CN110054664A - The branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D and its synthesis and application - Google Patents
The branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D and its synthesis and application Download PDFInfo
- Publication number
- CN110054664A CN110054664A CN201910320083.5A CN201910320083A CN110054664A CN 110054664 A CN110054664 A CN 110054664A CN 201910320083 A CN201910320083 A CN 201910320083A CN 110054664 A CN110054664 A CN 110054664A
- Authority
- CN
- China
- Prior art keywords
- fmoc
- ano
- resin
- leu
- amino acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention designs the branched fatty acid modified antimicrobial peptide analogues for having synthesized the amino acid of type containing D, it is using linear amphipathic alpha-helix natural antibacterial peptide Anoplin as template, D type amino acid substitution is enhanced enzymatic hydrolysis stability and carries out the fatty acid modifying enhancing active strategy of antimicrobial agent to D type amino acid side chain after replacement and is combined, branched fatty acid modified antimicrobial the peptide analogues Ano-D4,7-4C of the amino acid of type containing D of obtained a kind of brand newnAnd Ano-D4,7-7Cn, n=4-16.Antibacterial experiment in vitro, PI decoration method flow cytometry tests and enzymatic hydrolysis stability experiment show that the branched fatty acid modified antimicrobial peptide analogues of the present invention amino acid of type containing D have strong antimicrobial agent activity and high enzymatic hydrolysis stability；Compared to conventional antibiotic, the novel antibacterial peptide analogues that the present invention obtains have a good application prospect in terms of the exploitation of clinical antibacterials.
Description
Technical field
The present invention relates to technological field of biochemistry, are related to the branched fatty acid of the amino acid of type containing D of a kind of brand new
Modified antimicrobial peptide analogues and its synthesis and application, in particular to it is a kind of that there is strong antimicrobial agent activity and height to digest stability
The amino acid side chain of type containing D fatty acid modifying antibacterial peptide analogues and its synthesis and application.
Background technique
In recent years, the abuse due to conventional antibiotic in clinical application leads to antibody-resistant bacterium, i.e. " superbacteria " no
It is disconnected to occur, it is somebody's turn to do " superbacteria " and tolerance (Health is shown to most of or all available antibiotic
Econ.1996May-Jun；5(3):217-26).Polymyxin B and polymyxin e (also known as colistin) are as cationic peptides
Antimicrobial is used widely in the 1960s, but due to serious toxicity problem, in the 1970s, its clinic is answered
With greatly reducing.Although the appearance of the gramnegative bacterium with multidrug resistance with prevalence the 1970s, this
There is recovery again in the use of two kinds of antibacterials, becomes last antibiotic, but unfortunately, polymyxins is drug resistant
Also there is (Expert Rev Anti Infect Ther.2012Aug in succession in " superbacteria "；10(8):917-34；Biomed
Res Int.2015；2015:679109).Undoubtedly, the exploitation of a kind of antibiotics has become most important (Lancet
Infect Dis.2013Dec；13(12):1057-98).As a kind of new antibiotic with larger potentiality, antibacterial peptide
(AMPs), especially cationic antibacterial peptide, since it is with broad spectrum antibiotic activity, and can quick sterilization, receive very big pass
Infuse (Chembiochem.2015Jan 19；16(2):242-53).AMPs is usually generated by the biologic artifact of multiplicity, including thin
Bacterium, fungi, plant, insect, amphibian, shellfish, fish and mammal (Clin Microbiol
Rev.2006Jul；19(3):491-511).Mostly important, compared to conventional antibiotic, bacterium is not easy to no specific function
The antibacterial peptide of target spot generates drug resistance.The mode of action of antibacterial peptide is usually directed to the non-specific phase interaction with bacterial cytoplasm film
With so that reach bacterial membrane in antibacterial peptide accumulate, make permeability of the membrane increase and barrier function lose, eventually lead to carefully
The leakage of bacterium content and death (Eur.J.Biochem.2001,268,5589-5600；Nat Rev
Microbiol.2005Mar；3(3):238-50).
However, although AMPs can be expected to defeat " superbacteria ", but as ideal antibacterial compared with conventional antibiotic
Drug, antibacterial activity is bad, the sensibility of host cell toxicity, the intolerance of physiological condition, enzyme degradation, and due to multiple
High manufacturing cost caused by miscellaneous design, limits the clinical application of AMPs.A large number of studies show that the introducing of D type amino acid,
The degradation that protease can effectively be avoided improves enzymatic hydrolysis stability (the Sci Rep.2017Jul 31 of antibacterial peptide；7(1):
6953；Chem Biol Drug Des.2006Feb；67 (2): 162-73), but the introducing of D type amino acid normally results in it and resists
Bacterium activity reduces.And important component of the fatty acid as biological cell membrane phospholipid, hydrophobicity with higher are introduced into
In antibacterial peptide, be conducive to the affinity that it is enhanced to bacterial cell membrane by the hydrophobicity for increasing antibacterial peptide, to enhance it
Antibacterial activity, and fatty acid can also reduce the degradation of protease, enhance the enzymatic hydrolysis stability of antibacterial peptide, extend antibacterial peptibody
Interior action time (Biochem J, 2005,385 (Pt 1): 135-43；Biophys Chem, 2015,199:25-33).
Summary of the invention
An object of the present invention: provide a kind of brand new has strong antimicrobial agent activity and high enzymatic hydrolysis stability
The branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D.
The second object of the present invention: application of the above-mentioned antibacterial peptide analogues in the exploitation of clinical antibacterials is provided.
The third object of the present invention: the synthetic method of above-mentioned antibacterial peptide analogues is provided.
(1) the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D
The branched fatty acid modified antimicrobial peptide analogues of the present invention amino acid of type containing D are the part D in female peptide Anoplin
4 or 7 of type amino acid substitution analog Ano-D4,7 introduce the special non-natural ammonia of D type for having Side chain protective group Mtt
Base acid Fmoc-D-Lys (Mtt)-OH, then sloughs Side chain protective group, carries out not to the side chain of the special unnatural amino acid of D type
With the fatty acid (C of lengthn, n=4-16) and modification, obtain the branched fatty acid modified antimicrobial of the new structural amino acid of type containing D
Peptide analogues Ano-D4,7-4Cn, Ano-D4,7-7Cn, n=4-16.
Structural formula difference is as follows:
Gly-Leu-Leu-D-Lys(Cn)-Arg-Ile-D-Lys-Thr-Leu-Leu-NH2
Wherein n=4-16 is named as Ano-D4,7-4Cn；
Gly-Leu-Leu-D-Lys-Arg-Ile-D-Lys(Cn)-Thr-Leu-Leu-NH2
Wherein n=4-16 is named as Ano-D4,7-7Cn；
The synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the present invention amino acid of type containing D, including following technique
Step:
1、Ano-D4,7-4CnSynthesis
Fmoc-Leu-OH, HOBT, HBTU, DIEA dissolve to mixing in DMF, and with the MBHA that sloughs Fmoc protecting group
Resin carries out condensation reaction, obtains Fmoc-Leu-resin；With method successively condensation reaction amino acid Fmoc-Leu-OH, Fmoc-
Thr(tBu)-OH、Fmoc-D-Lys(Boc)-OH、Fmoc-Ile-OH、Fmoc-Arg(pbf)-OH、Fmoc-D-Lys(Mtt)-
OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Gly-OH obtain Fmoc-Gly-Leu-Leu-D-Lys (Mtt)-Arg-
Ile-D-Lys-Thr-Leu-Leu-resin, as Fmoc-Ano-D4,7-4 (Mtt)-resin；
It is molten with the DCM for being 1%TFA containing volume fraction by Fmoc-Ano-D4 obtained above, 7-4 (Mtt)-resin
Liquid sloughs side chain Mtt protecting group, obtains Ano-D4,7-4 (NH2)-resin；Respectively by fatty acid, HOBT, HBTU and DIEA in
It dissolves and mixes in DMF, and and Ano-D4,7-4 (NH2)-resin progress condensation reaction, obtain Ano-D4,7-4Cn-resin；It will
Ano-D4,7-4Cn- resin cutting, purifying obtain antibacterial peptide analogues Ano-D4,7-4Cn, n=4-16.
2、Ano-D4,7-7CnSynthesis
Fmoc-Leu-OH, HOBT, HBTU, DIEA dissolve to mixing in DMF, and with the MBHA that sloughs Fmoc protecting group
Resin carries out condensation reaction, obtains Fmoc-Leu-resin；With method successively condensation reaction amino acid Fmoc-Leu-OH, Fmoc-
Thr(tBu)-OH、Fmoc-D-Lys(Mtt)-OH、Fmoc-Ile-OH、Fmoc-Arg(pbf)-OH、Fmoc-D-Lys(Boc)-
OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Gly-OH obtain Fmoc-Gly-Leu-Leu-D-Lys-Arg-Ile-D-
Lys (Mtt)-Thr-Leu-Leu-resin, as Fmoc-Ano-D4,7-7 (Mtt) resin；
It is molten with the DCM for being 1%TFA containing volume fraction by Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin
Liquid sloughs side chain Mtt protecting group, obtains Ano-D4,7-7 (NH2)-resin；Respectively by fatty acid, HOBT, HBTU and DIEA in
It dissolves and mixes in DMF, and and Ano-D4,7-7 (NH2)-resin progress condensation reaction, obtain Ano-D4,7-7Cn-resin；It will
Ano-D4,7-7Cn- resin cutting, purifying obtain antibacterial peptide analogues Ano-D4,7-7Cn, n=4-16.
Each amino acid of the above, the concentration of fatty acid, HOBT, HBTU and DIEA in DMF are respectively 20-100mg/
ML, 20-100mg/mL, 10-40mg/mL, 20-100mg/mL, 20-60mg/mL；Each amino acid, fatty acid, HOBT, HBTU with
The molal weight ratio for sloughing the MBHA resin of Fmoc protecting group is 6:1-3:1, DIEA and the MBHA tree for sloughing Fmoc protecting group
The molal weight ratio of rouge is 6:1-12:1.
The cutting reagent is that the mixing that TFA, tri isopropyl silane and water are formed with volume ratio 9.5:0.25:0.25 is molten
Liquid.
The purification process is that thick peptide is first freeze-dried and obtains freeze-dried powder, then carries out RP-HPLC separation；RP-HPLC is pure
Change condition is mobile phase A: the aqueous solution of 0.05%TFA, Mobile phase B: the acetonitrile solution of 0.05%TFA；Linear gradient elution,
Collect the efflux of major absorbance peak.
Through Mass Spectrometric Identification, the method for the present invention successfully synthesizes the branched fatty acid modification of the new structural amino acid of type containing D
Antibacterial peptide analogues Ano-D4,7-4CnAnd Ano-D4,7-7Cn, n=4-16.
(2) activity research outside the branched fatty acid modified antimicrobial peptide similar object of the amino acid of type containing D
1, bacteriostatic experiment
The minimum inhibitory concentration of above-mentioned antibacterial peptide analogues, i.e. MIC value are measured using classical doubling dilution.It is selected
Experimental strain include standard normal strains: E.coli ATCC 25922, P.aeruginos ATCC 27853,
K.pneumoniae ATCC 700603, S.aureus ATCC 25923, B.subtilis ATCC 23857,
S.epidermidis ATCC 12228 and the multiple antibiotic resistant strain being clinically separated: A.baumannii 9828, A.baumannii
9840, P.aeruginosa 1240, P.aeruginosa 1190, E.coli 8500, E.coli 8040, S.aureus
4800, S.aureus 5200.Specific experimental method is as follows: being incubated overnight through MH culture medium to the experiment bacterium of growth logarithmic phase
It is diluted to 1 × 106The bacterial suspension of CFU/mL；Antibacterial peptide analogues are dissolved in sterile water, are made into through doubling dilution
A series of peptide solution of various concentrations of 1-128 μm of ol/L, mixes in equal volume with above-mentioned bacterial suspension, in 96 well culture plates
37 DEG C of incubation 18-24h, observation, the visible Cmin without obvious bacterial growth of naked eyes is minimum inhibitory concentration MIC；Antibiosis
Plain Erythromycin, Kanamycin, Penicillin make positive control drug；Parallel experiment above-mentioned in triplicate, as a result such as table
1 and table 2.
The minimum inhibitory concentration of the confrontation standard normal strains of table 1
The minimum inhibitory concentration of the confrontation multiple antibiotic resistant strain of table 2
Table 1 the result shows that, branched fatty acid modified antimicrobial the peptide analogues Ano-D4,7-4C of the amino acid of type containing DnAnd Ano-
D4,7-7CnThere is good antibacterial activity to standard normal bacteria bacterial strain, antibacterial activity has bright compared to female peptide Anoplin
It is aobvious to improve, and part is better than conventional antibiotic；Table 2 the result shows that, the branched fatty acid modified antimicrobial peptide of the amino acid of type containing D is similar
Object Ano-D4,7-4CnAnd Ano-D4,7-7CnThere is stronger antibacterial activity to the multidrug resistant bacteria strain being clinically separated, resist
Bacterium activity is significantly improved compared to female peptide Anoplin, and is better than conventional antibiotic；With the increase of fatty acid chain length,
Antibacterial peptide analogues significantly increase the antibacterial activity of reference culture and multi-drug resistant bacteria, but when fatty acid chain length increases to
When to a certain degree, antibacterial activity is not further added by.
2, flow cytometry tests
PI staining for flow cell art is carried out using Escherichia coli (ATCC 25922) reference culture and detects antibacterial peptide analogues
To bacterial membrane destruction.Specific experimental method is as follows: the Escherichia coli of culture to logarithmic phase are diluted to 10 × 108CFU/
After mL, PBS (10mM, pH 7.4) washing and half volume is resuspended, and obtains bacterial suspension；Antibacterial peptide analogues are dissolved in PBS,
Concentration is 8 × MIC, mixes in equal volume with above-mentioned bacterial suspension, is incubated for 2h altogether in 37 DEG C, is protected from light dyeing through Propidium iodide (PI)
After 15min, PBS washes away excess dyestuff, the intake ability through flow cytomery PI fluorescence, as a result such as Fig. 9.
Fig. 9 the result shows that, branched fatty acid modified antimicrobial the peptide analogues Ano-D4,7-4C of the amino acid of type containing DnAnd Ano-
D4,7-7Cn, all have preferable bacterial cell membrane damage capability；As branched fatty acid length increases, antibacterial peptide analogues pair
The damage capability of bacterial cell membrane is remarkably reinforced, and can make explanations for significantly increasing for above-mentioned antibacterial activity.
3, stability experiment is digested
By the trypsin solution (1mg/mL, 0.5mg/mL, 0.2mg/mL, 0.1mg/mL) 37 of peptide solution and various concentration
It is incubated for 1h and 6h DEG C altogether；It is identical as above-mentioned lowest bacteria fogging-resistant concentration determining method after 60 DEG C of inactivation 15min, it measures in different pancreas eggs
To the minimum inhibitory concentration MIC of E.coli ATCC 25922 in white enzyme solutions, the results are shown in Table 3.
To the minimum inhibitory concentration of E.coli ATCC 25922 under the conditions of 3 various concentration trypsase of table
Control: without in the presence of trypsase to the minimum inhibitory concentration of E.coli ATCC 25922
Table 3 the result shows that, female peptide Anoplin loses antibacterial activity under the trypsase environment of various concentration, performance
Low stability out；But the branched fatty acid modified antimicrobial peptide analogues Ano-D4,7-4C of the amino acid of type containing DnAnd Ano-D4,7-7Cn
Do not lose antibacterial activity in various concentration trypsase environment, slight change only occurs for minimum inhibitory concentration MIC, still
Preferable antibacterial activity is shown, illustrates the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D in trypsase ring
There is higher stability, stability is substantially better than female peptide under border.
To sum up, the present invention is to replace D type amino acid using linear amphipathic alpha-helix natural antibacterial peptide Anoplin as template
It changes enhancing enzymatic hydrolysis stability and the active tactful phase of fatty acid modifying enhancing antimicrobial agent is carried out to D type amino acid side chain after replacement
In conjunction with obtaining the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D of a kind of brand new.Bioactivity is ground
Study carefully the results show that this contain D type amino acid branched fatty acid modified antimicrobial peptide analogues have strong antimicrobial agent antibacterial activity and
Height enzymatic hydrolysis stability, has a good application prospect in the exploitation of clinical antibacterials.
Detailed description of the invention
Fig. 1 is antibacterial peptide analogues Ano-D4,7-4C of the present invention4Mass spectrogram；
Fig. 2 is antibacterial peptide analogues Ano-D4,7-4C of the present invention8Mass spectrogram；
Fig. 3 is antibacterial peptide analogues Ano-D4,7-4C of the present invention12Mass spectrogram；
Fig. 4 is antibacterial peptide analogues Ano-D4,7-4C of the present invention16Mass spectrogram；
Fig. 5 is antibacterial peptide analogues Ano-D4,7-7C of the present invention4Mass spectrogram；
Fig. 6 is antibacterial peptide analogues Ano-D4,7-7C of the present invention8Mass spectrogram；
Fig. 7 is antibacterial peptide analogues Ano-D4,7-7C of the present invention12Mass spectrogram；
Fig. 8 is antibacterial peptide analogues Ano-D4,7-7C of the present invention16Mass spectrogram；
Fig. 9 is the PI staining for flow cytometry experiment result figure of antibacterial peptide analogues of the present invention；In figure with from left to right, from
The sequence of top to bottm is followed successively by control group, Anoplin group, Ano-D4,7-4C8Group, Ano-D4,7-4C12Group, Ano-D4,7-7C8
Group and Ano-D4,7-7C12Group.
Specific embodiment
Conjunction below by specific embodiment to the branched fatty acid modified antimicrobial peptide analogues of the present invention amino acid of type containing D
It is described further at method.
Embodiment 1:Ano-D4,7-4C4Synthesis
(1) activation and pretreatment of resin
The MBHA resin (0.43mmol/g) for accurately weighing 0.47g is placed in Solid-phase synthesis peptides instrument, the swelling of DCM solution
It after 30min, is examined through ninhydrin, resin is colorless and transparent, shows that resin is normal.
(2) synthesis of Fmoc-Ano-D4,7-4 (Mtt)-resin
Fmoc protection is sloughed through the DMF solution containing 20% piperidines of volume fraction to the normal MBHA resin of above-mentioned inspection
Base, ninhydrin are examined, and resin is in bluish violet, show that protecting group has been sloughed；By Fmoc-Leu-OH (212mg), HOBT
(81mg), HBTU (228mg), DIEA (0.2mL) dissolve mixing in 5-10mL DMF, are added in synthesizer and slough with above-mentioned
The MBHA resin of Fmoc protecting group mixes, condensation reaction 1h；Ninhydrin is examined, and resin is colorless and transparent, then shows
Condensation reaction success, obtains Fmoc-Leu-resin；Method is same as above, successively condensation reaction subsequent amino-acid: Fmoc-Leu-OH
(212mg)、Fmoc-Thr(tBu)-OH(239mg)、Fmoc-D-Lys(Boc)-OH(281mg)、Fmoc-Ile-OH(212mg)、
Fmoc-Arg(pbf)-OH(390mg)、Fmoc-D-Lys(Mtt)-OH(376mg)、Fmoc-Leu-OH(212mg)、Fmoc-
Leu-OH (212mg), Fmoc-Gly-OH (238mg), HOBT, HBTU and DIEA dosage are same as above, wherein Fmoc-D-Lys (Mtt)-
OH condensation reaction time is 1.5h, remaining is 1h, obtains Fmoc-Gly-Leu-Leu-D-Lys (Mtt)-Arg-Ile-D-
Lys-Thr-Leu-Leu-resin, i.e. Fmoc-Ano-D4,7-4 (Mtt)-resin；
(3)Ano-D4,7-4C4The synthesis of-resin
Above-mentioned Fmoc-Ano-D4,7-4 (Mtt)-resin is sloughed into side chain with the DCM solution containing volume fraction 1%TFA
Mtt protecting group, ninhydrin are examined, and resin is in bluish violet, are shown that protecting group has been sloughed, are obtained Ano-D4,7-4 (NH2)-
resin；Respectively by butyric anhydride (Cn, n=4；0.87mL), HOBT (81mg), HBTU (228mg), DIEA (0.2mL) are in 5-10mL
It dissolves and mixes in DMF, be added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-4 (NH2)-resin mixing,
Condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete, obtains Ano-D4,7-
4C4-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protecting group, ninhydrin inspection are sloughed
It tests, resin is in bluish violet, shows that protecting group has been sloughed, obtains Ano-D4,7-4C4-resin。
(4) polypeptide is cut
By Ano-D4,7-4C4- resin is molten with the mixing of TFA, tri isopropyl silane and water volume ratio 9.5:0.25:0.25
Liquid is that cutting reagent is cut, and after ice ether and water extraction, freeze-drying obtains thick peptide freeze-dried powder；
(5) peptide purification
The thick peptide freeze-dried powder that above-mentioned freeze-drying is obtained is isolated and purified through RP-HPLC, collects efflux, then freeze dry
It is dry, Ano-D4,7-4C are obtained through Mass Spectrometric Identification4, molecular weight 1223Da, mass spectrogram is shown in Fig. 1；Wherein, RP-HPLC purification condition:
Mobile phase A: 0.05%TFA/ water；Mobile phase B: 0.05%TFA/ acetonitrile；Linear gradient elution collects the outflow of major absorbance peak
Liquid.
Embodiment 2:Ano-D4,7-4C8Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-4 (Mtt)-resin
With embodiment 1.
(3)Ano-D4,7-4C8The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-4 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-4(NH2)-resin；Respectively by caprylic anhydride (Cn, n=8；1.53mL),HOBT(81mg),HBTU(228mg),DIEA(0.2mL)
It dissolves and mixes in 5-10mL DMF, be added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-4 (NH2)-
Resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete, obtains
To Ano-D4,7-4C8-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protecting group, indenes three are sloughed
Ketone development process is examined, and resin is in bluish violet, is shown that protecting group has been sloughed, is obtained Ano-D4,7-4C8-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-4C are obtained through Mass Spectrometric Identification8, molecular weight 1279Da, mass spectrogram is shown in Fig. 2.
Embodiment 3:Ano-D4,7-4C12Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-resin
With embodiment 1.
(3)Ano-D4,7-4C12The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-4 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-4(NH2)-resin；Respectively by dodecanoic acid (Cn, n=12；240mg),HOBT(81mg),HBTU(228mg),DIEA
(0.2mL) dissolves in 5-10mL DMF to be mixed, and is added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-4
(NH2)-resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete
Entirely, Ano-D4,7-4C are obtained12-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protection is sloughed
Base, ninhydrin are examined, and resin is in bluish violet, are shown that protecting group has been sloughed, are obtained Ano-D4,7-4C12-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-4C are obtained through Mass Spectrometric Identification12, molecular weight 1335Da, mass spectrogram is shown in Fig. 3.
Embodiment 4:Ano-D4,7-4C16Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-resin
With embodiment 1.
(3)Ano-D4,7-4C16The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-4 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-4(NH2)-resin；Respectively by hexadecanoic acid (Cn, n=16；307mg),HOBT(81mg),HBTU(228mg),DIEA
(0.2mL) dissolves in 5-10mL DMF to be mixed, and is added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-4
(NH2)-resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete
Entirely, Ano-D4,7-4C are obtained16-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protection is sloughed
Base, ninhydrin are examined, and resin is in bluish violet, are shown that protecting group has been sloughed, are obtained Ano-D4,7-4C16-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-4C are obtained through Mass Spectrometric Identification16, molecular weight 1391Da, mass spectrogram is shown in Fig. 4.
Embodiment 5:Ano-D4,7-7C4Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-7 (Mtt)-resin
Fmoc protection is sloughed through the DMF solution containing 20% piperidines of volume fraction to the normal MBHA resin of above-mentioned inspection
Base, ninhydrin are examined, and resin is in bluish violet, show that protecting group has been sloughed；By Fmoc-Leu-OH (212mg), HOBT
(81mg), HBTU (228mg), DIEA (0.2mL) dissolve mixing in 5-10mL DMF, are added in synthesizer and slough with above-mentioned
The MBHA resin of Fmoc protecting group mixes, condensation reaction 1h；Ninhydrin is examined, and resin is colorless and transparent, then shows
Condensation reaction success, obtains Fmoc-Leu-resin；Method is same as above, successively condensation reaction subsequent amino-acid: Fmoc-Leu-OH
(212mg)、Fmoc-Thr(tBu)-OH(239mg)、Fmoc-D-Lys(Mtt)-OH(376mg)、Fmoc-Ile-OH(212mg)、
Fmoc-Arg(pbf)-OH(390mg)、Fmoc-D-Lys(Boc)-OH(281mg)、Fmoc-Leu-OH(212mg)、Fmoc-
Leu-OH (212mg), Fmoc-Gly-OH (238mg), HOBT, HBTU and DIEA dosage are same as above, wherein Fmoc-D-Lys (Mtt)-
OH condensation reaction time is 1.5h, remaining is 1h, obtains Fmoc-Gly-Leu-Leu-D-Lys-Arg-Ile-D-Lys
(Mtt)-Thr-Leu-Leu-resin, i.e. Fmoc-Ano-D4,7-4 (Mtt)-resin；
(3)Ano-D4,7-7C4The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-7(NH2)-resin；Respectively by butyric anhydride (Cn, n=4；0.87mL),HOBT(81mg),HBTU(228mg),DIEA(0.2mL)
It dissolves and mixes in 5-10mL DMF, be added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-7 (NH2)-
Resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete, obtains
To Ano-D4,7-7C4-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protecting group, indenes three are sloughed
Ketone development process is examined, and resin is in bluish violet, is shown that protecting group has been sloughed, is obtained Ano-D4,7-7C4-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-7C are obtained through Mass Spectrometric Identification4, molecular weight 1223Da, mass spectrogram is shown in Fig. 5.
Embodiment 6:Ano-D4,7-7C8Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-7 (Mtt)-resin
With embodiment 5.
(3)Ano-D4,7-7C8The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-7(NH2)-resin；Respectively by caprylic anhydride (Cn, n=8；1.53mL),HOBT(81mg),HBTU(228mg),DIEA(0.2mL)
It dissolves and mixes in 5-10mL DMF, be added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-7 (NH2)-
Resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete, obtains
To Ano-D4,7-7C8-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protecting group, indenes three are sloughed
Ketone development process is examined, and resin is in bluish violet, is shown that protecting group has been sloughed, is obtained Ano-D4,7-7C8-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-7C are obtained through Mass Spectrometric Identification8, molecular weight 1279Da, mass spectrogram is shown in Fig. 6.
Embodiment 7:Ano-D4,7-7C12Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-7 (Mtt)-resin
With embodiment 5.
(3)Ano-D4,7-7C12The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-7(NH2)-resin；Respectively by dodecanoic acid (Cn, n=12；240mg),HOBT(81mg),HBTU(228mg),DIEA
(0.2mL) dissolves in 5-10mL DMF to be mixed, and is added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-7
(NH2)-resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete
Entirely, Ano-D4,7-7C are obtained12-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protection is sloughed
Base, ninhydrin are examined, and resin is in bluish violet, are shown that protecting group has been sloughed, are obtained Ano-D4,7-7C12-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-7C are obtained through Mass Spectrometric Identification12, molecular weight 1335Da, mass spectrogram is shown in Fig. 7.
Embodiment 8:Ano-D4,7-7C16Synthesis
(1) activation and pretreatment of resin
With embodiment 1.
(2) synthesis of Fmoc-Ano-D4,7-7 (Mtt)-resin
With embodiment 5.
(3)Ano-D4,7-7C16The synthesis of-resin
By Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin, with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group is sloughed, ninhydrin is examined, and resin is in bluish violet, and show that protecting group has been sloughed, obtains Ano-D4,
7-7(NH2)-resin；Respectively by hexadecanoic acid (Cn, n=16；307mg),HOBT(81mg),HBTU(228mg),DIEA
(0.2mL) dissolves in 5-10mL DMF to be mixed, and is added in synthesizer and the above-mentioned Ano-D4 for sloughing side chain Mtt protecting group, 7-7
(NH2)-resin mixing, condensation reaction 1.5h；Ninhydrin is examined, and resin is colorless and transparent, shows that condensation reaction is complete
Entirely, Ano-D4,7-7C are obtained16-resin；With the DMF solution containing 20% piperidines of volume fraction, N-terminal Fmoc protection is sloughed
Base, ninhydrin are examined, and resin is in bluish violet, are shown that protecting group has been sloughed, are obtained Ano-D4,7-7C16-resin。
(4) polypeptide is cut
With embodiment 1.
(5) peptide purification
With embodiment 1, Ano-D4,7-7C are obtained through Mass Spectrometric Identification16, molecular weight 1335Da, mass spectrogram is shown in Fig. 8.
Claims (10)
1. the branched fatty acid modified antimicrobial peptide analogues of a kind of amino acid of type containing D, characterized in that the knot of the antibacterial peptide analogues
Structure formula are as follows:
Gly-Leu-Leu-D-Lys(Cn)-Arg-Ile-D-Lys-Thr-Leu-Leu-NH2
Ano-D4,7-4Cn, n=4-16；
Or
Gly-Leu-Leu-D-Lys-Arg-Ile-D-Lys(Cn)-Thr-Leu-Leu-NH2
Ano-D4,7-7Cn, n=4-16.
2. the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D are in clinical antibacterials as described in claim 1
Application in exploitation.
3. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as described in claim 1, special
Sign is:
Using classical solid phase synthesis process, the special unnatural amino acid Fmoc-D-Lys of D type of Side chain protective group Mtt will be had
(Mtt)-OH introduces the part D type amino acid substitution analog Ano-D4 of Anoplin, 4 of 7 sequences or 7, synthesizes Ano-
D4,7-4 (Mtt)-resin or Ano-D4,7-7 (Mtt)-resin；Then Side chain protective group is sloughed, to the special non-day of the D type
The side chain of right amino acid carries out the fatty acid modifying of different length；It most cut afterwards, obtain the side chain of the amino acid of type containing D after purification
Fatty acid modifying antibacterial peptide analogues Ano-D4,7-4CnOr Ano-D4,7-7Cn, wherein n=4-16.
4. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as claimed in claim 3, special
Sign is the synthetic method of the antibacterial peptide analogues specifically:
(1)Ano-D4,7-4CnSynthesis
Fmoc-Leu-OH, HOBT, HBTU, DIEA dissolve to mixing in DMF, and with the MBHA resin of sloughing Fmoc protecting group
Condensation reaction is carried out, Fmoc-Leu-resin is obtained；With method successively condensation reaction amino acid Fmoc-Leu-OH, Fmoc-Thr
(tBu)-OH、Fmoc-D-Lys(Boc)-OH、Fmoc-Ile-OH、Fmoc-Arg(pbf)-OH、Fmoc-D-Lys(Mtt)-OH、
Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Gly-OH obtain Fmoc-Gly-Leu-Leu-D-Lys (Mtt)-Arg-Ile-
D-Lys-Thr-Leu-Leu-resin, as Fmoc-Ano-D4,7-4 (Mtt)-resin；
Fmoc-Ano-D4 obtained above, 7-4 (Mtt)-resin are sloughed with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group obtains Ano-D4,7-4 (NH2)-resin；It is respectively that fatty acid, HOBT, HBTU and DIEA is molten in DMF
Solution mixes, and and Ano-D4,7-4 (NH2)-resin progress condensation reaction, obtain Ano-D4,7-4Cn-resin；By Ano-D4,
7-4Cn- resin cutting, purifying obtain antibacterial peptide analogues Ano-D4,7-4Cn, n=4-16；
(2)Ano-D4,7-7CnSynthesis
Fmoc-Leu-OH, HOBT, HBTU, DIEA dissolve to mixing in DMF, and with the MBHA resin of sloughing Fmoc protecting group
Condensation reaction is carried out, Fmoc-Leu-resin is obtained；With method successively condensation reaction amino acid Fmoc-Leu-OH, Fmoc-Thr
(tBu)-OH、Fmoc-D-Lys(Mtt)-OH、Fmoc-Ile-OH、Fmoc-Arg(pbf)-OH、Fmoc-D-Lys(Boc)-OH、
Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Gly-OH obtain Fmoc-Gly-Leu-Leu-D-Lys-Arg-Ile-D-Lys
(Mtt)-Thr-Leu-Leu-resin, as Fmoc-Ano-D4,7-7 (Mtt)-resin；
Fmoc-Ano-D4 obtained above, 7-7 (Mtt)-resin are sloughed with the DCM solution containing volume fraction 1%TFA
Side chain Mtt protecting group obtains Ano-D4,7-7 (NH2)-resin；It is respectively that fatty acid, HOBT, HBTU and DIEA is molten in DMF
Solution mixes, and and Ano-D4,7-7 (NH2)-resin progress condensation reaction, obtain Ano-D4,7-7Cn-resin；By Ano-D4,
7-7Cn- resin cutting, purifying obtain antibacterial peptide analogues Ano-D4,7-7Cn, n=4-16.
5. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as claimed in claim 4, special
Sign is that each amino acid, the concentration of each fatty acid, HOBT, HBTU and DIEA in DMF are respectively 20-100mg/mL, 20-
100mg/mL, 10-40mg/mL, 20-100mg/mL, 20-60mg/mL.
6. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as described in claim 4 or 5,
It is characterized in that the molal weight of each amino acid, each fatty acid, HOBT, HBTU and the MBHA resin for sloughing Fmoc protecting group
Than being 6:1-3:1, DIEA and the molal weight ratio for sloughing the MBHA resin of Fmoc protecting group are 6:1-12:1.
7. the synthesis of the branched fatty acid modified antimicrobial peptide analogues such as the described in any item amino acid of type containing D of claim 3-5
Method, characterized in that the cutting reagent is that TFA, tri isopropyl silane and water are mixed with what volume ratio 9.5:0.25:0.25 was formed
Close solution.
8. the synthesis of the branched fatty acid modified antimicrobial peptide analogues such as the described in any item amino acid of type containing D of claim 3-5
Method, characterized in that the purification process is, after freeze-dried, carry out RP-HPLC and isolates and purifies；RP-HPLC purification condition
For mobile phase A: the aqueous solution of 0.05%TFA, Mobile phase B: the acetonitrile solution of 0.05%TFA；Linear gradient elution collects master
Want the efflux of absorption peak.
9. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as claimed in claim 6, special
Sign is that each amino acid, each fatty acid, the molal weight ratio of HOBT, HBTU and the MBHA resin for sloughing Fmoc protecting group are equal
For 6:1-3:1, the molal weight ratio of DIEA and the MBHA resin for sloughing Fmoc protecting group is 6:1-12:1.
10. the synthetic method of the branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D as claimed in claim 6,
It is characterized in, the purification process is to carry out RP-HPLC after obtained thick peptide is freeze-dried and isolate and purify；RP-HPLC purifying
Condition is mobile phase A: the aqueous solution of 0.05%TFA, Mobile phase B: the acetonitrile solution of 0.05%TFA；Linear gradient elution is received
Collect the efflux of major absorbance peak.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910320083.5A CN110054664B (en) | 2019-04-19 | 2019-04-19 | Side chain fatty acid modified antibacterial peptide analogue containing D-type amino acid and synthesis and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910320083.5A CN110054664B (en) | 2019-04-19 | 2019-04-19 | Side chain fatty acid modified antibacterial peptide analogue containing D-type amino acid and synthesis and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110054664A true CN110054664A (en) | 2019-07-26 |
| CN110054664B CN110054664B (en) | 2023-05-26 |
Family
ID=67319804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910320083.5A Active CN110054664B (en) | 2019-04-19 | 2019-04-19 | Side chain fatty acid modified antibacterial peptide analogue containing D-type amino acid and synthesis and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110054664B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563802A (en) * | 2019-09-04 | 2019-12-13 | 倪京满 | group of antibacterial peptide analogues containing N-methylated amino acid and N-terminal fatty acid modification, and synthetic method and application thereof |
| CN113072619A (en) * | 2021-04-09 | 2021-07-06 | 倪京满 | Alpha helical antibacterial short peptide with high antibacterial activity and low toxicity and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632600A (en) * | 2016-10-19 | 2017-05-10 | 倪京满 | D-type non-natural amino acid containing antimicrobial peptide analog, synthesis therefor and application of D-type non-natural amino acid containing antimicrobial peptide analog |
| CN109265518A (en) * | 2018-10-10 | 2019-01-25 | 倪京满 | N- terminal aliphatic acid modified antimicrobial peptide analogues and its synthesis and application with high enzymatic hydrolysis stability and strong antibacterial activity |
-
2019
- 2019-04-19 CN CN201910320083.5A patent/CN110054664B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632600A (en) * | 2016-10-19 | 2017-05-10 | 倪京满 | D-type non-natural amino acid containing antimicrobial peptide analog, synthesis therefor and application of D-type non-natural amino acid containing antimicrobial peptide analog |
| CN109265518A (en) * | 2018-10-10 | 2019-01-25 | 倪京满 | N- terminal aliphatic acid modified antimicrobial peptide analogues and its synthesis and application with high enzymatic hydrolysis stability and strong antibacterial activity |
Non-Patent Citations (2)
| Title |
|---|
| ÀNGEL OLIVERAS ET AL: "Antimicrobial activity of linear lipopeptides derived from BP100 towards plant pathogens", 《PLOS ONE》 * |
| KOSTAS CHIONIS ET AL: "Synthesis and biological activity of lipophilic analogs of the cationic antimicrobial active peptide anoplin", 《JOURNAL OF PEPTIDE SCIENCE》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563802A (en) * | 2019-09-04 | 2019-12-13 | 倪京满 | group of antibacterial peptide analogues containing N-methylated amino acid and N-terminal fatty acid modification, and synthetic method and application thereof |
| CN110563802B (en) * | 2019-09-04 | 2023-04-07 | 倪京满 | Group of antibacterial peptide analogues containing N-methylated amino acid and N-terminal fatty acid modification, and synthetic method and application thereof |
| CN113072619A (en) * | 2021-04-09 | 2021-07-06 | 倪京满 | Alpha helical antibacterial short peptide with high antibacterial activity and low toxicity and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110054664B (en) | 2023-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tam et al. | Antimicrobial dendrimeric peptides | |
| Strahilevitz et al. | Spectrum of antimicrobial activity and assembly of dermaseptin-b and its precursor form in phospholipid membranes | |
| CA2145313C (en) | Antimicrobial peptides | |
| AU709204B2 (en) | Anti-fungal and anti-bacterial histatin-based peptides | |
| CN109232719B (en) | PH-responsive antibacterial peptide and preparation method and application thereof | |
| Monroc et al. | De novo designed cyclic cationic peptides as inhibitors of plant pathogenic bacteria | |
| WO1992001462A1 (en) | Amphiphilic peptide compositions and analogues thereof | |
| EP1853620A2 (en) | Antimicrobial hexapeptides | |
| CN111363010B (en) | Symmetrical short-sequence antibacterial peptide analogue and application thereof | |
| CN109265518A (en) | N- terminal aliphatic acid modified antimicrobial peptide analogues and its synthesis and application with high enzymatic hydrolysis stability and strong antibacterial activity | |
| Saido-Sakanaka et al. | Synthesis and characterization of bactericidal oligopeptides designed on the basis of an insect anti-bacterial peptide | |
| EP2595496B1 (en) | Antimicrobial peptide, branched forms thereof and their use in the treatment of bacteria infections | |
| CN110054664A (en) | The branched fatty acid modified antimicrobial peptide analogues of the amino acid of type containing D and its synthesis and application | |
| JP6124139B2 (en) | Low erythrocyte lytic antimicrobial peptide, pharmaceutical composition and use thereof | |
| TWI403330B (en) | Low hemolysis antibacterial peptide pharmaceutical compositions and use thereof | |
| WO1999065506A2 (en) | Cancer therapy with indolicidin or cationic peptides and their polymer conjugates | |
| CN112625106A (en) | Antibacterial polypeptide compound, synthesis method and application thereof | |
| CN112625092A (en) | Antibacterial polypeptide compound based on polybia-MPI and synthesis and application thereof | |
| CN110437308B (en) | Beta amino acid-containing antibacterial peptide analogue with specific activity on pseudomonas aeruginosa and application thereof | |
| Lee et al. | HP (2–20) derived from the amino terminal region of Helicobacter pylori ribosomal protein L1 exerts its antifungal effects by damaging the plasma membranes of Candida albicans | |
| CN113999297A (en) | Antibacterial peptide hrNCM and preparation method and application thereof | |
| CN115010788B (en) | N-terminal fatty acid modified low-toxicity broad-spectrum antibacterial peptide analogue with antibacterial film activity and application thereof | |
| CA2047317A1 (en) | Amphiphilic peptide compositions and analogues thereof | |
| Oh et al. | The comparison of characteristics between membrane-active antifungal peptide and its pseudopeptides | |
| CN107652364A (en) | The multimeric forms of antibacterial peptide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230919 Address after: 730000 No. 222 Tianshui South Road, Chengguan District, Gansu, Lanzhou Patentee after: LANZHOU University Address before: 730000 room 609, 680 Dingxi Road, Chengguan District, Lanzhou City, Gansu Province Patentee before: Ni Jingman Patentee before: Wang Rui |