CN104650243A - Novel double-epitope combinatorial peptide and application thereof - Google Patents
Novel double-epitope combinatorial peptide and application thereof Download PDFInfo
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Abstract
The invention provides a novel double-epitope combinatorial peptide capable of regulating blood sugar and regulating fat. B cell antigen epitope analysis software and an on-line analysis tool are used for analyzing a B cell antigen of HMG-CoA reductase of diabetic complication associated protein; an obtained B epitope is connected in series with a T cell epitope IPALDSLTPANED at a C end of a P277 peptide to obtain a novel double-epitope combinatorial peptide H2-P2, namely 23 peptide; the amino acid sequence of the novel double-epitope combinatorial peptide is shown in SEQ ID No.1. By immunizing an STZ induced I-type diabetes C57BL/6J mouse in a subcutaneous injection way, the blood sugar and blood fat of the I-type diabetes mouse can be regulated. Meanwhile, the novel peptide provided by the invention can be also applied to recombinant microorganisms and transgenic animals or transgenic plants, so that the recombinant microorganisms and the transgenic animals or transgenic plants can be used as a production plant for producing the novel peptide or preparing oral vaccines. The novel double-epitope combinatorial peptide can be used for regulating both blood sugar and blood fat and can be used for preventing and treating diabetes, atherosclerosis, hyperlipidemia and cardia-cerebrovascular diseases.
Description
Technical field
The present invention relates to a kind of novel two epi-position combined peptides and uses thereof, especially have and adjust blood sugar new peptides having Regulation serum lipids concurrently and uses thereof, and contain the derivative of this new peptides and main composition fragment thereof and similar pharmaceutical preparation, the present invention relates to pharmacy and medical science association area.
Background technology
Diabetes (Diabetes mellitus, DM) due to Regular Insulin definitely or relative deficiency and cause, with hyperglycemia and multiple complication and the endocrine metabolism disease of to deposit etc. as feature, be one of modal chronic disease.Usually diabetes are divided into two large types, type 1 diabetes (Type 1diabetes mellitus, T1DM) is because the cell of excreting insulin is destroyed a kind of autoimmune disorder caused; Diabetes B (Type 2diabetes mellitus, T2DM) be the Regular Insulin that patient can not effectively utilize self to secrete, and export many metabolic disorder such as too much along with insulin resistant, insulin secretion obstacle and liver starch in pathogenic process.Think that TIDM is the autoimmune disorder of T cell mediation at present, based on heredity, under the effect of some environmental factors (microorganism, chemical substance, food composition), bringing out with insulitis is the B cell autoimmune response of pathological characters, impaired isle β cell makes it lose the function of synthesis and excreting insulin, causes metabolism disorder.
Atherosclerosis (AS) is one of common complication of diabetes, is one group and is called the most common, most important one in arteriosclerotic vascular disease.Feature gets involved the pathology of artery from inner membrance, successively have multiple pathology to merge to exist, comprise that local has that lipid and compound carbohydrate gather, proliferation of fibrous tissue and calcinosis form patch, and having medial regression gradually, secondary arthritis still has patch internal hemorrhage, plaque rupture and local thrombus to be formed.Diabetes atherogenicity can throughout each vitals of whole body, can great vessels be involved, also can involve capillary blood vessel, cause coronary heart disease, cerebrovascular accident, renal arteriosclerosis, diabetic nephropathy, diabetic retinopathy, nervous system lesion, diabetic foot etc., harm is serious.Most of diabetic subject dies from the heart, cerebrovascular arteries is atherosis or diabetic nephropathy.
Hyperlipidemia, namely serum cholesterol, triglyceride level increases, high-density lipoprotein (HDL) reduces, and is the major cause causing cardiovascular and cerebrovascular diseases.Confirm through many experiments research, triglyceride level and total cholesterol rising more remarkable in normal mouse in the type 1 diabetes mice serum obtained with abdominal injection STZ, high-density lipoprotein (HDL) significantly reduces.A large amount of epidemiology surveys and research all show, hyperlipidaemia is the important factor of the various diseases such as atherosclerosis, coronary heart disease, hypertension, diabetes, gallbladdergallstonecholetithiasis, serious harm human health.The pathogenetic mechanism of cardiovascular and cerebrovascular is a lot, and wherein lipid metabolism disorders is one of wherein important cause of disease.Current research shows, triglyceride level, total cholesterol raise and high-density lipoprotein (HDL) declines can promote atherosclerotic formation, thus causes vascular lesion, cycle penalty and hemodynamic responses, finally causes the generation of cardiovascular and cerebrovascular disease.Therefore, reduction triglyceride level, total cholesterol, high density lipoprotein increasing can treat hyperlipidemia and cardiovascular and cerebrovascular disease.
P277 peptide is one section of specific polypeptide of 437 ~ 460 of HSP60, totally 24 amino acid, is also the antigenic determinant that can react with effector T cell, is the specific fragment played a role in T1DM.DiaPep277 is at present to enter III phase clinical study.Have and experimental studies have found that according to the identical subcutaneous administration mode of external DiaPep277, carry out administration with P277 peptide, can vascular endothelial cell damage be caused, and bring out body generation antibody thus bring out serious atherosclerosis; And P277 is divided into P1 peptide section (437 ~ 450) and P2 peptide section (448 ~ 460) two portions, find that P1 polypeptide has certain pro-atherogenic effect, and P2 polypeptide does not have, and P2 can bring out the immune response being equal to P277, and the T epitope Fragments that the autoimmune diabetes that P2 polypeptide covers Elias report is correlated with, prove that P2 may be the crucial t cell epitope that P277 is used for the treatment of diabetes.
3-hydroxy-3-methylglutaric acid list acyl coenzyme A (HMG-CoA) reductase enzyme is the key enzyme of cholesterol biosynthesis, and the material of HMG-CoA reductase activity can be suppressed to have good hypolipidemic activity.Statins realizes reducing blood lipid mainly through suppressing HMG-CoA reductase activity.Hyperglycemia and hyperlipidemia have inseparable relation, statins is applied to the treatment of diabetic clinically, therefore, select HMG-CoA reductase as target spot, the object for the treatment of diabetes can be reached by immunosuppression HMG-CoA reductase activity.
Epitope is the antigenic basic substance of immunogen, carries out and has great importance to the diagnosis of antigen and the design etc. of molecular vaccine to the research of epitope.Exist between t cell epitope and B cell epi-position and interact, the existence of B cell epi-position can strengthen the effect of t cell epitope.Therefore contriver uses B cell antigen epitope analysis software and the B cell antigen of on-line analysis instrument to diabetic complication associated protein HMG-CoA reductase to analyze, obtain B epi-position, connect with the t cell epitope IPALDSLTPANED of P277 PEPC end and obtain novel couple of epi-position combined peptide H2-P2, the new peptides obtained estimates the blood sugar of the type 1 diabetes mouse that can reduce STZ induction, and can adjusting blood lipid, and be expected to the exploitation for type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular medicine.
Summary of the invention
Goal of the invention:
The object of this invention is to provide a kind of have adjust blood sugar to have the new peptides H2-P2 of regulating lipid concurrently.
Technical scheme:
A kind of new peptides H2-P2, is characterized in that a kind of two epi-position combined peptide, its amino acid composition sequence as shown in SEQ ID No.1, and main composition fragment is the B epi-position EPEIELPRER of HMG-CoA reductase and the t cell epitope IPALDSLTPANED of P277 PEPC end.
Described new peptides H2-P2 is adjusting the application on blood sugar, tune fat prod, the application of described new peptides in preparation control type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular medicine.
The application on blood sugar, tune fat prod adjusted by the pharmaceutical composition that described new peptides and one or more pharmaceutically acceptable auxiliary materials, pharmaceutically active substance or pharmaceutically acceptable carrier form and preparation, the pharmaceutical composition that described new peptides and one or more pharmaceutically acceptable auxiliary materials, pharmaceutically active substance or pharmaceutically acceptable carrier form and the application of preparation in prevention or treatment type 1 diabetes, atherosclerosis and cardiovascular and cerebrovascular medicine.
The described preparation that is effective constituent with new peptides H2-P2 is injection, sustained release dosage, subdermal implants, tablet, pulvis, granule, capsule or oral liquid containing H2-P2.
Described auxiliary material is weighting agent, thinner, vehicle etc.Such as include but not limited to: lactose, sucrose, glucose, starch, cellulose family (as carboxymethyl cellulose, HPMC etc.), ethylene glycol, soya-bean oil, sesame oil, ethanol, stroke-physiological saline solution, sterilized water etc.
Described pharmaceutical carrier is heat shock protein(HSP) HSP60/65, Asparaginase-TTP, Asparaginase-TTP-CETPC, and pharmaceutically active substance is Regular Insulin and analogue, GLP-1 and analogue thereof, Exendin-4 and analogue, sulfourea, biguanides, Statins; Wherein sulfourea comprises U26452, gliclazide, Mick pancreas, Ge Liebo urea, gram sugar profit, gliquidone, Glurenor, Gliguidone, glipizide; Described biguanides comprises phenformin, N1,N1-Dimethylbiguanide, W-37; Statins comprises lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, Cerivastatin, Rosuvastatin.
A kind of preparation method of novel two epi-position combined peptide vaccines, it is characterized in that the determination of aminoacid sequence realizes in accordance with the following steps: use B cell antigen epitope analysis software and the B cell antigen of on-line analysis instrument to diabetic complication associated protein HMG-CoA reductase to analyze, obtain B epi-position, connect with the t cell epitope IPALDSLTPANED of P277 PEPC end and obtain novel couple of epi-position combined peptide H2-P2, its aminoacid sequence is as shown in SEQ ID No.1.
Beneficial effect:
P277 peptide 437VLGGGCALLRCIPALDSLTPANED460 is HSP60 mono-section of specific polypeptide, totally 24 amino acid, is also the antigenic determinant that can react with effector T cell, is the specific fragment played a role in T1DM.DiaPep277 has entered III phase clinical study at present.Existing experiment grinds high discovery according to the identical subcutaneous administration mode of external DiaPep277, administration is carried out with P277 peptide, vascular endothelial cell damage can be caused, and bring out body generation antibody thus bring out serious atherosclerosis, and P277 is divided into P1 peptide section (437 ~ 450) and P2 peptide section (448 ~ 460) two portions, find that P1 polypeptide has certain pro-atherogenic effect, and P2 polypeptide does not have, and P2 can bring out the immune response being equal to P277, and the T epitope Fragments that the autoimmune diabetes that P2 polypeptide covers Elias report is correlated with, prove that P2 may be the crucial t cell epitope that P277 is used for the treatment of diabetes.
The invention discloses a B cell epi-position EPEIELPRER of HMG-CoA reductase, connect with the t cell epitope IPALDSLTPANED of P277 PEPC end and obtain novel couple of epi-position combined peptide H2-P2, sequence is as shown in SEQ ID No.1, prove by experiment, H2-P2 has effect that is hypoglycemic and adjusting blood lipid, can be used for the polypeptide vaccine preparing prevention or treatment type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular disease, there is the wide application prospect of important theory value, great Social benefit and economic benefit can be produced.
Accompanying drawing explanation
Fig. 1 ESI-MS measures the molecular weight of new peptides H2-P2 of the present invention
Fig. 2 new peptides H2-P2 is on the impact (A:40mg/kg of the type 1 diabetes mouse blood sugar value after various dose STZ modeling; B:35mg/kg)
Fig. 3 new peptides H2-P2 is on the impact (A: triglyceride level of type 1 diabetes lipid of mice after 35mg/kgSTZ modeling; B: total cholesterol; C: high-density lipoprotein (HDL))
Marginal data: compared with group of solvents: * * p < 0.01; * p < 0.05
Compared with P277 group: ##p < 0.01; #p < 0.05
Embodiment
Embodiment 1: the preparation process of novel polypeptide H2-P2
A kind of two epi-position combined peptide of synthesis, its aminoacid sequence is as shown in SEQ NO.1, called after H2-P2, another positive drug P277, aminoacid sequence is as shown in SEQ NO.2, above-mentioned peptide class adopts the synthesis of FMOC solid-phase synthesis by the biochemical Shanghai company limited of gill, and HPLC detects purity > 90%.
The concrete building-up process of H2-P2 is as follows:
1. select resin
Peptide systhesis is according to sequence inverse composition, and polypeptide connects to N end from C end, first Fmoc-Asp (Otbu)-OH Wang Resin;
2. remove Fmoc
Protection liquid (20% hexahydropyridine and 80%DMF) will be gone to add reactor, blow about 30min with nitrogen, then take out, clean 5-6 time with DMF, then detect color of resin (general in blue or brown).Blocking group on will removing before connecing next amino acid on an amino amino.
3. amino acid whose condensation
Go to protect and rear ready raw material and solid condensing agent (tbtu, hobt) are added reactor, then add DMF and pass into nitrogen.After amino acid and condensing agent dissolve completely, add liquid activated dose (DIEA) accordingly react.Raw material and solid activator charging capacity are all generally three times.After the reaction regular hour, the resin that takes a morsel detects, and when resin is water white transparency, shows to react completely.
4. cut
Join in cutting liquid by synthetic polypeptide, agitator leaches cutting liquid after stirring 2-3h, and add ether wherein, polypeptide can be separated out.Filter paper filtering obtains polypeptide, then washes 4-5 all over obtaining crude product peptide with ether.
5. peptide purification
Crude product peptide is drained rear purifying, obtains the sterling of HPLC purity > 90%.
ESI-MS detects synthetic peptide molecular weight, and the results are shown in Figure 1. new peptides H2-P2 molecular weight is 2604.88.
The pharmacodynamic evaluation of embodiment 2:H2-P2
The foundation of 1.1 patients with type Ⅰ DM model mouses (40mg/kg)
Adopt low dose of continuous several times abdominal injection streptozotocin (STZ) inducing mouse type 1 diabetes model.4 week age male C 57 BL/6 J mouse (purchased from Yangzhou University's comparative medicine center, credit number: SCXK (Soviet Union) 2012-0004.) with 0.1MpH4.4 citrate buffer configuration STZ, by 40mg/kg dosage abdominal injection, every day 1 time, continuously injection 5 times.
2.40mg/kg animal pattern immune protection is tested
30 diabetic mices are divided into 3 groups by the blood glucose value surveyed every other day after modeling, make often to organize MBG and reach unanimity, and often organize 10.Be respectively: solvent control group (negative control group), P277 group (positive controls), H2-P2 group (administration group).Administration group drug level is 1mg/ml, and subcutaneous administrations amount is 100 μ g//times, i.e. 100 μ l liquids; Negative control group: 100 μ l finishes/only/time.Medicine ordinance method is dissolved in the ratio provisional configuration finish of 1.1ml20%Lipofundin in 1.1mg+44mg N.F,USP MANNITOL.
Measure while blood sugar, adopt kapillary to get blood through mouse intraocular corner of the eyes ball rear vein beard, centrifugal 2 separation of serum, the serum obtained in-70 DEG C of Refrigerator stores, for detecting blood fat indices.
3. on the impact of type 1 diabetes mouse blood sugar (40mg/kg)
Every other day grouping after carry out subcutaneous inoculation, afterwards weekly immunity once, continuous five times.Blood is got in the docking of type 1 diabetes mouse, when getting blood, detects mouse blood sugar level by blood glucose meter.Result is as shown in the A figure of Fig. 2, and after modeling the 7th week, the blood sugar mean value of H2-P2 group was starkly lower than P277 group (p < 0.01); Blood sugar obviously reduces (p < 0.05) compared with Placebo group.Result illustrates that H2-P2 can regulate the blood sugar of type 1 diabetes mouse (40mg/kg).
The foundation of 4.1 patients with type Ⅰ DM model mouses (35mg/kg)
Adopt low dose of continuous several times abdominal injection streptozotocin (STZ) inducing mouse type 1 diabetes model.4 week age male C 57 BL/6 J mouse (purchased from Yangzhou University's comparative medicine center, credit number: SCXK (Soviet Union) 2012-0004.) with 0.1MpH4.4 citrate buffer configuration STZ, by 35mg/kg dosage abdominal injection, every day 1 time, continuously injection 5 times.
5.35mg/kg animal pattern immune protection is tested
30 diabetic mices are divided into 3 groups by the blood glucose value surveyed every other day after modeling, make often to organize MBG and reach unanimity, and often organize 10.Be respectively: solvent control group (negative control group), P277 group (positive controls), H2-P2 group (administration group).Administration group drug level is 1mg/ml, and subcutaneous administrations amount is 100 μ g//times, i.e. 100 μ l liquids; Negative control group: 100 μ l finishes/only/time.Medicine ordinance method is dissolved in the ratio provisional configuration finish of 1.1ml20%Lipofundin in 1.1mg+44mg N.F,USP MANNITOL.
Measure while blood sugar, adopt kapillary to get blood through mouse intraocular corner of the eyes ball rear vein beard, centrifugal 2 separation of serum, the serum obtained in-70 DEG C of Refrigerator stores, for detecting blood fat indices.
6. on the impact of type 1 diabetes mouse blood sugar (35mg/kg)
Start to carry out animal subcutaneous inoculation after modeling terminates to divide into groups every other day, afterwards weekly immunity once, continuous five times.Blood is got in the docking of type 1 diabetes mouse, when getting blood, detects mouse blood sugar level by blood glucose meter.Result is as shown in the B figure of Fig. 2, and after modeling the 2nd week, the blood sugar mean value of H2-P2 group was starkly lower than P277 group (p < 0.05); Blood sugar obviously reduces (p < 0.05) compared with Placebo group.Result illustrates that H2-P2 can regulate the blood sugar of type 1 diabetes mouse (35mg/kg).
7. on the impact of type 1 diabetes lipid of mice after 35mg/kgSTZ modeling
The content of the Placebo group of the control experiment of 35mg/kg modeling, P277 group, H2-P2 group the 6th week mice serum serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) (HDL-C) is detected with test kit.If the content of Fig. 3-A, H2-P2 group serum triglyceride is significantly lower than Placebo group (p < 0.05), decrease compared with P277 group; If the content of Fig. 3-B, H2-P2 group serum total cholesterol is significantly lower than Placebo group (p < 0.05), decrease compared with P277 group; As Fig. 3-C, H2-P2 group serum high-density LP content is significantly higher than Placebo group (p < 0.05) and P277 group (p < 0.05).Result illustrates, H2-P2 can adjusting blood lipid.
Conclusion: it can thus be appreciated that new peptides H2-P2 significantly can regulate the blood sugar of type 1 diabetes mouse, and significantly can regulate the blood fat of laboratory animal, may be used for the exploitation of type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular medicine.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by referring to some preferred embodiment invented, invention has been described, but those of ordinary skill in the art is to be understood that, various change can be made to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (10)
1. new peptides H2-P2, is made up of 23 amino acid, has the aminoacid sequence shown in SEQ ID No.1, it is characterized in that, is in series by the B cell epi-position of HMG-CoA reductase and the t cell epitope IPALDSLTPANED of P277 PEPC end.
2. new peptides according to claim 1 adjusts the application on blood sugar, tune fat prod in preparation.
3. the application of new peptides according to claim 1 in preparation control type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular medicine.
4. the pharmaceutical composition of new peptides according to claim 1, is characterized in that, comprises the peptide described in claim 1 and one or more pharmaceutically acceptable auxiliary materials, pharmaceutically active substance or pharmaceutically acceptable carrier.
5. composition according to claim 4, is characterized in that: the described preparation that is effective constituent with new peptides H2-P2 is injection, sustained release dosage, subdermal implants, tablet, pulvis, granule, capsule or oral liquid containing H2-P2.
6. auxiliary material according to claim 4 is weighting agent, thinner, vehicle etc.Such as include but not limited to: lactose, sucrose, glucose, starch, cellulose family (as carboxymethyl cellulose, HPMC etc.), ethylene glycol, soya-bean oil, sesame oil, ethanol, stroke-physiological saline solution, sterilized water etc.
7. pharmaceutical carrier according to claim 4 is heat shock protein(HSP) HSP60/65, Asparaginase-TTP, Asparaginase-TTP-CETPC.
8. pharmaceutically active substance according to claim 4 is Regular Insulin and analogue, GLP-1 and analogue thereof, Exendin-4 and analogue, sulfourea, biguanides, Statins; Wherein sulfourea comprises U26452, gliclazide, Mick pancreas, Ge Liebo urea, gram sugar profit, gliquidone, Glurenor, Gliguidone, glipizide; Described biguanides comprises phenformin, N1,N1-Dimethylbiguanide, W-37; Statins comprises lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, Cerivastatin, Rosuvastatin.
9. the preparation according to the composition shown in claim 4 and claim 5 adjusts blood sugar in preparation, the application of adjusting in fat prod.
10. the application of the preparation according to the composition shown in claim 4 and claim 5 in control type 1 diabetes, atherosclerosis, hyperlipidemia and cardiovascular and cerebrovascular disease.
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| CN106554402A (en) * | 2017-01-11 | 2017-04-05 | 中国药科大学 | A kind of new type of peptides for having blood sugar lowering and anti-oxidative stress |
| CN108330112A (en) * | 2015-06-01 | 2018-07-27 | 中国药科大学 | Two B cell epitopes of HMG-CoA reductase and the Antigenic Peptide comprising wherein one or two epitope |
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| CN102633873A (en) * | 2012-05-09 | 2012-08-15 | 中国药科大学 | Novel peptide, applications and preparation method thereof |
| CN103265636A (en) * | 2013-05-23 | 2013-08-28 | 中国药科大学 | Novel peptide with hypoglycemic effect |
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| CN102633873A (en) * | 2012-05-09 | 2012-08-15 | 中国药科大学 | Novel peptide, applications and preparation method thereof |
| CN103265636A (en) * | 2013-05-23 | 2013-08-28 | 中国药科大学 | Novel peptide with hypoglycemic effect |
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| CN108330112A (en) * | 2015-06-01 | 2018-07-27 | 中国药科大学 | Two B cell epitopes of HMG-CoA reductase and the Antigenic Peptide comprising wherein one or two epitope |
| CN106554402A (en) * | 2017-01-11 | 2017-04-05 | 中国药科大学 | A kind of new type of peptides for having blood sugar lowering and anti-oxidative stress |
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