CN103987398A - Use of hepatitis c virus immunogenic peptide or its derivative in preparing medicine for preventing or treating colitis - Google Patents
Use of hepatitis c virus immunogenic peptide or its derivative in preparing medicine for preventing or treating colitis Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
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Abstract
The invention provides the use of the hepatitis C virus immunogenic peptide or its derivative as represented by formula I in preparing the medicine for preventing or treating colitis, especially ulcerative colitis induced by trinitrobenzenesulfonic acid. Xaa1-Gln-Xaa2-Xaa3-Thr-Ser-Gly-Xaa4 (formula I), wherein Xaa1 is deletion, Ala, Gly, Val, Leu or Ile, Xaa2 is Thr or Ser, Xaa3 is Tyr, Phe or Trp, and Xaa4 is deletion, Ala, Gly, Val, Leu, Ile or Pro.
Description
Application of the hepatitis C virus immunogen peptide or derivatives thereof in the medicine for preparing prevention or treatment colitis
Technical field
The invention belongs to pharmaceutical technology field, specifically, the present invention relates to the application in preparing the application in preventing or treating the medicine of colitis, more particularly to the peptide or derivatives thereof to prepare the medicine of prevention or treatment ulcerative colitis of hepatitis C virus immunogen peptide and its derivative.Background technology
Colitis is a kind of common intestines problem, patients with clinical manifestations is becomes thin, weak, heating, anaemia etc., small part patient is in the chronic course of disease, the state of an illness can deteriorate suddenly, show severe diarrhea, daily 10-30 times, discharge contains blood, purulence, the excrement of mucus, and have hyperpyrexia, vomiting, tachycardia, exhaustion, mistake water and rock-soil coupling, even perforation of colon of losing consciousness, treatment not in time can cause death.In recent years, by medicine（Such as, TNB etc.）Caused colitis increasingly causes the concern of people, so research also one of Main Topics as this area of the active drug for this kind of colitis disease.
The present inventor discloses a kind of hepatitis C virus immunogen peptide or derivatives thereof in Chinese patent CN1194986C and CN1216075C（Identical title is also used in abbreviation 7P peptides or derivatives thereof, the present invention）It is a kind of immunogenic peptide initially designed according to HCV, and prove that described 7P peptides or derivatives thereof have inducing cytokine r-IFN, IL-4, the function that IL-10 and antibody are produced, r-IFN is the cell factor of Thl secretions, is one of the major cytokine that human immune system supports viral infection resisting, for HCV (HCVs）Removing have considerable meaning, therefore 7P peptides or derivatives thereof have prevent and/or treatment hepatitis C effect.According to the record of the first patent, described 7P polypeptides or derivatives thereof can be synthesized by solid-phase synthesis well known to those skilled in the art or liquid phase synthesizing method, also by genetic engineering amalgamation and expression and acquisition can be purified, and specifically describes peptide and its derivative that sequence is GQTYTSG and prevent and/or treating the effect of hepatitis C.Jin mono- Walk's, the present inventor discloses purposes of the described 7P peptides or derivatives thereof in prevention and treatment hepatic injury in patent application PCT/CN2006/001176, according to the record of the earlier application, described 7P peptides or derivatives thereof significantly reduce the level of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase in serum, and performance is to significantly prevention or the therapeutic action of hepatic injury caused by immunological liver injury and hepatotoxicity wind agitation chemical substance.Hereafter, this hair
Person of good sense Jin mono- Walk in Chinese patent application CN101559217A, which disclose described 7P peptides or derivatives thereof, also certain therapeutic action for ephritis, it is administered especially by gastral mode, the ephritis induced by haemocyanin and Heymann's ephritis can be significantly reduced.
Colitis has entirely different pathogenesis with hepatic injury and ephritis, with entirely different clinical manifestation, had been surprisingly found that in the research of the present inventor, described peptide or derivatives thereof also has the effect for improving colitis disease states, particularly there is the effect for improving the disease states to inducing the ulcerative colitis produced by TNB, and the report not in the prior art also being applied to described peptide or derivatives thereof in the prevention and treatment of colitis.The content of the invention
The invention provides application of the above-mentioned hepatitis C virus immunogen peptide or derivatives thereof in the medicine for preparing prevention or treatment colitis, new clinical method is provided for the treatment and prevention of colitis class disease, the potential medicinal applications of the 7P peptides have also been widened.
Present invention also offers a kind of method using described hepatitis C virus immunogen peptide or derivatives thereof treatment colitis, by applying the medicine of the peptide containing therapeutically effective amount or derivatives thereof to patient, the purpose for the disease states for significantly improving colitis is reached.
The invention provides application of the peptide shown in formula I or derivatives thereof in the medicine for preparing prevention or treatment colitis：
The n-Xaa2-Xaa3-Thr-S er of 1-G of Xaa 1 ~ y-Xaa4 of G 1 (Formulas I) wherein,
Xaal be missing, Ala, Gly, Val, Leu or l ie,
Xaa2 is Thr or Ser,
Xaa3 be Tyr, Phe or Trp, and
Xaa4 is missing, Ala, Gly, Val, Leu, l ie or Pro;
The derivative includes the peptide pharmaceutically acceptable salt or ester.
Described peptide using effective dose or derivatives thereof can effectively prevent or treat colitis, can especially prevent or treat ulcerative colitis, and the ulcerative colitis can be induced by TNB and produced.Clinically, induce that the ulcerative colitis produced is mainly shown as colonic mucosa congestion and edema, exuviation, necrosis, ulcer is formed, submucosa has substantial amounts of inflammatory cell infiltration by TNB,
Some ulcer can be obvious as deep as muscle layer, fibrous connective tissue and blood vessel hyperplasia.The basic structure and composition of peptide shown in above-mentioned Formulas I or derivatives thereof are inventor's hepatitis C virus immunogen peptide resulting in research before or derivatives thereof, therefore are referred to as 7P peptides or derivatives thereof.
Herein, described " pharmaceutically acceptable ester " refers to suitable for being contacted and without the ester of excessive toxicity, stimulation or allergy etc. with the tissue of human or animal.Generally, hydrolysis of the protease in body to peptide can be reduced after esterification modification.Terminal amino group, carboxyl or side-chain radical progress modification to the peptide of the present invention can form pharmaceutically acceptable ester.Modification to amino acid side groups includes but is not limited to the esterification that threonine, lysine side chains hydroxyl and carboxylic acid occur.Preferred amino acid end group is protected with protectiveness group known to the technical staff in protein chemistry field, such as acetyl group, trifluoroacetyl group, Fmoc (9- fluorenyls-methoxycarbonyl group）, Boc (tertbutyloxycarbonyls）, Alloc (allyloxycarbonyls）、 d—3Protective embankment base, C6—12Fragrant protective embankment base etc..It is described in detail about the medicinal ester of the 7P peptides in PCT/CN2006/001176, therefore the related content is incorporated to this case as reference.In the embodiment of the present invention, inventor has found, the peptide of the present invention is also enough to be treated in physiological conditions without modification, therefore amino and the carboxyl and amino acid side groups of C-terminal preferably not to Formulas I polypeptide N-terminal is modified, and the chemical group of SP N-terminals is still the alpha-amido (- Ν Η Β on first amino acid2Β), the chemical group of C-terminal is the carboxyl of C-terminal amino acid（-C00H) .
Herein, " pharmaceutically acceptable salt " refers to suitable for being contacted and without the salt of excessive toxicity, stimulation or allergy etc. with the tissue of human or animal.Pharmaceutically acceptable salt is well known in the art.This salt can be prepared during the final separation and purifying of polypeptide of the present invention, and peptide can also be manufactured separately with appropriate organic or inorganic acid or alkali reaction.Representative acid-addition salts include but is not limited to acetate, two caproates, alginates, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionates, lactate, maleate, mesylate, nicotinate, 2- naphthalene sulfonates, oxalates, 3- phenylpropionic acid salt, propionate, succinate, tartrate, phosphate, glutamate, bicarbonate, tosilate and 11 protective embankment hydrochlorates.The preferred acid that can be used to form pharmaceutically-acceptable salts is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, butanedioic acid and citric acid.Cation in pharmaceutically acceptable base addition salts includes but is not limited to alkali metal or alkaline-earth metal ions such as lithium, sodium, potassium, calcium and magnesium etc., quaternary ammonium cation（Such as tetramethyl-ammonium, tetraethyl ammonium）, and ammonium, methyl
The cation of amine, dimethyl amine, Trimethylamine, triethylamine, diethylamide, ethylamine, diethylamine, monoethanolamine, diethanol amine, piperidines, piperazine etc..It is preferred that base addition salts include phosphate, trihydroxy methyl amino first protective embankment（) and acetate tris.These salt are generally possible to increase the dissolubility of polypeptide, and the salt formed not substantially changes the activity of polypeptide.The polypeptide of the present invention can be used alone, and can also be used in pharmaceutically acceptable salt form.
In a word, according to the solution of the present invention, the prevention and/or the medicine for treating colitis can directly use the peptide or pharmaceutical salts or the pharmaceutical preparation of acceptable ester form using the peptide.
Jin mono- Walk's, described peptide or derivatives thereof is the peptide or its pharmaceutically acceptable salt or ester shown in formula Π：Gly-Gln-Thr-Tyr-Thr-Ser-Gly (formula Π).According to amino acid representation well known in the art, the peptide shown in Formula II can also be abbreviated as GQTYTSG.
In the solution of the present invention, described peptide or derivatives thereof can use appropriate dosage form according to prevention and/or therapeutic purposes, and route of administration, for example：Injection,（Injection）Freeze-dried powder, spray, oral administration solution, oral administration mixed suspension, tablet, capsule, enteric coatel tablets, pill, pulvis, granule, sustained release agent（The formulation that controllable medicament active ingredient slowly discharges）Or controlled release agent（The formulation of controllable medicament active ingredient release）, can be comprising conventional pharmaceutically acceptable carrier in the preparation Deng preparation, " pharmaceutically acceptable carrier " refers to nontoxic solid-state, semisolid or liquid filler, diluent, adjuvant, lapping or other pharmaceutical adjuncts, for example：Physiological saline, isotonic glucose solution, buffered saline, glycerine, the combination of ethanol and above-mentioned solution.The medicine being made up of described peptide or derivatives thereof is preferably applied with injection system in the solution of the present invention, SP is preferred using injection or freeze drying powder injection, to be dissolved using physiological saline as carrier.
A kind of method for treating colitis that the present invention is provided, including, the medicine of the peptide shown in the above-mentioned Formulas I containing therapeutically effective amount or derivatives thereof is applied to patient, the derivative includes the peptide pharmaceutically acceptable salt or ester.
As peptide of active ingredient or derivatives thereof can be the peptide or its pharmaceutically acceptable salt or ester shown in above-mentioned Formula II in the medicine for treatment according to the preferred scheme of the present invention.
The medicine of the above-mentioned peptide containing therapeutically effective amount or derivatives thereof（Described peptide or derivatives thereof is used as active ingredient）It can effectively prevent or treat colitis, can especially prevent or treat ulcerative colitis, be more advantageously that treatment induces the ulcerative colitis produced by TNB.In an embodiment of the invention, to patient apply containing therapeutically effective amount for 180-3000 μ g the peptide or its spread out
Biological medicine.Jin mono- Walk are preferred, apply the medicine for containing therapeutically effective amount for the 240-1800 peptide or derivatives thereof to patient.Therapeutically effective amount in the present invention program is for general adult's body weight, the effective dose of single administration.
In an embodiment of the invention, the medicine of the peptide containing therapeutically effective amount or derivatives thereof is preferably applied with injection system.Jin mono- Walk's, preferred pair patient is administered with the dosage of unit formulation, the preparation of unit formulation active ingredient for needed for meeting single administration, a common unit formulation such as unit（Piece）Tablet, a unit（Pin）The content of injection or powder-injection etc., wherein active ingredient is the amount needed for single administration.The amount of medicine needed for patient's applied once can be obtained conveniently by the body weight and the product of per weight dosage needed for patient's a drug for calculating patient.For example, during medicine is prepared, it is considered that adult's body weight is 50-70kg, can be calculated with the body weight value.The per weight dosage of experimental animal and people can be calculated by dose,equivalent conversion relation.For example, according to experimental animal known to ordinary skill in the art and people dose,equivalent conversion relation（Reference can be made to the instruction of the medicine administrative organ such as FDA, SFDA, also can be found in（Huang Jihan etc., " the dose,equivalent conversion in pharmacological testing between animal between animals and human beingses body ", Chinese Clinical pharmacology and acology, 2004 Sep; 9 (9) :1069-1072) effective dose of people can be derived from the dosage of experimental animal.In embodiments of the present invention, can convert the dosage of people and rat according to the body surface area conversion factor 0. 018 of people and rat.According to embodiment of the present invention, therapeutic effect is preferable when peptide or derivatives thereof described in the unit formulation is applied to rat with 30-300 μ g/kg rat dosage, when with 40-180 g/kg rat dosage, such as when the μ g/kg rat dosage of 174,87 or 43. 5 is applied to rat, therapeutic effect is more preferably.Pharmaceutical manufacturer can obtain the active constituent content in the unit formulation for people according to above-mentioned conversion method, to applied in its pharmacy procedure.In the inventive solutions, according to dose,equivalent conversion relation and the conventional weight of people, and comprehensive drug safety, cost and drug effect, it is preferred that, described peptide containing 300-3000 dosage or derivatives thereof in the unit formulation, preferably comprise described peptide of 400-1800 g dosage or derivatives thereof, such as 1740 g, 870 g, or 435 μ g the peptide or derivatives thereof.
According to the research of the present invention, described peptide or derivatives thereof is used to prevent or colitis is treated, colitis disease states can be effectively improved, particularly improve the disease states that the colitis produced is induced by TNB, group (including the high, medium and low dosage group using the peptide or derivatives thereof is can be seen that from the data of following examples）, compared to model group, show the rat knot significantly mitigated
The lesion degree of enteritis.Therefore the implementation of the present invention, contributes to the exploitation to colitis or treating correlative diseases medication.
In order to make it easy to understand, the present invention will be described in detail by specific embodiment below.It is important to note that instantiation is merely to illustrate, and be not meant to limit the scope of the invention.Obvious one of ordinary skill in the art can be according to illustrating herein, and make various modifications and variations to the present invention within the scope of the invention, these modifications and variations are also included in the scope of the present invention.In addition, the present invention refer to open source literature, these documents also for more clearly describing the present invention, their entire contents include the present invention and as a part for description of the invention.Embodiment
Protective effects of the peptide A of embodiment 1 to rat colonitis
1. experiment material
1. 1 animal：
SPF grades of SD rats, body weight 180g 220g, male and female half and half, purchased from Chinese military medicine academy of sciences Experimental Animal Center.
1. 2 medicines：
Using by Solid-phase peptide synthesis, Perkin Elmer companies (are purchased from by the automatic peptide synthesizer of 413A types）The following sequence of peptide of synthesis：GQTYTSG (hereinafter referred to as peptide A), specific He Cheng Walk please participate in the record of embodiment 1 in PCT/CN2006/001176 suddenly, physiological saline solution when using.
Positive control drug：Wei Liufen（Salicylazosulfapyridine, SASP), purchased from Shanghai Sunve Pharmaceutical Co., Ltd..
1. 3 packets and drug dose
SD rats, male and female half and half are randomly divided into 6 groups, rat every group 10, and packet situation is：Model group（Using physiological saline and TNB）；Blank control group（Using the physiological saline with model group equivalent）, positive drug group（Using with the physiological saline of model group equivalent, TNB and 50mg/kg. d SASP), the high, medium and low dosage group of peptide A medicines（It is respectively that 174 μ g/kg d, 87 μ g/kg d, 43. 5 μ g/kg d peptide A are configured to need the peptide solution A of concentration with physiological saline using TNB and dosage）, the high, medium and low dosage group of peptide A medicines lead to
Cross injected s. c to be administered, 0. 1 ml peptide solution A is administered per 100g body weight for rat, blank control group uses the physiological saline of equivalent（Rat gives 0. 1 ml physiological saline per 100g body weight）.
2. test method
2. 1 experimental program：
Each group rat is administered in such a way, during administration, unless otherwise instructed, daily to each group rat diet：
1st, blank control group normal diet did not applied any medicine；Remaining each group rat in addition to blank control group, whole day fasting in 24 hours but can't help water；
On the day of the 2nd day, to remaining each group rat in addition to blank control group, with 0. 2ml ketalars through intraperitoneal injection of anesthesia, gently inserted with gavage syringe needle from rat anus, enteron aisle about 8cm is inserted, enteron aisle is cleaned with physiological saline, every rat pours into the 5ml of 50 % (w/w) ethanol solution 2. of the TNB containing 30mg, clutch anus and keep flat 5 min, postoperative conventinal breeding；
Since the 2nd day（Including the 2nd day）, blank control group and model group are subcutaneously injected in each interval of one day the physiological saline with the high, medium and low dosage group equivalent of peptide A medicines, co-injection 7 times；The peptide A of corresponding dosage is applied respectively to the rat of the high, medium and low dosage group of peptide A medicines, hypodermic injection or gastric infusion once, are administered 7 times altogether every other day afterwards;SASP is applied by gastric infusion approach to positive drug group, once a day, continuous 14 days.
Observed that defecation frequency occur in succession in model group rats to be increased, the symptom such as agitation, mucus pus and blood stool on 4th, show that colon is inflamed lesion.Compared with model group, there is defecation frequency and reduced compared with model group model respectively in the high, medium and low dosage groups of peptide A, positive drug group rat, mucus pus and blood stool symptom mitigation.
After 24 h of each group last time administration, rat is put to death, the position clip 2cm colons of colonic pathological change most serious are selected, fixed, routine paraffin wax embedding, film-making are put into 10% neutral buffered formalin solution, HE is dyed, and observes Colonic Mucosa of The Rat degree of impairment.According to colonic mucosal injury light and heavy degree, quantification of successively " 1 point（It is a small amount of or slight）2 points of ", "（Moderate or moderate）3 points of ", "（A large amount of or severe）4 points of ", "（Pole severe）", extremely slight lesion is calculated as " 0. 5 points ", and no pathological tissues are calculated as " 0 point ".Add up all fractions, draws total score, and calculate every group of every animal divides equally (± SD), and score value is lower, and prompting lesion degree is lighter.
2.2 data processing：
Data processing is carried out to all data, histological scores are used with rank test, and statistic analysis result.
3. result
Histopathology research to rat TNB induction type colitis shows, its colonic mucosa congestion and edema, exuviation, necrosis, ulcer formation, submucosa have substantial amounts of inflammatory cell infiltration, some ulcer can be as deep as muscle layer, fibrous connective tissue and blood vessel hyperplasia substantially, and the scorching lesion of peptide A medicinal applications postcolon has different degrees of mitigation.As can be seen that the order of therapeutic effect from high to low is followed successively by peptide A high dose groups, peptide A middle dose groups, peptide A low dose groups have significant difference ＜ 0.05 or * * compared with model group< 0.01).The lesion light and heavy degree code of points recorded according to the present embodiment, the comprehensive grading result of each pathological examination index is obtained using rank test method, it is as shown in the table.As can be seen that the therapeutic effect and positive drug of peptide A medicine middle dose groups（SASP) effect of group is suitable, and peptide A low dose groups have shown that effective prevention or the treatment to colitis lesion.
Table 1:Another IJ number of animals (only) ~ ~ lesion score of ulcerative colitis lesion light and heavy degree appraisal result group（± SD) 10 1. 33 ± 0.65** of blank control group model groups 10 6.86 ± 1.57
10 4.15 ± 1.68* of positive drug SASP groups
10 4.37 ± 1.76* of peptide A medicine low dosages
10 4.10 ± 1.15* of peptide A medicine middle dosages
10 3.43 ± 1.66** of peptide A medicine high doses
Compared with model group： * <0.05, * *< 0.01
Claims (15)
- Claim1st, application of the peptide shown in formula I or derivatives thereof in the medicine for preparing prevention or treatment colitis：The n-Xaa2-Xaa3-Thr-S er of 1-G of Xaa 1 ~ y-Xaa4 of G 1 (Formulas I) wherein,Xaal be missing, Ala, Gly, Val, Leu or l ie,Xaa2 is Thr or Ser,Xaa3 be Tyr, Phe or Trp, andXaa4 is missing, Ala, Gly, Val, Leu, l ie or Pro;The derivative includes the peptide pharmaceutically acceptable salt or ester.2nd, application according to claim 1, wherein described peptide or derivatives thereof is the peptide or its pharmaceutically acceptable salt or ester shown in Formula II：The y-Gl n-Thr-Ty r-Thr-S er of the G 1 ~ y (formulas of G 1.3rd, application according to claim 1 or 2, wherein the medicine is unit preparation.4th, the application according to claim 1 or 3, the medicine is ejection preparation.5th, application according to claim 1 or 2, wherein the colitis is ulcerative colitis.6th, application according to claim 5, the ulcerative colitis is to induce the colitis produced by TNB.7th, a kind of method for treating colitis, including, the medicine of the peptide shown in the Formulas I containing therapeutically effective amount or derivatives thereof is applied to patient：The y-Xaa4 (Formulas I) of 1-G of Xaa, 1 n-Xaa2-Xaa3-Thr-S er-G 1 wherein,Xaal be missing, Ala, Gly, Val, Leu or l ie,Xaa2 is Thr or Ser,Xaa3 be Tyr, Phe or Trp, andXaa4 is missing, Ala, Gly, Val, Leu, l ie or Pro;The derivative includes the peptide pharmaceutically acceptable salt or ester.8th, method according to claim 7, the peptide or derivatives thereof is the peptide or its pharmaceutically acceptable salt or ester shown in Formula Il：The y-Gl n-Thr-Ty r-Thr-S er of the G 1 ~ y (formulas of G 1. 9th, the method according to claim 7 or 8, including, apply the medicine containing therapeutically effective amount for the 180-3000 μ g peptide or derivatives thereof to patient.10th, method according to claim 9, including, apply the medicine containing therapeutically effective amount for the 240-1800 μ g peptide or derivatives thereof to patient.11st, the method according to claim any one of 7-10, wherein, patient is administered with the dosage of unit formulation.12nd, method according to claim 11, wherein containing peptide or derivatives thereof described in 300-3000 in the unit formulation.13rd, method according to claim 12, wherein containing peptide or derivatives thereof described in 400-1800 in the unit formulation.14th, the method according to claim any one of 7-13, it includes being administered with injection system.15th, the method according to claim 7 or 8, wherein the colitis is ulcerative colitis.16th, application according to claim 15, the ulcerative colitis is to induce the colitis produced by TNB.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2011/080435 WO2013044499A1 (en) | 2011-09-30 | 2011-09-30 | Use of hepatitis c virus immunogenic peptide or its derivative in preparing medicine for preventing or treating colitis |
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| CN103987398A true CN103987398A (en) | 2014-08-13 |
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| CN201180073655.6A Pending CN103987398A (en) | 2011-09-30 | 2011-09-30 | Use of hepatitis c virus immunogenic peptide or its derivative in preparing medicine for preventing or treating colitis |
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| WO (1) | WO2013044499A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822816A (en) * | 2010-05-27 | 2010-09-08 | 程云 | Application of 7P peptide in preventing or treating pneumonia |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5031827B2 (en) * | 2006-06-01 | 2012-09-26 | 程云 | Peptides to prevent or treat liver damage |
| CN101883781B (en) * | 2008-04-18 | 2013-06-05 | 程云 | 7P peptide and its derivant, the use thereof |
-
2011
- 2011-09-30 WO PCT/CN2011/080435 patent/WO2013044499A1/en active Application Filing
- 2011-09-30 CN CN201180073655.6A patent/CN103987398A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822816A (en) * | 2010-05-27 | 2010-09-08 | 程云 | Application of 7P peptide in preventing or treating pneumonia |
Non-Patent Citations (2)
| Title |
|---|
| 朱炳喜等: "细胞因子在大鼠溃疡性结肠炎模型中的表达研究", 《吉林医学》 * |
| 李金波: "HCV HVR1模拟肽诱导小鼠免疫应答及机制的初步研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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