CN104356202A - Cationic antibacterial peptide as well as preparation method and application thereof - Google Patents
Cationic antibacterial peptide as well as preparation method and application thereof Download PDFInfo
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- CN104356202A CN104356202A CN201410615808.0A CN201410615808A CN104356202A CN 104356202 A CN104356202 A CN 104356202A CN 201410615808 A CN201410615808 A CN 201410615808A CN 104356202 A CN104356202 A CN 104356202A
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Abstract
The invention discloses cationic antibacterial peptide as well as a preparation method and application thereof. The sequence of the cationic antibacterial peptide is as follows: SK1:FRWWR-NH2((Phe-Arg-Trp-Trp-Arg-NH2); the preparation method is a solid phase chemical synthesis method. the cationic antibacterial peptide provided by the invention has broad-spectrum killing activity to gram-positive bacteria and gram-negative bacteria and has higher bactericidal activity when being compared with natural antibacterial peptide; besides, the cationic antibacterial peptide has the advantages that the structure is simple, artificial synthesis is convenient, no decorative connection is required, the hemolytic toxicity is small, and no toxic effect is caused to animal and plant cells; the cationic antibacterial peptide has very important values in the aspects of development and application of antibacterial medicines.
Description
Technical field
The invention belongs to biological pharmacy technical field, relate to antibacterial peptide and its preparation method and application, be specifically related to cationic antibacterial peptide and preparation method thereof and the application in treatment bacterial infective diseases.
Background technology
Since microbiotic invention, the mankind achieve huge achievement in control and treatment infected by microbes.But along with current antibiotic lasting use, microbial resistance has become the significant problem that infected by microbes controls, to such an extent as to now certain micro-organisms bacterium does not control the material killed, as in clinical drug therapy, the staphylococcus of Vancomycin resistant, faecalis and other gram positive bacterial infection diseases, the treatment of these diseases is all worldwide difficult problems.
Antibacterial peptide is the micromolecule polypeptide that a class is extensively present in microorganism and animal and plant body, is usually made up of more than 30 amino-acid residues, and molecular weight is 2-7KDa.The bactericidal mechanism of antibacterial peptide is that it can destroy the cytolemma of bacterium, causes entocyte to overflow because of high osmotic pressure, finally causes bacterial death.
Antibacterial peptide medically demonstrates good application prospect because of biologic activity widely, but existing natural antibacterial peptide also existing defects in content, anti-microbial activity and hemolytic action etc.Due to antibacterial peptide, content is atomic in animal body, extracts low, the time-consuming length of yield of antibacterial peptides, complex process, somewhat expensive in animal body, and this becomes the biggest obstacle that restriction natural antibacterial peptide enters practical application.
In recent years, the effect of improvement on synthesis in human body is found by scientific circles more and more, and its medical benefit produced also result in showing great attention to of people.Wherein cationic antibacterial peptide can as the novel microbiotic of a class, using cytolemma as major target class, by assembling on cytolemma and causing the increase of cell permeability, thus makes cytolemma lose its function of shielding, and then causes necrocytosis.But, at present disclosed cationic antibacterial peptide complex structure, anti-microbial activity is lower and have higher hemolytic toxicity, therefore, exploitation has that structure is simple, anti-microbial activity is high, chemosynthesis is easy and the cationic antibacterial peptide of the low feature of hemolytic toxicity is urgent can not treat.
Summary of the invention
For prior art above shortcomings, the object of this invention is to provide that a kind of structure is simple, anti-microbial activity is high and the cationic antibacterial peptide that hemolytic toxicity is low.
Another object of the present invention is to provide the preparation method of quick, easy a kind of cationic antibacterial peptide.
The present invention also provides the application of above-mentioned cationic antibacterial peptide.
Realize above-mentioned purpose, the present invention adopts following technical scheme: a kind of cationic antibacterial peptide, it is characterized in that, antibacterial peptide sequence Lactoferricin B4-9(RRWQWR in natural discovery) basis on, combined with virtual combinatorial libraries designing technique, design one group and contain 5 amino acid whose peptide sequences, sequence is: SK1:FRWWR-NH2 ((Phe-Arg-Trp-Trp-Arg-NH2).
The preparation method of above-mentioned cationic antibacterial peptide, adopts solid-state chemical reaction method method to synthesize from N-terminal to C-terminal; Specifically comprise the steps:
(1) preparation of antibacterial peptide:
Prepare and hold C end to carry out one by one from N, automatically controlled by Peptide synthesizer, first the resin combining first amino acid and Phe of 0.1 mmol is weighed, dress post, use 20%(v/v again) piperidines dimethyl formamide solution deprotection, then clean with dimethyl formamide, the amino acid Arg protected with 9-tablet held before the breast by officials methoxycarbonyl (Fmoc) is dissolved in carbodiimide (DCC), and add hydroxybenzotriazole (HOBt)/diisopropyl ethyl amine (DIPEA), solution after dissolving is after post cocycle coupled reaction 30 min, clean with trifluoroacetic acid (TFA), and repeat above deprotection to coupled reaction step until in SK1 sequence all amino acid be all access in, preparation terminates, with ether, the polypeptide in trifluoroacetic acid is separated out, cleaning, form solid crude product antibacterial peptide,
(2) purifying of antibacterial peptide:
Weigh 10mg dried solid crude product antibacterial peptide SK1, be dissolved in 10mL 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution in, with reversed-phase liquid chromatography (Vydac 218TP1022 post after sample preparation, 2.2 × 25cm) carry out purifying, elutriant: mobile phase A is 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution, Mobile phase B is 0.1%(v/v) acetonitrile (ACN) ultrapure water solution; Gradient is: A phase: 5% ~ 30%(v/v); Flow velocity 15 mL/min, determined wavelength 220nm, sampling volume is 4 mL, collects elution peak; And the target peak be purified by reversed-phase liquid chromatography (RP-HPLC) is placed in Freeze Drying Equipment, after-50 DEG C of freeze-drying, then confirm correctness with mass spectrum, HPLC detects purity.
Compared to existing technology, the present invention has following beneficial effect:
(1) subject cationic antibacterial peptide structure is simple, and synthetic is convenient, connects, lay a good foundation for the present invention is prepared on a large scale without any need for modification.
(2) hemolysis rate under subject cationic antibacterial peptide SK1 high density is very low, shows that the hemolytic toxicity of antibacterial peptide of the present invention is minimum, for practical application exploitation is laid a good foundation.
(3) subject cationic antibacterial peptide SK1 has wide spectrum killing activity to gram-positive microorganism and Gram-negative bacteria, and has stronger sterilization and bacteriostatic activity compared with natural antibacterial peptide.
(4) subject cationic antibacterial peptide SK1 mechanism of action is different from conventional antibiotic, all has good anti-microbial effect to the multiple drug-resistant bacteria of experiment, intends being developed as a kind of drug-resistance bacteria medicine.
(5) subject cationic antibacterial peptide SK1 is when agar hole diffusion process measures external activity, can keep long anti-microbial activity, show that antibacterial peptide has good resistant to hydrolysis ability.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of subject cationic antibacterial peptide SK1.
Embodiment
Below in conjunction with drawings and Examples, the present invention is described in further detail.
In embodiment, all reagent for the preparation of antibacterial peptide is all purchased from Applied biosystems, and all various bacterial strains for active determination test are all purchased from Products in China calibrating institute.
The present invention designs as follows: at Lactoferricin B
4-9(RRWQWR) on basis, combined with virtual newly closes storehouse designing technique, use DNAstar, analysis software and the websites such as Bioedit, sequence logo, obtain serial pentapeptide molecule after being replaced and intercepting by amino acid, and after campaign, find that this antibacterial peptide has remarkable anti-microbial activity, and compare LfcinB6 and do not occur hemolytic toxicity, be expected to the new drug research as treatment bacteriological infection and exploitation.
embodiment 1:
(1) preparation (to prepare 0.1mmol amount) of antibacterial peptide:
Prepare and hold C end to carry out one by one from N, automatically controlled by pioneer Peptide synthesizer.First the resin (being purchased from Applied biosystems) combining first amino acid and Phe of 0.1mmol is weighed, dress post, use 20%(v/v again) piperidines dimethyl formamide solution deprotection, then clean with dimethyl formamide, the amino acid Arg protected with 9-tablet held before the breast by officials methoxycarbonyl (Fmoc) is dissolved in carbodiimide (DCC), and add hydroxybenzotriazole (HOBt)/diisopropyl ethyl amine (DIPEA), solution after dissolving is after post cocycle coupled reaction 30min, clean with trifluoroacetic acid (TFA), and repeat above deprotection to coupled reaction step until in SK1 sequence all amino acid be all access in, preparation terminates, (concrete operation step is shown in pioneer Peptide synthesizer operational guidance), with ether, the polypeptide in trifluoroacetic acid is separated out, cleaning, form solid crude product antibacterial peptide.
(2) purifying of antibacterial peptide:
Weigh a certain amount of (10mg) dried solid crude product antibacterial peptide SK1, be dissolved in 10mL 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution in, with reversed-phase liquid chromatography (Vydac 218TP1022 post after sample preparation, 2.2 × 25cm) carry out purifying, elutriant: mobile phase A is 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution, Mobile phase B is 0.1%(v/v) acetonitrile (ACN) ultrapure water solution; Gradient is: A phase: 5% ~ 30%(v/v); Flow velocity 15 mL/min, determined wavelength 220nm, sampling volume is 4mL, collects elution peak.And the target peak be purified by reversed-phase liquid chromatography (RP-HPLC) is placed in Freeze Drying Equipment, after-50 DEG C of freeze-drying, then confirm correctness with mass spectrum, HPLC detects purity.
(3) qualification of antibacterial peptide:
See Fig. 1, the cationic antibacterial peptide SK1 of preparation analyzes through MALDI-TOF and EPI mass spectrum (MS), and Mass Spectrometry Conditions is: ESI positive ion mode, spray voltage: 4.5 KV; Sheath gas: 35 arb; Assisted gas: 10 arb; Capillary temperature: 300 DEG C; Collision gas: argon gas (1.5 mtorr), result shows, and it is 848.99 that SK1 shows molecular weight in mass spectrum, and the theoretical value calculated by peptide sequence is 849.00.Namely prove that the polypeptide prepared is the SK1 antibacterial peptide of design.Qualified antibacterial peptide product is for subsequent use.
In order to further investigate the Structure and Function of subject cationic bioactive peptide SK1, cationic antibacterial peptide SK1 disclosed by the invention and antibacterial peptide LfcinB6 in contrast prepared by the Pioneer polypeptide positively charged ion instrument utilizing application system biotech firm of the U.S. to produce, and carries out following active determination test.
(4) mensuration of antibacterial peptide fungicidal activity:
Adopt the fungicidal activity of agar plate diffusion process to synthetic antibacterial peptide SK1 to detect, and with the antibacterial peptide LfcinB6 of mechanochemical method synthesis in contrast, evaluate the fungicidal activity of antibacterial peptide SK1 in the present invention, step is as follows:
Bacterial classification is recovered, and inoculates inclined-plane respectively in 37 DEG C of overnight incubation, then chooses bacterium in common LB substratum, 37 DEG C of overnight incubation, and dilution bacterium liquid makes bacteria concentration be 10
5~ 10
6cfu/mL, be inoculated in 15mL LB solid culture ware by each dull and stereotyped 100 μ L bacterium liquid, after to be solidified and coating is even, punching 5mm, 3/dull and stereotyped, adding concentration is respectively that (LfcinB6 is as positive control for each 10 μ L solution of the cationic antibacterial peptide SK1 solution of 1 mg/mL, the LfcinB6 solution of 1 mg/mL and ultrapure water, ultrapure water is as negative control), after 4 DEG C of standing 3h, flat board is placed in 37 DEG C and cultivates 8h, measure inhibition zone size, judge sterilizing ability, observe the change of inhibition zone within 7d simultaneously, judge sterilization time length length.The results are shown in Table 1.
the mensuration of table 11 mg/mL antibacterial peptide to the anti-microbial activity of different bacterium compares
"+", represents 5mm.
In table "+" number more the bright sterilizing ability of multilist is stronger.Upper table display cationic antibacterial peptide SK1 sterilizing ability of the present invention obviously and be better than contrast antibacterial peptide LfcinB6.
In addition, synthetic antibacterial peptide SK1 of the present invention is in the time of lasting 7d, and inhibition zone size does not change, and contrast antibacterial peptide inhibition zone occur obviously reduce, show that the synthetic antibacterial peptide SK1 sterilizing ability time length of the present invention is long.
(5) bacteriostatic activity of antibacterial peptide detects:
Adopt the fungicidal activity of 96 well plate method to cationic antibacterial peptide SK1 to detect, and the cationic antibacterial peptide LfcinB6 prepared with mechanochemical method in contrast, to evaluate the bacteriostatic activity of antibacterial peptide SK1 in the present invention.
Testing sequence is as follows: bacterial classification is recovered, and bacterium, in 37 DEG C of overnight incubation, is then chosen in common LB substratum, 37 DEG C of overnight incubation in inoculation inclined-plane, and dilution bacterium liquid makes bacteria concentration be 10
4~ 10
5cfu/mL, is inoculated in 96 orifice plates by every hole 100 μ L bacterium liquid, by antibacterial peptide according to after serial dilution, adds 10 μ L in every hole, 96 orifice plates are placed in 37 DEG C of overnight incubation, and microplate reader detects OD
620value.Detected result is in table 2.
Wherein, the growth concentration (OD of the bacterium containing antibacterial peptide
620) antibacterial peptide concentration when being greater than 90% with the ratio of bacterial growth concentration not adding antibacterial peptide is minimal inhibitory concentration (minimal inhibitory concentration (MIC) is defined as the minimum concentration of remarkable bacteria growing inhibiting).
table 2 antibacterial peptide is to the comparison of the anti-microbial activity minimal inhibitory concentration (MIC) of different bacterium
Minimal inhibitory concentration value in table is less, then represent antibacterial ability stronger.Find out from upper table, antibacterial peptide SK1 of the present invention has significant bacteriostatic activity, and MIC is obviously better than LfcinB6, and particularly for the effect of gram-positive microorganism, the antibacterial ability of synthetic antibacterial peptide of the present invention is better than contrast antibacterial peptide greatly.
(6) hemolysis in vitro Activity determination:
Whether this experiment has hemolytic activity for detecting cationic antibacterial peptide SK1 to human erythrocyte, and the cationic antibacterial peptide LfcinB6 prepared with mechanochemical method in contrast.The blood sample used is taken at normal human blood.
Detecting step is as follows: use agar plate hole diffusion process to detect, the blood sample used is taken at normal people's erythrocyte, add in 40 DEG C of solid LB nutrient solutions according to the ratio of 1:20, mixing LB solid culture liquid is toppled over by each dull and stereotyped 15mL, after to be solidified, punching 5mm, 4/dull and stereotyped, add the cationic antibacterial peptide SK1 solution of concentration 1 mg/mL respectively, the LfcinB6 solution of 1 mg/mL, (tween 80 is as positive control for tween 80 and each 50 μ L of physiological saline, physiological saline is as negative control), after 4 DEG C of standing 3h, flat board is placed in 37 DEG C and cultivates 24h, whether observe within 72h has haemolysis to iris out now, determine whether hemolytic action.The results are shown in Table 3.
table 3 hemolysis in vitro activity assays result
Cationic antibacterial peptide SK1 of the present invention is under 1 mg/mL concentration, and 72h, without haemolysis circle, does not namely occur hemolytic toxicity.Illustrate that subject cationic antibacterial peptide SK1 does not show hemolytic toxicity in higher concentrations, be better than contrast antibacterial peptide LfcinB6, for the key foundation of patent medicine has been established in the medicine practical application of research and development treatment bacteriological infection.
(7) hemolysis in vitro Activity determination:
The present embodiment for detecting synthetic antibacterial peptide to human erythrocyte hemolysis rate, and with mechanochemical method synthesis antibacterial peptide LfcinB6 in contrast.The blood sample used is taken at normal human blood.
This experiment detects based on the release of Freshman red blood cell suspension oxyphorase under 414nm of 4%.Detecting step is as follows: Freshman red corpuscle is through PBS(PBS:35mM phosphoric acid buffer/0.15MNaCl, PH7.2) wash, and be configured to 8%(v/v) HRBC suspension, get 100 μ L HRBC suspensions in 96 orifice plates, every hole adds 100 μ L antibacterial peptide solution, 37 DEG C after one hour, centrifugal 5 minutes of 1500rpm, shift 100 μ L supernatants in 96 new orifice plates, the absorption under 414nm is detected by microplate reader, negative control is PBS solution (PBS:35mM phosphoric acid buffer/0.15MNaCl, PH7.2), positive control 0.1%(v/v) Triton X-100 solution.Detected result is in table 4.
table 4 antibacterial peptide haemolysis is invigorated blood circulation detected result
In table, the hemolysis rate value of antibacterial peptide is less, then the hemolytic toxicity representing antibacterial peptide is less.It is very low compared to the hemolysis rate of contrast natural antibacterial peptide that table 4 shows cationic antibacterial peptide SK1, particularly do not have significantly haemolysis to occur in higher concentrations, for solid foundation established by lower one step patent medicine.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although applicant's reference preferred embodiment is to invention has been detailed description, those of ordinary skill in the art is to be understood that, technical scheme of the present invention is modified or equivalent replacement, and do not depart from the aim of technical solution of the present invention and scope, all should be encompassed in the middle of right of the present invention.
<110> Southwestern University;
<120> cationic antibacterial peptide and preparation method thereof and application;
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> artificial sequence
<220>
Aminoacid sequence shown in <223> cationic antibacterial peptide SK1
<400> 1
Phe Arg Trp Trp Arg 5
Claims (4)
1. a cationic antibacterial peptide, is characterized in that, at the antibacterial peptide sequence Lactoferricin B of natural discovery
4-9(RRWQWR), on basis, combined with virtual combinatorial libraries designing technique, design one group and contain 5 amino acid whose peptide sequences, sequence is: SK1:FRWWR-NH
2((Phe-Arg-Trp-Trp-Arg-NH
2).
2. a preparation method for cationic antibacterial peptide as claimed in claim 1, is characterized in that, adopts solid-state chemical reaction method method to synthesize from N-terminal to C-terminal; Specifically comprise the steps:
(1) preparation of antibacterial peptide:
Prepare and hold C end to carry out one by one from N, automatically controlled by Peptide synthesizer, first the resin combining first amino acid and Phe of 0.1 mmol is weighed, dress post, use 20%(v/v again) piperidines dimethyl formamide solution deprotection, then clean with dimethyl formamide, the amino acid Arg protected with 9-tablet held before the breast by officials methoxycarbonyl (Fmoc) is dissolved in carbodiimide (DCC), and add hydroxybenzotriazole (HOBt)/diisopropyl ethyl amine (DIPEA), solution after dissolving is after post cocycle coupled reaction 30 min, clean with trifluoroacetic acid (TFA), and repeat above deprotection to coupled reaction step until in SK1 sequence all amino acid be all access in, preparation terminates, with ether, the polypeptide in trifluoroacetic acid is separated out, cleaning, form solid crude product antibacterial peptide,
(2) purifying of antibacterial peptide:
Weigh 10mg dried solid crude product antibacterial peptide SK1, be dissolved in 10mL 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution in, with reversed-phase liquid chromatography (Vydac 218TP1022 post after sample preparation, 2.2 × 25cm) carry out purifying, elutriant: mobile phase A is 0.1%(v/v) trifluoroacetic acid (TFA) ultrapure water solution, Mobile phase B is 0.1%(v/v) acetonitrile (ACN) ultrapure water solution; Gradient is: A phase: 5% ~ 30%(v/v); Flow velocity 15 mL/min, determined wavelength 220nm, sampling volume is 4 mL, collects elution peak; And the target peak be purified by reversed-phase liquid chromatography (RP-HPLC) is placed in Freeze Drying Equipment, after-50 DEG C of freeze-drying, then confirm correctness with mass spectrum, HPLC detects purity.
3. the application of cationic antibacterial peptide in preparation treatment bacterial infective diseases medicine as claimed in claim 1.
4. the application of cationic antibacterial peptide in preparation treatment Gram-negative bacteria and/or gram-positive microorganism disease medicament as claimed in claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248572A (en) * | 2021-04-30 | 2021-08-13 | 重庆理工大学 | Anti-multidrug-resistant bacteria cyclopeptide and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641370A (en) * | 2007-02-02 | 2010-02-03 | 诺瓦生命科学有限公司 | Basic peptides and their use as combined antibacterial-antifungine agents |
| CN102432672A (en) * | 2011-12-13 | 2012-05-02 | 重庆理工大学 | Novel synthesis antibacterial peptides and application thereof |
-
2014
- 2014-11-06 CN CN201410615808.0A patent/CN104356202A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641370A (en) * | 2007-02-02 | 2010-02-03 | 诺瓦生命科学有限公司 | Basic peptides and their use as combined antibacterial-antifungine agents |
| CN102432672A (en) * | 2011-12-13 | 2012-05-02 | 重庆理工大学 | Novel synthesis antibacterial peptides and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| LEONARD T. NGUYEN ET AL.: "Serum Stabilities of Short Tryptophan- and Arginine-Rich Antimicrobial Peptide Analogs", 《PLOS ONE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248572A (en) * | 2021-04-30 | 2021-08-13 | 重庆理工大学 | Anti-multidrug-resistant bacteria cyclopeptide and application thereof |
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