CN104292301A - Micromolecule synthesized anti-microbial peptide, as well as preparation method and application thereof - Google Patents
Micromolecule synthesized anti-microbial peptide, as well as preparation method and application thereof Download PDFInfo
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- CN104292301A CN104292301A CN201410616342.6A CN201410616342A CN104292301A CN 104292301 A CN104292301 A CN 104292301A CN 201410616342 A CN201410616342 A CN 201410616342A CN 104292301 A CN104292301 A CN 104292301A
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Abstract
The invention discloses a micromolecule synthesized anti-microbial peptide, as well as a preparation method and application thereof. The sequence of a cationic anti-microbial peptide is SQ1: R-W-W-R-F-NH2 (Arg-Arg-Trp-Trp-Arg-NH2), and the preparation method is the solid-phase chemosynthesis method. The micromolecule synthesized anti-microbial peptide has broad-spectrum cytotoxicity to gram-positive bacteria and gram-negative bacteria, has stronger bactericidal activity than a natural anti-microbial peptide, is simple in structure, convenient for artificial synthesis without any modification and connection, has the advantages of small hemolytic toxicity and no poison effects on animal and plant cells, and has an important value in development and application of antimicrobial agents.
Description
Technical field
The invention belongs to biological pharmacy technical field, be specifically related to a kind of small molecules synthetic antibacterial peptide and its preparation method and application.
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 small molecules synthetic antibacterial peptide that hemolytic toxicity is low.
The present invention is also to provide a kind of method of quick, the above-mentioned small molecules synthetic antibacterial peptide of simple preparation.
The present invention also provides the application of described small molecules synthetic antibacterial peptide in medicine.
To achieve these goals, the present invention adopts following technical scheme: a kind of small molecules synthetic antibacterial peptide, is characterized in that, the basis of the sequence to natural antibacterial peptide, structural analysis designs and synthesizes, and its sequence is: SQ1:R-W-W-R-F-NH
2(Arg-Arg-Trp-Trp-Arg-NH
2).
The preparation method of described small molecules synthetic antibacterial peptide, adopt solid-state chemical reaction method method to synthesize from N-terminal to C-terminal, concrete steps are:
(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 Arg 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 SQ1 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 SQ1, 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.
Further, the present invention also provides the application of described small molecules synthetic antibacterial peptide in preparation treatment bacterial infective diseases medicine, and the application in preparation treatment Gram-negative bacteria and/or gram-positive microorganism.
Compared to existing technology, the present invention has following beneficial effect:
(1) small molecules synthetic antibacterial peptide structure of the present invention is simple, and do not need to carry out any modification connection, preparation cost is cheap, lays a good foundation for the present invention is prepared on a large scale.
(2) small molecules synthetic antibacterial peptide of the present invention 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.
(3) hemolysis rate under small molecules synthetic antibacterial peptide SQ1 high density of the present invention 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.
(4) small molecules synthetic antibacterial peptide SQ1 mechanism of action of the present invention 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) small molecules synthetic antibacterial peptide SQ1 of the present invention 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 small molecules synthetic antibacterial peptide SQ1 of the present invention.
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.
Design philosophy of the present invention is as follows: find after test of many times 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 small molecules synthetic 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 Arg 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 SQ1 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 SQ1, 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 220 nm, 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) qualification of antibacterial peptide:
See Fig. 1, the small molecules synthetic antibacterial peptide SQ1 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 SQ1 shows molecular weight in mass spectrum, and the theoretical value calculated by peptide sequence is 848.99, proves that the polypeptide prepared is the antibacterial peptide SQ1 of design.And by for subsequent use for qualified antibacterial peptide SQ1 cryopreservation.
In order to further investigate the Structure and Function of small molecules synthetic antibacterial peptide SQ1 of the present invention, cationic antibacterial peptide SQ1 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 hole diffusion process to cationic antibacterial peptide SQ1 to detect, with LfcinB6 in contrast, evaluate the fungicidal activity of subject cationic antibacterial peptide SQ1, concrete steps are as follows:
Bacterial classification is recovered, and is inoculated in inclined-plane respectively, and in 37 DEG C of overnight incubation, then choose bacterium in common LB substratum, 37 DEG C of overnight incubation, 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 SQ1 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.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.Cationic antibacterial peptide SQ1 sterilizing ability of the present invention is shown and to contrast antibacterial peptide LfcinB6 suitable in upper table.
(5) bacteriostatic activity of small molecules synthetic antibacterial peptide detects:
Adopt the fungicidal activity of 96 well plate method to cationic antibacterial peptide SQ1 to detect, and the cationic antibacterial peptide LfcinB6 prepared with mechanochemical method in contrast, to evaluate the bacteriostatic activity of antibacterial peptide SQ1 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 SQ1 of the present invention has significant bacteriostatic activity, and MIC is obviously better than LfcinB6, shows that antibacterial ability is better than the antibacterial peptide LfcinB6 of contrast greatly.
(6) hemolysis in vitro Activity determination:
Whether this experiment has hemolytic activity for detecting cationic antibacterial peptide SQ1 to animal erythrocyte, and the cationic antibacterial peptide LfcinB6 prepared with mechanochemical method in contrast.The blood sample used is taken at defiber Sheep Blood.
Detecting step is as follows: use agar plate hole diffusion process to detect, defiber sheep erythrocyte adds 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 SQ1 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
Small molecules synthetic antibacterial peptide SQ1 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 SQ1 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:
This test for detecting small molecules synthetic antibacterial peptide SQ1 to sheep erythrocyte hemolysis rate, and with the obtained cationic antibacterial peptide LfcinB6 of mechanochemical method in contrast.The blood sample used is taken at defiber Sheep Blood.
This experiment detects based on the release of fresh sheep red blood cell suspension oxyphorase under 414nm of 4%.Step is as follows: fresh sheep erythrocytes is through PBS(PBS:35mM phosphoric acid buffer/0.15MNaCl, PH7.2) wash, and be configured to 8%(v/v) fresh sheep erythrocytes suspension, get 100 μ L red cell 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.The hemolysis rate that table 4 shows cationic antibacterial peptide SQ1 is very low, very low compared to contrast natural antibacterial peptide LfcinB6 hemolytic toxicity, does not particularly 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> small molecules synthetic 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> small molecules synthetic antibacterial peptide SQ1
<400> 1
Arg Arg Trp Trp Arg 5
Claims (4)
1. a small molecules synthetic antibacterial peptide, is characterized in that, the basis of the sequence to natural antibacterial peptide, structural analysis designs and synthesizes, and its sequence is: SQ1:R-W-W-R-F-NH
2(Arg-Arg-Trp-Trp-Arg-NH
2).
2. the preparation method of small molecules synthetic antibacterial peptide as claimed in claim 1, is characterized in that, adopt solid-state chemical reaction method method to synthesize from N-terminal to C-terminal, concrete steps are:
(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 Arg 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 SQ1 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 SQ1, 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 small molecules synthetic antibacterial peptide in preparation treatment bacterial infective diseases medicine as claimed in claim 1.
4. the application of small molecules synthetic 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 (6)
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| CN105237626A (en) * | 2015-10-19 | 2016-01-13 | 河南科技学院 | Antimicrobial peptide HJH-3 and application thereof |
| CN106916205A (en) * | 2017-03-31 | 2017-07-04 | 重庆理工大学 | Antibacterial hexapeptide and its derivative and application |
| CN107344958A (en) * | 2017-03-31 | 2017-11-14 | 重庆理工大学 | Antibacterial pentapeptide derivative and its application |
| CN108264539A (en) * | 2017-12-28 | 2018-07-10 | 河南科技学院 | A kind of antibacterial peptide RL-18 and its application |
| CN109758572A (en) * | 2018-12-20 | 2019-05-17 | 中国农业科学院饲料研究所 | The application of N6 derived peptide |
| CN111253470A (en) * | 2019-11-22 | 2020-06-09 | 宁波大学 | Immunomodulatory factor IDR-1018 derived peptides and uses thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237626A (en) * | 2015-10-19 | 2016-01-13 | 河南科技学院 | Antimicrobial peptide HJH-3 and application thereof |
| CN105237626B (en) * | 2015-10-19 | 2018-12-18 | 河南科技学院 | A kind of antibacterial peptide HJH-3 and its application |
| CN106916205A (en) * | 2017-03-31 | 2017-07-04 | 重庆理工大学 | Antibacterial hexapeptide and its derivative and application |
| 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 |
| CN108264539A (en) * | 2017-12-28 | 2018-07-10 | 河南科技学院 | A kind of antibacterial peptide RL-18 and its application |
| CN108264539B (en) * | 2017-12-28 | 2020-12-25 | 河南科技学院 | Antibacterial peptide RL-18 and application thereof |
| CN109758572A (en) * | 2018-12-20 | 2019-05-17 | 中国农业科学院饲料研究所 | The application of N6 derived peptide |
| CN111253470A (en) * | 2019-11-22 | 2020-06-09 | 宁波大学 | Immunomodulatory factor IDR-1018 derived peptides and uses thereof |
| CN111253470B (en) * | 2019-11-22 | 2023-01-10 | 宁波大学 | Immunomodulatory factor IDR-1018 derived peptides and uses thereof |
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Application publication date: 20150121 |