CN104817622A

CN104817622A - Oligopeptide CD04, and preparation method and application thereof

Info

Publication number: CN104817622A
Application number: CN201410044222.3A
Authority: CN
Inventors: 陈光健
Original assignee: Individual
Current assignee: Individual
Priority date: 2014-01-30
Filing date: 2014-01-30
Publication date: 2015-08-05

Abstract

The invention discloses a small molecule oligopeptide and a preparation method thereof, specifically an oligopeptide CD04, and a preparation method and application thereof. The invention discloses the amino acid sequence of the oligopeptide as shown in SEQ ID: 1; the oligopeptide CD04 can be prepared by adopting methods like synthesis, extraction or genetic engineering; and the oligopeptide CD04 of the invention is applied in preparation of drugs having good therapeutic effects in anti-inflammation, analgesia, wound repair and immunity improvement.

Description

Oligopeptides CD04 and its preparation method and application

Technical field

The invention belongs to protein field, particularly oligopeptides and application thereof.

Background technology

Oligopeptides is the one classification of polypeptide, and molecular weight section, generally below 1000 dalton, also referred to as little peptide, is generally made up of 2--6 amino acid.

Inflammation is the defensive raction that the biological tissue with vascular system occurs damage factor.Be called inflammatory reaction to the reaction that the local organization of the damage of body presents, the inflammatory development later stage can produce transudate, and the compressing of exudate and the effect of inflammatory mediator can cause patient pain.The clinical application medicine of present anti-inflammatory is mainly chemical synthetic drug, as nabumetone, indomethacin, piroxicam, Ibuprofen BP/EP etc., although these chemicals antiphlogistic effects are obvious, but can not effect a permanent cure, can not eliminate and cause scorching fundamental cause, mostly there is more serious untoward reaction, cause suffering to patient and lose.

Wound repair, the surface of a wound to be normal skin (tissue) in the external world the cause injury factor as surgical operation, external force, heat, electric current, chemical substance, low temperature and body internal factor as under the effects such as local blood supply obstacle the infringement that causes.Normal with the destruction of skin integrity and the loss of a certain amount of healthy tissues, meanwhile, the normal function of skin is impaired.Also referred to as wound or wound.Wound repair is wound repair both.

Gastrointestinal ulcer, stomach ulcer, duodenal ulcer are referred to as Gastrointestinal ulcer.Because rhythm of life is accelerated, operating pressure strengthens, and the sickness rate of Gastrointestinal ulcer not only has no decline in recent years, anti-on the rise.The symptom of this disease also becomes and is not true to type during the nearly last ten years, and irregular stomach secret anguish does not often cause the attention of people, until generation spitting blood or melena time side go to see a doctor.Peptide ulceration mainly refers to occur in stomach and duodenal chronic ulcer, also can betide Meike that (MECKEL) diverticulum around distal esophagus, stomach intestinal anastomosis mouth and containing ectopic gastric mucosa.The formation of these ulcer is relevant with pepsic digestion with hydrochloric acid in gastric juice, therefore claims peptide ulceration.Research in recent years finds that the formation of ulcer is relevant with the existence that deep and remote door spiral shell revolves Rod bacterium (HP).This disease most (more than 95%) is positioned at stomach and duodenum, therefore also known as gastro-duodenal ulcer.The total incidence of this disease accounts for the 5-10% of population, and duodenal ulcer is common compared with stomach ulcer, multiple with person between twenty and fifty, and man is more than female, and children also can fall ill, and gerontal patient's proportion also increases year by year to some extent.Because recurrence rate is very high, bring misery to patient.

Immunizing power is the defense mechanism of human body self, is human bioequivalence and any foreign matter (virus, bacterium etc.) eliminating external intrusion; Process is old and feeble, damage, the ability of mutant cell and virus infected cell in the own cells of dead, sex change and identification and handling body.Immunology Today is thought, immunizing power is the physiological response of human bioequivalence and eliminating " dissident ".Old personnel due to self immune system more weak, so need the recognition capability improving cell.Hypoimmunity to cause human body to be easily subject to extraneous infection, function reduction.

Summary of the invention

Multi-angle the human body surface of a wound and relieving inflammation and relaxing pain can be protected in order to find one; improve the medicine that human body exempts from function simultaneously; contriver is by a large amount of synthetic test; screen widely; the amino acid of Fmoc protection is adopted to synthesize; obtain a large amount of oligopeptides molecule, wherein part oligopeptides molecule obtains beyond thought technique effect.Be surprised to find that the good oligopeptides CD04 of result for the treatment of, it is made up of Y, E, H3 amino-acid residue, and molecular weight is 447.45Da, and its aminoacid sequence is as shown in SEQ ID:1.

The preparation method of above-mentioned oligopeptides can use synthesis, and extraction purification from organism also can be adopted to obtain.The preparation method of oligopeptides, is characterized in that comprising following step:

A. synthesis order is for hold N to hold from C; Peptide synthesizer reactor put into by the resin getting 1 times of molar equivalent, add DCM (methylene dichloride) swelling half an hour, then DCM is taken out, add the amino acid/11 0mmol of first Fmoc protection in sequence, the DIEA (diisopropylethylamine) of 2 times of molar equivalents, appropriate DMF (dimethyl formamide), DCM solution (refer in right amount be advisable so that resin can be made fully to agitate), react 60min with nitrogen bubble; Then add about 5 times of molar equivalent methyl alcohol, react half an hour, take out reaction solution, with DMF, methanol cleaning;

B. add appropriate piperidines and remove Fmoc(9-fluorenylmethyloxycarbonyl) protecting group, clean, triketohydrindene hydrate detects;

C. in reactor, second amino acid (being also 2 times of molar equivalents) in sequence is added, 2 times of molar equivalent HBTU(benzotriazole-N, N, N'; N'-tetramethyl-urea hexafluorophosphate) and DIEA, nitrogen bubble reacts half an hour, takes out liquid; with DMF, methanol cleaning, triketohydrindene hydrate detects;

D. the mode repeated according to step b, c adds amino acid in sequence successively, takes out liquid, cleans with DMF, and triketohydrindene hydrate detects;

E. after resin nitrogen being dried up, take off from reaction column and take weight, pouring in flask, then in flask, adding a certain amount of 95%TFA(trifluoroacetic acid) cutting liquid, concussion reaction 2h, object is got off from cracking resin carrier by polypeptide and removes amino acid whose side chain protected group;

F. filter resin, obtain filtrate, then in filtrate, add a large amount of ether, separate out crude product, then centrifugal, cleaning can obtain the crude product of this sequence;

G. analyze and purify and mass spectrometric detection: use ESI(electron spray ionisation) ion-source mass spectrometer and sequenator detect the exactness of this sequence, and with high performance liquid chromatography crude product purified to and require purity;

H. the target oligopeptide solution that collection purifying is good is put into Freeze Drying Equipment and is concentrated, and is lyophilized into white powder.

Oligopeptides provided by the invention can be used as the integral part of bread and cheese, healthcare products or medicine.The present invention also provides a kind of composition of oligopeptides, wherein containing pharmacy acceptable carrier.Composition can exist with pharmaceutical dosage forms, preferably injection, more preferably freeze drying injection, this pharmaceutical dosage forms pharmaceutical composition, can prepare according to technology of pharmaceutics routine techniques, comprise active constituents of medicine, oligopeptides of the present invention mixes with pharmaceutical carrier, makes required formulation according to technology of pharmaceutics routine techniques.

Oligopeptides in the present invention, molecular weight is little, synthetic is convenient, purity is very high, production aspect, be applicable to scale operation, in application aspect, these oligopeptides anti-inflammatory pain-stopping effect are obvious, have significant result for the treatment of to surface of a wound damage, burn, scald, digestive tract ulcer; This oligopeptides can improve the effect of animal immune function in addition, and oligopeptides can in antibacterial, the relieving inflammation and relaxing pain of preparation, the antitumor and application that improves in the medicine of immunizing power.

Embodiment

Being below combine specifically to test explanation of the present invention, is not limiting the scope of the invention.The preparation method of oligopeptides in embodiment 1 the present invention

Raw material: resin (Wang Resin), the amino acid of Fmoc protection,

Reagent: N, N-dimethylformamide (DMF), DCM, MEOH, diacetyl oxide, pyridine, DIEA, HBTU, hexahydropyridine

Instrument: 12 passage semi-automatic polypeptide synthesizers, high performance liquid chromatography (HPLC), model: Waters2695 detection reagent: phenol reagent, pyridine, ninhydrin reagent

(1) synthesis order is for hold N to hold from C.

(2) Peptide synthesizer reactor put into by the resin getting 10mmol equivalent; add DCM (methylene dichloride) swelling half an hour; then DCM is taken out; add the amino acid/11 0mmol of first Fmoc protection in sequence; the DIEA (diisopropylethylamine) of 20mmol; appropriate DMF (dimethyl formamide), DCM solution (refer in right amount be advisable so that resin can be made fully to agitate), react 60min with nitrogen bubble.Then add about 50mmol equivalents of methanol, react half an hour, take out reaction solution, with DMF, methanol cleaning.

(3) add appropriate piperidines and remove Fmoc(9-fluorenylmethyloxycarbonyl) protecting group, clean, triketohydrindene hydrate detects.

(4) in reactor, second amino acid (being also 20mmol) in sequence is added, 20mmolHBTU(benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate) and DIEA, nitrogen bubble reacts half an hour, takes out liquid, with DMF, methanol cleaning, triketohydrindene hydrate detects.

(5) repeat according to step 3,4 mode add amino acid in sequence successively, take out liquid, with DMF clean, triketohydrindene hydrate detect.

(6) after resin nitrogen being dried up; take off from reaction column and take weight; pour in flask; then in flask, a certain amount of 95%TFA(trifluoroacetic acid is added) cutting liquid; concussion reaction 2h, object is got off from cracking resin carrier by polypeptide and removes amino acid whose side chain protected group.

(7) filter resin, obtain filtrate, then in filtrate, add a large amount of ether, separate out crude product, then centrifugal, cleaning can obtain the crude product of this sequence.

(8) analyze and purify and mass spectrometric detection: use ESI(electron spray ionisation) ion-source mass spectrometer detects the exactness of this acid molecules amount, and with high performance liquid chromatography crude product purified to and require purity.

(9) the target oligopeptide solution that collection purifying is good is put into Freeze Drying Equipment and is concentrated, and is lyophilized into white powder.

Embodiment 2 oligopeptides is on the impact of mice auricle swelling degree, and anti-inflammation detumescence analgesic acts on

Get Kunming mouse, male and female half and half, body weight 25-30g, by sample size random packet: often organize 10.HY01-HY24 (250mg/kg) (2mg/ml), nabumetone (250mg/kg), saline control group (0.1ml/10g) crude extract dosage are all converted as former animal crude drug dosage (lower same).Each group of equal per os gastric infusion, control group per os gavage physiological saline.Each group every day gavage 1 time, continuous 4d, after last gavage 2h, tail vein injection Evan ' s blue50mg/kg, in mouse right ear two-sided painting dimethylbenzene 25ul/ face, after 20h, draw neck to put to death mouse, cut ears along auricle baseline, round auricle is laid at the same position of ears respectively with the punch tool of diameter 7.5mm, scales/electronic balance weighing, obtains weight difference, in order to represent swelling (swelling=left ear auricle weight-auris dextra auricle weight).Calculate swelling inhibition percentage as follows.

Inhibiting rate (%)=(the average swelling of control group-average swelling of administration group) average swelling * 100% of/control group.

Table 1

Group	Swelling (mg)	Inhibiting rate (%)	P value
				CD04	11.41±4.15	42.66	<0.01
Nabumetone group	13.24±2.31	33.47	<0.05
				Physiological saline group	19.90±2.53	--	--

Analysis of experiments: oligopeptides carries out the test of mice caused by dimethylbenzene xylene auricle edema respectively, observes whether it inhibited.The mouse auricle oedema of dimethylbenzene induction is the inflammatory model of acute non-specific, the acute inflammation that causes change comprise vasodilation, capillary permeability increases, oozes out.Viewed from test-results, oligopeptides is respond well to suppressing the acute inflammation of mouse, and result has statistical significance.

Embodiment 3 oligopeptides Dichlorodiphenyl Acetate causes the impact of mouse writhing reaction, analgesic activity

Get Kunming mouse, male and female half and half, body weight 25-30g, random packet, oligopeptides administration group (250mg/kg), control group 5% Asprin Zulkovsky starch solution (250mg/kg), physiological saline group.After administration group and physiological saline group last gavage 2h, abdominal injection 0.6% Glacial acetic acid respectively, observes the writhing number of times that in 15min, each group is caused by acetic acid for each group after giving algogen 0.2ml, all more than 15min not writhing person treat by without writhing response.

Table 2

Result shows, oligopeptides group effectively can alleviate mouse acetic acid abdominal cavity pain reaction.

Embodiment 4 oligopeptides is to the test of skin burn

1, experiment material

1.1 samples: obtain sample by embodiment 1: CD04.

1.2 laboratory animal: 18-22g KM mouse, 320, male and female half and half.

1.3 experiment reagents: sodium chloride injection, moist expose burn ointment (Shantou Mebo Pharmaceuticals Co., Ltd.).

2, skin wound repairing effect evaluation method

2.1 impacts that mouse experiment is scalded

160 KM mouse are divided into 16 groups at random by sex and body weight, 10/group (referring to table 1), during test, right back for mouse sufficient sole of the foot position is placed in and is adjusted to 55 DEG C of waters bath with thermostatic control 15 seconds in advance, after this mouse is respectively organized respectively at right sufficient sole of the foot portion coating 1 time every half an hour, administration 3 times altogether, takes off cervical vertebra and puts to death, cut two sufficient sole of the foot portions in same position by mouse after 4.5 hours, weigh with precision torsion balance, deduct left lumping weight amount for swelling with the right lumping weight of every mouse and calculate inhibitory rate of intumesce.

2.2 impacts that mouse experiment is burnt

Asbestos paper centre being hollowed out 2cm × 2cm is placed in mouse back, and draw 100uL dehydrated alcohol with micropipet and drip on 20mg cotton balls, be placed in exposure place, ignition causes II degree of bum model.By sex and burn surface area random packet, 10/group.Each group of difference coating, is coated with 15d continuously, Bid, takes pictures after last administration with digital camera, measure each treated animal burn surface area with IPP5.1 image analysis software bag.

3, skin wound repairing effect evaluation result

The impact that 3.1 samples are scalded mouse experiment

The impact that table 3 sample is scalded mouse experiment

Note: *: P<0.05 compares with control group

Result shows, and CD04 scalds to hot water the swelling causing the mouse foot sole of the foot reduction in various degree, and more all have notable difference (P<0.05) with control group, prompting CD04 has better protecting effect to scald.

The impact that 3.2 samples are burnt on mouse experiment

The impact (x ± SD) that table 4 sample is burnt on mouse experiment

Note: compare * P<0.05 with model group

Result shows, and compares, administration 15 days with control group, and the surface of a wound incrustation area of CD04 group mouse all obviously reduces (P<0.05).

3.3 functional evaluation results are shown by above-mentioned experimental result: CD04 all has repair to skin wound caused by burn and scald.

Embodiment 5 oligopeptides is to the therapeutic action of stomach ulcer

1, experiment material

1.1 samples: obtain sample by embodiment 1: CD04.

1.2 laboratory animal: KM mouse, 18 ~ 22g, 160, male and female half and half.SD rat, 200 ~ 220g, 204, male and female half and half.

1.3 experiment reagents: ranitidine hydrochloride capsules, reach happiness (hydrotalcite tablet).

2, sample is to the defencive function evaluation method of stomach ulcer mucous membrane

2.1 dehydrated alcohols cause the test of Mouse Gastric Mucous Membrane damage model

160 KM mouse are by sex and body weight random packet, 10/group (referring to table 5), each group gives corresponding medicine, continuous 8 days, fasting 24h after administration in 7th day, freely drink water, 1h after last administration, all animals equal ig dehydrated alcohol 0.2ml/ only, animal is put to death after 1 hour, ligation pylorus, 1% formaldehyde is fixed, observe and evaluate ulcer index (standard: the length of streak damage is greater than 1mm person, measure its length, count 1 point for every millimeter, its width is greater than 1mm person's score to be doubled, length and width are all less than 1mm, count 0.5 point, score is added the ulcer index being this mouse) and calculate ulcer inhibition percentage.

2.2 acetic acid cause the test of rat chronic gastric ulcer model

Except sham operated rats (12), all the other rats

10% acetic acid is adopted to sting 0.4-0.5mm modeling under stomach serous coat by 0.05ml/ is only flat.Postoperative modeling rat divides into groups (referring to table 6) further, and starts administration on 2nd, every day 1 time, administration 14 days, and after doomsday administration, fasting taboo water one puts to death animal after night.The maximum major diameter of ulcer and the maximum wide footpath perpendicular to maximum major diameter is measured with vernier callipers.Calculate ulcer index (the maximum major diameter of ulcer index=ulcer × perpendicular to the maximum wide footpath of maximum major diameter) and ulcer inhibition rate.

3, sample is to the defencive function evaluation result of stomach ulcer mucous membrane

3.1 samples cause the impact of Mouse Gastric Mucous Membrane damage to dehydrated alcohol

Table 5 sample causes the impact of Mouse Gastric Mucous Membrane damage to dehydrated alcohol

Note: *: P<0.05 compares with control group

Result shows, and compares with control group, and the ulcer index that CD04 can make dehydrated alcohol cause Mouse Gastric Mucous Membrane damage obviously reduces (P<0.05), and prompting CD04 causes gastric mucosa injury to dehydrated alcohol better protecting effect.

3.2 samples cause the impact of rat chronic gastric ulcer model to acetic acid

Table 6 sample causes the impact of rat chronic gastric ulcer model to acetic acid

Note: compare * P<0.05 with model group

Shown by upper table, ulcer index and the sham operated rats of model group are variant (P < 0.05); The ulcer index of CD04 compares with model group have clear improvement (P < 0.05).

3.3 functional evaluation results are shown by above-mentioned experimental result: the mucous membrane of CD04 to acute and chronic stomach ulcer has repair.

Embodiment 6 oligopeptides improves the immunity function of body

1, experiment material

Sample: by the sample that embodiment 1 is obtained.

Laboratory animal: quality is the male BALB/C mice of 18 ~ 22g SPF level, and male, random packet is tested.

Experimental technique: flown by mouse to be divided into normal group, model group, positive group and sample CD04 dosage group at random, often organizes 10.Sample is made into 0.5mg/ml by after test solution to mouse stomach, normal group and model group give normal saline, and positive group gives Radix Astragali essenc by 20mL/kg, every day ig once, continuous 14 days.In administration the 1st, 2,3,8,9,10, except normal group, all the other respectively organize ip in mice 50mL/kg cAMP, totally 6 times, induction of immunity hypofunction model.

2, immunity function evaluation method is improved

Hypoimmunity mice Immune Organs Index by experiment: thymus index, spleen index, liver exponential sum phagocytic index, engulf coefficient, with hemolysin level in spectrophotometry mice serum.

3, strengthening immunity functional evaluation result

3.1 impacts on hypoimmunity mice Immune Organs Index

Table 7 is on the impact of hypoimmunity mice Immune Organs Index

Note * to represent that compared with normal group P < 0.05, # represents and compares P < 0.05 with model group

As shown in Table 7, sample CD04 thymus index, spleen index and liver index, higher than model group, have statistics (P < 0.05).

3.2 on hypoimmunity mice phagocytic index and the impact of engulfing coefficient

Table 8 is on hypoimmunity mice phagocytic index and the impact of engulfing coefficient

As shown in Table 8, sample CD04 phagocytic index and engulf coefficient higher than model group, has statistics (P < 0.05).

3.3 impacts on Hemolysin formation in hypoimmunity mice delayed type hypersensitivity and serum

The impact that table 9 generates hypoimmunity mice delayed type hypersensitivity and serum hemolysin

As shown in Table 9, in sample CD04 mice serum, hemolysin level is higher than model group, has statistical significance.（P＜0.05）。Above-mentioned experiment shows that this oligopeptides can improve the crowd of hypoimmunity.

Embodiment 8 improves aged mouse immunity function

1, experiment material

Sample: by the sample that embodiment 1 is obtained.

Laboratory animal: SPF level 80 weeks ICR male mices, SPF level ICR male mice in 6 week age 10, grouping is tested.

Experimental technique: rat mouse in 80 week age is divided at random model group, positive group and sample CD04-CD14 dosage group, is made into).0.5mg/ml often organizes 10, totally 16 groups; And the normal mouse group in 6 week age is synchronously set, often organize 10.Give mouse stomach by sample preparation one-tenth by after test solution, normal group and model group give normal saline, and positive group gives Radix Astragali essenc by 20mL/kg, successive administration 30 days.

2, immunity function evaluation method is improved

Hypoimmunity mice Immune Organs Index by experiment: thymus index, spleen index, liver exponential sum phagocytic index, engulf coefficient, by the ability of MDA, SOD and total antioxidation in hemolysin level, cerebral tissue in spectrophotometry mice serum.

2, strengthening immunity functional evaluation result

2.1 impacts on aged mouse organ index

The impact of the aged mouse organ index of table 10

As shown in Table 10, sample CD04 thymus index, spleen index and liver index, higher than model group, have statistics (P < 0.05).

2.2 on aged mouse phagocytic index and the impact of engulfing coefficient

Table 11 is on aged mouse phagocytic index and the impact of engulfing coefficient

As shown in Table 11, sample CD04 phagocytic index and engulf coefficient higher than model group, has statistics (P < 0.05).

2.3 impacts on Hemolysin formation in aged mouse delayed type hypersensitivity and serum

The impact that table 12 generates aged mouse delayed type hypersensitivity and serum hemolysin

As shown in Table 12, in sample CD04 mice serum, hemolysin level is higher than model group, has statistical significance.（P＜0.05）。

2.4 impacts on Aging marker in aged murine brain

The impact of Aging marker in the aged murine brain of table 13

As shown in Table 13, sample CD04MDA is lower than model group, SOD and T-AOC, higher than model group, has statistics (P < 0.05).

Above-mentioned test represents that oligopeptides CD04 can well improve the elderly's immunological competence.

Embodiment 9 Toxicological evaluation

(1) sample: by the oligopeptides CD04 that embodiment 1 is obtained.

(2) laboratory animal: cleaning grade Kunming mouse and SD rat

(3) Toxicological evaluation method: acute toxicity test (MTD method), Genetic toxicity and rat are carried out to oligopeptides and feeds experiment in 30 days.Wherein Genetic toxicity comprises Ames experiment, mouse polychromatic erythrocytes micronucleus test and mouse sperm deformity experiment.

(4) Toxicological evaluation result

Acute oral toxicity is tested: the acute oral MTD of SD rat and Kunming mouse is all greater than 20g/kg.bw and belongs to actual non-toxic type.Genetic toxicity Ames tests: mouse polychromatic erythrocytes micronucleus test and mouse sperm deformity are tested 3 Genetic toxicity results and be feminine gender, shows that this product is without mutagenesis and teratogenesis.Rat feeds experiment in 30 days: maximum dose level is 100 times of human body recommended amounts, and this product does not cause the ANOMALOUS VARIATIONS of every important indicator such as rat holistic health biochemical functions and organ-tissue morphology.

Above test card understands that the oligopeptides of this patent can have anti-inflammatory, analgesia, wound repair, treatment stomach ulcer, immunity raising etc. effect.

Described is only the preferred embodiment of the present invention; it should be pointed out that for common skill personnel in the art, under the prerequisite not departing from core technical features of the present invention; can also make some improvement, these improvements and modifications also should be considered as protection scope of the present invention.

Claims

1. an oligopeptides CD04, is characterized in that, be made up of Y, E, H 3 amino-acid residues, molecular weight is 447.45 Da, and its aminoacid sequence is as shown in SEQ ID:1.

2. a preparation method for oligopeptides described in claim 1, is characterized in that comprising following step:

E. after resin nitrogen being dried up, take off from reaction column and take weight, pouring in flask, then in flask, adding a certain amount of 95%TFA(trifluoroacetic acid) cutting liquid, concussion reaction 2 h, object is got off from cracking resin carrier by polypeptide and removes amino acid whose side chain protected group;

G. analyze and purify and mass spectrometric detection: use ESI(electron spray ionisation) ion-source mass spectrometer detects the exactness of this acid molecules amount, and with high performance liquid chromatography crude product purified to and require purity;

3. the application in anti-inflammatory or analgesic prepared by the oligopeptides as described in claim 1.

4. the application in wound repairing medicine prepared by the oligopeptides as described in claim 1.

5. the application of the oligopeptides as described in claim 1 in preparation treatment skin injury medicine.

6. the application of the oligopeptides as described in claim 1 in preparation treatment digestive tract ulcer medicine.

7. the application of the oligopeptides as described in claim 1 in preparation raising immune drug.

8. oligopeptides according to claim 1 can be used as the integral part of bread and cheese, healthcare products or medicine.

9. the composition containing one or more oligopeptides according to claim 1, wherein containing pharmacy acceptable carrier.

10. composition according to claim 9 can exist with pharmaceutical dosage forms, preferably injection, more preferably freeze drying injection, this pharmaceutical dosage forms pharmaceutical composition, can prepare according to technology of pharmaceutics routine techniques, comprise active constituents of medicine, oligopeptides of the present invention mixes with pharmaceutical carrier, makes required formulation according to technology of pharmaceutics routine techniques.