CN102391362A - Group of animal-derived cationic antibacterial peptides and its application - Google Patents
Group of animal-derived cationic antibacterial peptides and its application Download PDFInfo
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Abstract
The invention provides a group of novel artificially designed animal-derived cationic antibacterial peptides, which is synthesized on the basis of a structural analysis of a natural lactoferricin antibacterial peptide sequence, the series of the antibacterial peptide sequence is shown as the following: CQUT-a: Phe Arg Trp Trp Trp Gln Arg; CQUT-b: Arg Arg Gln Trp Phe Trp. The antibacterial peptides are obtained by using a solid phase chemical method. The animal-derived cationic antibacterial peptides have the advantages that antibacterial spectrum is wide, no modification or connection is required, the structure is simple and artificial synthesis is convenient. Experiment proves that both G<+>bacteria (gram positive bacteria) and G<->bacteria (gram negative bacteria) possess the advantages of substantial bacteriostasis and bactericidal activity, long continuance and no hemolytic toxin; the animal-derived cationic antibacterial peptides have important value on aspects of exploitation and application of medicines for treating bacterial infection diseases.
Description
Technical field
The present invention relates to the application of one group of novel animal derived cationic antibacterial peptide and verivate thereof at the treatment infectation of bacteria; Antibacterial peptide can suppress microbial growth; And be prepared into pharmaceutical composition be used for the treatment and the prevention by the caused infection of multiple mikrobe, wherein said mikrobe comprises gram-positive microorganism and gram-positive microorganism.
Background technology
Bacterial infection is one of important diseases that threatens the human life always, and the eighties of last century antibiotic discovery thirties also is widely used in clinical treatment, saved countless patients life (Neu, H.C. (1992) Science 257,1064-1073).Because the antibiotic a large amount of uses of tradition have caused increasing rapidly of multidrug resistant disease pathogenic microorganism.Therefore, (Travis, J.1994 Science 264,360-362) with the resistance of reply serious day by day pathogeny bacterium in the world wide to demand the development of new antiradiation drug now urgently.
The control of bacterial infection is the appearance of perplexing people's an important difficult problem, particularly bacterial drug resistance for a long time, has more given prominence to the complex nature of the problem and the urgency of dealing with problems.Because the cationic antibacterial peptide mechanism of action is unique, external do not have Resistant strain to produce, and the has a broad antifungal spectrum of many cationic antibacterial peptides, and gram-positive microorganism and negative bacterium are all had effect, makes it become traditional antibiotic ideal substitute most probably.
Antibacterial peptide is extensive in distributed in nature, is the endogenous material of resisting exogenous infection that organism produces, and goes through millions of years and seldom produces tolerance, have effect rapidly, characteristics such as efficient, wide spectrum.Thereby in it was found, (Koczulla AR, Bals R.2003.Drugs 63,389-406) just to have caused the concern of pharmacy circle and high-tech biological industry circle.
Antibacterial peptide is one type and extensively is present in mikrobe and the intravital micromolecule polypeptide of plant-animal that be made up of more than 30 amino-acid residues usually, molecular weight is 2-7KDa.The bactericidal mechanism of antibacterial peptide is that it can destroy the cytolemma of bacterium, causes entocyte to overflow, and finally causes bacterial death.
Cationic antibacterial peptide can be represented one type of novel antibacterials; Though the mechanism of action of cationic antibacterial peptide is not also confirmed; But nearly all amphipathic cationic antibacterial peptide all produces with cytolemma and interacts, thereby cytolemma is the main action target spot of numerous antibacterial peptides.The antibacterial peptide molecule can be assembled on cytolemma and cause its permeability to increase, and causes membranolysis and apoptosis.Therefore, be that the antibacterial peptide of target spot produces resistance hardly with the cytolemma, reason is to develop immunity to drugs to need cytolemma lipid composition generation material alterations.
At present, in numerous antibacterial peptides, cationic Bovinelactoferrin plain (Lactoferricin B) is the most common antibacterial peptide, particularly its antibiotic core sequence Lactoferricin B
4-9RRWQWR (Arg-Arg-Trp-Gln-Trp-Arg) still has good antibacterial activity, but still has problems such as anti-microbial activity is low, hemolytic toxicity.
Summary of the invention
The object of the invention provides a kind of have remarkable bacteria growing inhibiting and novel animal derived cationic antibacterial peptide and verivate thereof long-acting, no hemolytic toxicity; And provide that to have a synthetic convenient, the preparation method that cost is low.
Another purpose of the object of the invention provides the purposes of said novel animal derived cationic antibacterial peptide and verivate thereof.
Realize above-mentioned purpose, the technique means that the present invention adopts is: a treated animal source property cationic antibacterial peptide, it is characterized in that, and be synthetic to design on the plain antibacterial peptide sequence of natural cow's milk iron, the basis of structural analysis, this antibacterial peptide sequence comprises:
CQUT-a：Phe?Arg?Trp?Trp?Gln?Arg；
CQUT-b：Arg?Arg?Gln?Trp?Phe?Trp。
One treated animal source property cationic antibacterial peptide series; It is characterized in that; Comprise above-mentioned sequence, comprise also that the N-terminal in the above polypeptide or the verivate and/or the modification of C-terminal, amino acid whose replacement, replacement, cyclisation, L-type amino acid become D-type amino acid, disappearance or adding and the functionally similar polypeptide that obtains or intend peptide.
Further, said animal derived cationic antibacterial peptide is in the application of treatment infectation of bacteria.And suppressing microbial growth, and be prepared into pharmaceutical composition and be used for treatment and prevention by the caused infection of multiple mikrobe, wherein said mikrobe comprises gram-positive microorganism and gram-positive microorganism.
The present invention is at the antibacterial peptide sequence Lactoferricin B of existing natural discovery
4-9On the basis of RRWQWR, combined with virtual combinatorial libraries designing technique, DNAstar, Bioedit, sequence logo etc. analyze software and website, and having designed one group contains 6 amino acid natural polypeptides sequences, and this group polypeptide is compared LfcinB
4-9Greatly improve the sterilization and the bacteriostatic activity of antibacterial peptide, and solved LfcinB
4-9The hemolytic toxicity problem.Compare natural animal source type cationic antibacterial peptide, the present invention has remarkable bacteria growing inhibiting and effect long-acting, no hemolytic toxicity.
A treated animal source property cationic antibacterial peptide of the present invention comprises also that N-terminal in the above polypeptide or the verivate and/or the modification of C-terminal, amino acid whose replacement, replacement, cyclisation, L-type amino acid become D-type amino acid, disappearance or adding and the functionally similar polypeptide that obtains or intend peptide.
Antibacterial peptide its preparation method of the present invention can be that mechanochemical method is directly synthetic.The antibacterial peptide of preparation is identified through mass spectrum.
Antibacterial peptide of the present invention also might act on high organism and comprise human body cell in efficient sterilizing, because the mode of action of antibacterial peptide all is that perforation causes cell generation seepage dead on cytolemma.So, can make red corpuscle generation seepage whether have a toxic standard antibacterial peptide as it, if antibiotic Toplink makes the oxyphorase generation seepage in the red corpuscle, can be through detecting OD
490Value is confirmed toxic size.The present invention has also detected the hemolytic activity of antibacterial peptide to human erythrocyte, and experiment shows that the antibacterial peptide hemolysis rate is still very low under high density, explains that the hemolytic toxicity of antibacterial peptide of the present invention is minimum.
In sum, the present invention provides the antibacterial peptide of one group of novel artificial designing animal source sexual type cationic antibacterial peptide.These antibacterial peptides can adopt mechanochemical method easily.This synthetic antibacterial peptide has the wide spectrum killing activity to gram-positive microorganism, Gram-negative bacteria, and than natural antibacterial peptide stronger fungicidal activity is arranged, and the animal and plant cell is not had any toxic action.
One group of novel animal derived cationic antibacterial peptide has a broad antifungal spectrum according to the invention, without any need for modify to connect and simple in structure, synthetic convenient.No matter the experiment proof is G
+Bacterium (gram-positive microorganism) is G still
-Bacterium (Gram-negative bacteria) all has significant antibacterial and fungicidal activity and longer duration, no hemolytic toxicity, shows that it has important value aspect development and application of treating the bacterial infective diseases medicine.
Description of drawings
Fig. 1 is the mass spectrum of antibacterial peptide CQUT-a;
Fig. 2 is the mass spectrum of antibacterial peptide CQUT-b.
Among Fig. 1, the MS parameter:
Sample size (Injection Volume): 1.00 μ l; Molecular weight (MW): 978.68; Airshed ion source (Probe): ESI;
The temperature (DL Temp) of DL pipe: 300 ° of C; The flow velocity of spraying gun (Gas Flow): 1.5L/min;
Heat fast temperature (Block Temp): 250 ° of C; The flow velocity of moving phase (T.Flow): 0.2ml/min;
The ratio of moving phase (B.conc): 50%H2O/50%ACN.
Among Fig. 2, the MS parameter:
Sample size (Injection Volume): 1.00 μ l; Molecular weight (MW): 1008.14; Airshed ion source (Probe): ESI;
The temperature (DL Temp) of DL pipe: 300 ° of C; The flow velocity of spraying gun (Gas Flow): 1.5L/min;
Heat fast temperature (Block Temp): 250 ° of C; The flow velocity of moving phase (T.Flow): 0.2ml/min;
The ratio of moving phase (B.conc): 50%H2O/50%ACN.
Embodiment
A treated animal source property cationic antibacterial peptide that the present invention relates to is synthetic to design on the plain antibacterial peptide sequence of natural cow's milk iron, the basis of structural analysis, and this series antibacterial peptide sequence comprises:
Sequence 1: antibacterial peptide sequence C QUT-a:Phe Arg Trp Trp Gln Arg;
Sequence 2: antibacterial peptide sequence C QUT-b:Arg Arg Gln Trp Phe Trp.
Design of the present invention is following: basic Lactoferricin B
4-9The RRWQWR sequence works out the peptide sequence among the present invention through test of many times, and experiment shows that the novel animal derived cationic antibacterial peptide of this series all has remarkable anti-microbial activity, and compares LfcinB
4-9Hemolytic toxicity all do not occur, be expected to be used to treat the new drug research and the exploitation of infectation of bacteria.
In order to further investigate biological activity antibacterial peptide structure and function relationship among the present invention, the Pioneer Peptide synthesizer that utilizes U.S. application system biotech firm to produce prepares polypeptide among the present invention and as the antibacterial peptide of contrast, for experimental study.
Utilize agar hollow plate cave diffusion process and 96 well plate method to detect the sterilization and the bacteriostatic activity of polypeptide, with synthetic natural antibacterial peptide Lactoferricin B in advance
4-9RRWQWR is contrast, carries out fungicidal activity and detects, and the result shows that the fungicidal activity of antibacterial peptide among the present invention significantly is better than the fungicidal activity of contrast antibacterial peptide.
Novel animal derived cationic antibacterial peptide CQUT-a, CQUT-b and contrast antibacterial peptide Lactoferricin B
4-9Solid phase synthesis.
Fmoc solid phase program artificial synthetic antimicrobial peptide according to standard: CQUT-a (Phe-Arg-Trp-Trp-Gln-Arg), CQUT-b (Arg-Arg-Gln-Trp-Phe-Trp) and contrast antibacterial peptide Lactoferricin B
4-9(Vydac 218TP1022 post 2.2 * 25cm) purifying adopt acetonitrile/water/trifluoroacetic acid system wash-out, MALDI-TOF and EPI mass spectroscopy to (Arg-Arg-Trp-Gln-Trp-Arg) synthetic peptide through reversed-phase HPLC.Antibacterial peptide synthetic by purple territory, Shanghai bio tech ltd (Shanghai Ziyu Biotechnology Co., Ltd.Shanghai, China).
1. the preparation of antibacterial peptide (CQUT-a with preparation 0.1mmol amount is an example)
Below all the preparation antibacterial peptides reagent all purchase in u.s.a. applied biosystem company.
The CQUT-a peptide sequence of preparation is: Phe-Arg-Trp-Trp-Gln-Arg-NH
2
Preparation holds the N end to carry out one by one from C, is controlled automatically by synthesizer.At first the combination of weighing 0.1mmol first amino acid be the resin (purchasing) of Phe in u.s.a. applied biosystem company; The dress post; With the protection of 20% piperidines dimethyl formamide solution, N cleans again, and the total free aminoacids of 9-tablet held before the breast by officials methoxycarbonyl (Fmoc) protection is dissolved in carbodiimide (DCC); Hydroxybenzotriazole (HOBt)/diisopropyl ethyl amine (DIPEA); Solution after the dissolving is at post cocycle coupled reaction 30min, and trifluoroacetic acid (TFA) cleans the above deprotection of repetition and finishes (the concrete operations step is seen pioneer Peptide synthesizer operational guidance) to the coupled reaction step up to preparation, with ether the polypeptide in the trifluoroacetic acid is separated out; Clean, form the solid crude product polypeptide.
2. the purifying of antibacterial peptide
The dried polypeptide of weighing 100mg is dissolved in 0.1% trifluoroacetic acid 10ml, and reversed-phase liquid chromatography after the sample preparation (RP-HPLC) carries out purifying.System is the H of 0.1% trifluoroacetic acid (TFA)
2O and 0.1% acetonitrile (ACN) are collected elution peak.The target peak that purifying in the liquid chromatography (HPLC) comes out is placed freeze-drying in the Freeze Drying Equipment (50 ℃), after carry out mass spectrum (MS) once more and confirm correctness, HPLC detects purity.
3. the evaluation of antibacterial peptide
As shown in Figure 1, the antibacterial peptide CQUT-a of preparation analyzes through mass spectrum (MS), and CQUT-a shows that in mass spectrum the molecular weight that calculates CQUT-a is 978.68.The theoretical value that is calculated by peptide sequence is 978.12.The polypeptide of proof preparation is the CQUT-a antibacterial peptide of design.The antibacterial peptide product of accreditation is subsequent use.
Antibacterial peptide CQUT-b and contrast antibacterial peptide Lactoferricin B
4-9Employing is similar to preparing method's preparation of CQUT-a antibacterial peptide.
1, the fungicidal activity of animal derived cationic antibacterial peptide detects
Employed various bacterial strains are purchased in Chinese biological goods calibrating institute in following examples.
Adopt the agar plate diffusion process that the fungicidal activity of animal source type cationic antibacterial peptide is detected, and with mechanochemical method synthetic antibacterial peptide Lactoferricin B
4-9RRWQWR is as contrast, to estimate two antibacterial peptide CQUT-a and the fungicidal activity of CQUT-b among the present invention.
Measure the fungicidal activity of antibacterial peptide according to the following steps:
The bacterial classification recovery, the 37 ℃ of overnight cultures in inoculation inclined-plane are chosen bacterium in common LB substratum, 37 ℃ of overnight cultures, it is 10 that dilution bacterium liquid makes bacteria concentration
5～10
6Cfu/ml is inoculated in the 15ml LB solid culture ware by each dull and stereotyped 100 μ l bacterium liquid, and after waiting to solidify, after the coating evenly, punching 5mm, adds concentration 1 mg/ml 10 μ l synthetic antimicrobial peptide solution and LfcinB respectively by 3/flat board
4-9Solution and ultrapure water (LfcinB
4-9As positive control, ultrapure water is as negative control), 4 ℃ leave standstill 3h after, place 37 ℃ to cultivate 8h the flat board after, measure the inhibition zone size, judge sterilizing ability, observe the variation of inhibition zone within 7d simultaneously, judge sterilization time length length.The result sees table 1.
Three kinds of antibacterial peptides of table 11 mg/ml compare the mensuration of the anti-microbial activity of different bacterium
"+", represented 5mm.
In the last table+and number many more, explain that sterilizing ability is strong more.Last table shows that animal derived cationic antibacterial peptide sterilizing ability of the present invention is obvious and is superior to contrasting antibacterial peptide.
In addition, synthetic antibacterial peptide of the present invention is in the time that continues 7d, and the inhibition zone size does not change, and contrast antibacterial peptide inhibition zone takes place obviously to dwindle, and its sterilizing ability longer duration is described.
2, the bacteriostatic activity of animal derived cationic antibacterial peptide antibacterial peptide detects:
Employed various bacterial strains are purchased in Chinese biological goods calibrating institute in following examples.
Adopt 96 well plate method that the fungicidal activity of synthetic antibacterial peptide is detected, and with mechanochemical method synthetic antibacterial peptide Lactoferricin B
4-9RRWQWR is as contrast, to estimate two antibacterial peptide CQUT-a and the bacteriostatic activity of CQUT-b among the present invention.
Measure the bacteriostatic activity of antibacterial peptide according to the following steps:
The bacterial classification recovery, the 37 ℃ of overnight cultures in inoculation inclined-plane are chosen bacterium in common LB substratum, 37 ℃ of overnight cultures, it is 10 that dilution bacterium liquid makes bacteria concentration
4～10
5Cfu/ml is inoculated in 96 orifice plates by every hole 100 μ l bacterium liquid, with polypeptide according to serial dilution after, add 10 μ l in every hole, 96 orifice plates are placed 37 ℃ of overnight cultures, ELIASA detects OD
490Value.Detected result is seen table 2.
Growth concentration (the OD that contains the bacterium of antibacterial peptide
490) the antibacterial peptide concentration that is lower than with the bacterium absorbancy 50% that does not add antibacterial peptide when above is minimal inhibitory concentration (minimal inhibitory concentration (MIC) is defined as the minimum concentration of remarkable bacteria growing inhibiting).
Four kinds of antibacterial peptides of table 2 are to the comparison of the anti-microbial activity minimal inhibitory concentration (MIC) of different bacterium
Minimal inhibitory concentration value in the last table is more little, then represents antibacterial ability strong more.Last table shows that the MIC of animal derived cationic antibacterial peptide of the present invention compares LfcinB
4-9All little, the spy is the effect to gram-positive microorganism, and the antibacterial ability of animal derived cationic antibacterial peptide of the present invention obviously is superior to correlated antibacterial peptide.
3, external hemolytic activity detects:
This case study on implementation is used to detect animal derived cationic antibacterial peptide whether human erythrocyte is had hemolytic activity, and with the synthetic Lactoferricin B of mechanochemical method
4-9RRWQWR is as contrast.The blood sample that uses is taken at normal human blood.
The detection step of the hemolytic activity of animal derived cationic antibacterial peptide antibacterial peptide is:
Agar plate hole diffusion process detects.The HRBC adds in 40 ℃ of solid LB nutrient solutions according to the ratio of 1:20, topples over by each dull and stereotyped 15ml and mixes LB solid culture liquid, and after waiting to solidify, punching 5mm, adds concentration 1 mg/ml 50 μ l synthetic antimicrobial peptide solution and LfcinB respectively by 4/flat board
4-9Solution, tween 80 and ultrapure water (tween 80 is as positive control, and saline water is as negative control), 4 ℃ leave standstill 3h after, place 37 ℃ to cultivate 24h flat board, observe whether to have haemolysis to iris out within the 72h existing, whether judge has hemolytic action.The result sees table 3.
Whether occur the haemolysis circle in three kinds of antibacterial peptide 72h of table 3 and judge that antibacterial peptide has or not hemolytic activity
Animal derived cationic antibacterial peptide antibacterial peptide of the present invention is under 1 mg/ml concentration, and 72h does not have the haemolysis circle, hemolytic activity promptly do not occur.Explain that antibacterial peptide does not show hemolytic poison blood under high density, be better than the contrast antibacterial peptide, established the key foundation of patent medicine for the medicine practical application of research and development treatment infectation of bacteria.
4, external hemolytic activity detects:
This case study on implementation is used to detect animal derived cationic antibacterial peptide to the human erythrocyte hemolysis rate, and with mechanochemical method synthetic antibacterial peptide Lactoferricin B
4-9RRWQWR is as contrast.The blood sample that uses is taken at normal human blood.
The detection step of the hemolysis rate of synthetic antibacterial peptide is:
The release of Freshman red cell suspension oxyphorase under 414nm of 4% detects.(8% HRBC's suspension of getting 100 μ l is in 96 orifice plates for PBS:35mM phosphoric acid buffer/0.15MNaCl, PH7.2) washing through PBS for the HRBC; Every hole adds 100 μ l antibacterial peptide solution, and 37 ℃ after one hour, centrifugal 5 minutes of 1500rpm; Shift 100 μ l supernatants in 96 new orifice plates; Detect the absorption under the 414nm through ELIASA, negative control is used PBS solution, and positive control is with 0.1% Triton X-100 solution.Detected result is seen table 4.
Three kinds of antibacterial peptide haemolysis of table 4 detected result of invigorating blood circulation
The hemolysis rate value of antibacterial peptide is more little in the table, then represents the hemolytic toxicity of antibacterial peptide more little.Last table shows that animal derived cationic antibacterial peptide hemolysis rate is very low, and is very low than contrast natural antibacterial peptide hemolytic toxicity, significantly haemolysis generation particularly do not arranged, for next step patent medicine has important effect under high density.
<210> 1
<211> 6
<212> PRT
< 213>synthetic
<220>
< 223>antibacterial peptide sequence C QUT-a
<400> 1
Phe?Arg?Trp?Trp?Gln?Arg
1 5 6
<210> 2
<211> 6
<212> PRT
< 213>synthetic
<220>
< 223>antibacterial peptide sequence C QUT-b
<400> 2
Arg?Arg?Gln?Trp?Phe?Trp
1 5 6
Claims (6)
1. a treated animal source property cationic antibacterial peptide is characterized in that this antibacterial peptide sequence comprises:
CQUT-a：Phe?Arg?Trp?Trp?Gln?Arg；
CQUT-b：Arg?Arg?Gln?Trp?Phe?Trp。
2. a treated animal source property cationic antibacterial peptide is serial; It is characterized in that; Comprise the said sequence of claim 1, comprise also that the N-terminal in polypeptide or the verivate and/or the modification of C-terminal, amino acid whose replacement, replacement, cyclisation, L-type amino acid become D-type amino acid, disappearance or adding and the functionally similar polypeptide that obtains or intend peptide.
3. animal derived according to claim 1 cationic antibacterial peptide is characterized in that, in the application of treatment infectation of bacteria.
4. animal derived according to claim 1 cationic antibacterial peptide; It is characterized in that; Suppressing microbial growth, and be prepared into pharmaceutical composition and be used for treatment and prevention by the caused infection of multiple mikrobe, wherein said mikrobe comprises gram-positive microorganism and gram-positive microorganism.
5. like the said animal derived cationic antibacterial peptide series of claim 2, it is characterized in that, in the application of treatment infectation of bacteria.
6. like the said animal derived cationic antibacterial peptide series of claim 2; It is characterized in that; Suppressing microbial growth, and be prepared into pharmaceutical composition and be used for treatment and prevention by the caused infection of multiple mikrobe, wherein said mikrobe comprises gram-positive microorganism and gram-positive microorganism.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382217A (en) * | 2012-12-11 | 2013-11-06 | 任发政 | Cell-penetrating peptide and pharmaceutical composition and preparation method and application thereof |
| CN107344958A (en) * | 2017-03-31 | 2017-11-14 | 重庆理工大学 | Antibacterial pentapeptide derivative and its application |
| CN109553677A (en) * | 2018-11-30 | 2019-04-02 | 东北农业大学 | Derived peptide W8 and its preparation method and application based on amphibian animal frog derived antimicrobial peptide |
| CN113248572A (en) * | 2021-04-30 | 2021-08-13 | 重庆理工大学 | Anti-multidrug-resistant bacteria cyclopeptide and application thereof |
| CN114149487A (en) * | 2021-11-11 | 2022-03-08 | 东北农业大学 | Antibacterial peptide WR and hyaluronic acid coating substance and application thereof |
Citations (1)
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| WO2009050279A1 (en) * | 2007-10-19 | 2009-04-23 | Pharmasurgics In Sweden Ab | Peptides based on the sequence of human lactoferrin and their use |
-
2011
- 2011-12-13 CN CN201110414617.4A patent/CN102391362B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009050279A1 (en) * | 2007-10-19 | 2009-04-23 | Pharmasurgics In Sweden Ab | Peptides based on the sequence of human lactoferrin and their use |
Non-Patent Citations (2)
| Title |
|---|
| HANNE H. HAUKLAND, ET AL.: "Post-antibiotic effect of the antimicrobial peptide lactoferricin on Escherichia coli and Staphylococcus aureus", 《JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY》 * |
| JOHAN SVENSON,ET AL.: "Metabolic Fate of Lactoferricin-Based Antimicrobial Peptides: Effect of Truncation and Incorporation of Amino Acid Analogs on the In Vitro Metabolic Stability", 《THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382217A (en) * | 2012-12-11 | 2013-11-06 | 任发政 | Cell-penetrating peptide and pharmaceutical composition and preparation method and application thereof |
| CN107344958A (en) * | 2017-03-31 | 2017-11-14 | 重庆理工大学 | Antibacterial pentapeptide derivative and its application |
| CN107344958B (en) * | 2017-03-31 | 2020-09-04 | 重庆理工大学 | Antibacterial pentapeptide derivative and application thereof |
| CN109553677A (en) * | 2018-11-30 | 2019-04-02 | 东北农业大学 | Derived peptide W8 and its preparation method and application based on amphibian animal frog derived antimicrobial peptide |
| CN109553677B (en) * | 2018-11-30 | 2021-12-14 | 东北农业大学 | Derivative peptide W8 based on amphibious frog-derived antibacterial peptide and preparation method and application thereof |
| CN113248572A (en) * | 2021-04-30 | 2021-08-13 | 重庆理工大学 | Anti-multidrug-resistant bacteria cyclopeptide and application thereof |
| CN114149487A (en) * | 2021-11-11 | 2022-03-08 | 东北农业大学 | Antibacterial peptide WR and hyaluronic acid coating substance and application thereof |
| CN114149487B (en) * | 2021-11-11 | 2022-09-02 | 东北农业大学 | Antibacterial peptide WR and hyaluronic acid coating substance and application thereof |
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| CN102391362B (en) | 2014-05-07 |
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