing from the gist and scope of the invention. In addition, the appended claims include such modifications or variations that fall within the gist of the present invention.

Claims

a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1-derived peptide; and a cell-permeable peptide or a half-life extending peptide; a pharmaceutical composition for preventing or treating hypertension comprising a fusion peptide.
The method of claim 1, wherein the Cacb1-derived peptide in steps a) and b) is a peptide consisting of an amino acid sequence represented by any one selected from the group consisting of SEQ ID NOs: 1 to 8, or a fatty acid-peptide complex in which a fatty acid is bonded thereto. , A pharmaceutical composition for preventing or treating hypertension.
The method of claim 2, wherein the fatty acid of the fatty acid-peptide complex is Myristic acid, Stearic acid, Linoleic acid, Palmitic acid, and Oleic acid. ) And lauric acid (Lauric acid) is one or more selected from the group consisting of, a pharmaceutical composition for preventing or treating hypertension.
The method of claim 2, wherein the fatty acid-peptide complex is any one selected from the group consisting of SEQ ID NOs: 20 and 21, a pharmaceutical composition for preventing or treating hypertension.
The pharmaceutical for preventing or treating hypertension according to claim 1, wherein the fusion peptide in step b) is a peptide in which any one Cacb1 derived peptide selected from the group consisting of SEQ ID NOs: 1 to 9 and a cell-permeable peptide are fused. Ever composition.
The pharmaceutical composition for preventing or treating hypertension according to claim 5, wherein the cell-permeable peptide is represented by the amino acid sequence of SEQ ID NO: 10.
The pharmaceutical composition for preventing or treating hypertension according to claim 1, wherein the half-life extending peptide is a peptide consisting of an amino acid sequence represented by SEQ ID NO: 24 or a peptide having a fatty acid bonded thereto.
The method of claim 7, wherein the fatty acid bound to the half-life extending peptide is Myristic acid, Stearic acid, Linoleic acid, Palmitic acid, and Oleic acid. acid) and lauric acid (Lauric acid) at least one selected from the group consisting of, a pharmaceutical composition for preventing or treating hypertension.
The method of claim 7, wherein the fatty acid-bound peptide is SEQ ID NO: 23, a pharmaceutical composition for preventing or treating hypertension.
The pharmaceutical composition for preventing or treating hypertension according to claim 1, wherein the fusion peptide is represented by any one amino acid sequence selected from the group consisting of SEQ ID NOs: 11 to 19 and SEQ ID NO: 22.
a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1 derived peptide; and a cell-permeable peptide or a half-life extending peptide; a composition for relaxation of blood vessels comprising a fusion peptide.
The method of claim 11, wherein the Cacb1-derived peptide in steps a) and b) is a peptide consisting of an amino acid sequence represented by any one selected from the group consisting of SEQ ID NOs: 1 to 8, or a fatty acid-peptide complex in which a fatty acid is bonded thereto. , A composition for relaxing blood vessels.
a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1-derived peptide; and a cell-permeable peptide or a half-life extending peptide; a food composition for preventing or improving hypertension comprising a fusion peptide.
The method of claim 13, wherein the Cacb1-derived peptide in steps a) and b) is a peptide consisting of an amino acid sequence represented by any one selected from the group consisting of SEQ ID NOs: 1 to 8, or a fatty acid-peptide complex in which a fatty acid is bound thereto. , Food composition for preventing or improving hypertension.
a) Cacb1 (Voltage-dependent L-type calcium channel subunit beta-1) derived peptide; or

b) Cacb1-derived peptide; and a cell-permeable peptide or a half-life extending peptide; a method for preventing or treating hypertension comprising administering a fusion peptide to an individual.
The method of claim 15, wherein the Cacb1-derived peptide in steps a) and b) is a peptide consisting of an amino acid sequence represented by any one selected from the group consisting of SEQ ID NOs: 1 to 8, or a fatty acid-peptide complex in which a fatty acid is bound thereto. , Hypertension prevention or treatment method.