CN102911257B - Cyclic lipopeptide antibiotic and preparation and application thereof - Google Patents
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Abstract
The invention relates to a novel cyclic lipopeptide antibiotic (cyclic nonapeptide avermectin) and preparation and application thereof, belonging to the technical field of biomedicine. The fermentation medium is inoculated with paenibacillus, the paenibacillus is cultured at 28-35 DEG C for 24-96 hours, the fermentation broth is centrifuged to take the supernatant, the supernatant is adsorbed by a macroporous adsorption resin, and separation and purification are performed further to obtain the cyclic lipopeptide antibiotic which can be used for preparing the bacterial-infection resisting medicament. The invention provides the cyclic nonapeptide avermectin with higher toxicity than polymyxin B and higher medical application value and the preparation and application of the cyclic nonapeptide avermectin. The experiments in vitro prove that the compound can inhibit all the tested Gram-positive and negative pathogens including the multiple and super medicament resisting bacteria significantly, and the in-vivo experiments prove that the compound can prevent and treat the mouse septicemia caused by theextended-spectrum medicament resisting pseudomonas aeruginosa significantly.
Description
Technical field
The present invention relates to a kind of new cyclic lipopeptide microbiotic-ring nonapeptide rhzomorph and preparation and application thereof, belong to field of biomedicine technology.
Background technology
Due to antibiotic widespread use or abuse, make the microbiotic that once plays remarkable effect in bacterial infection disease treatment occur losing efficacy widely.Many common bacterias constantly strengthen the resistance of common antibiotics.At present, the bacterial drug resistance serious threat mankind's health.Methicillin-resistant staphylococcus aureus, the multi-drug resistant bacterias such as the escherichia coli of penicillin resistance pneumococcus and product extended spectrumβ-lactamase (ESBLs) and klebsiella have become spreading rate and the very high pathogenic agent of lethality rate in hospital.The quick appearance of vancomycin-resistant enterococcus (VRE), has aggravated the worry of people to pathogenic bacterium resistance problem.
In addition, along with the widespread use of immunosuppressor and Broad spectrum antibiotics, the popularization of conduit, intubate, burn rescue, chemicotherapy and organ transplantation, the sickness rate of fungi infestation also increases year by year.According to incompletely statistics, over nearly 10 years, the sickness rate of systemic fungal infection has increased by 3～5 times, and poor prognosis, mortality ratio are high.According to chemical structure, the antifungal drug of listing can be divided into four large classes: propylene class (Terbinafine), polyenoid class (amphotericin B etc.), azole (itraconazole etc.), echinocandin class (Caspofungin) etc.Terbinafine curative effect is low, can not be individually dosed; Polyenoid class has serious untoward reaction; Azole only can suppress and can not killing fungus; Although echinocandin class is all effective for Candida and Eurotium, and security is higher, faces and there is no oral dosage form and the two large problems such as expensive, so limited their application clinically.
Given this, the new antibiotic that find novel structure, is difficult for producing crossing drug resistant and applicable suitability for industrialized production is long-term and difficult task by of being facing mankind.
Summary of the invention
The object of the invention is to overcome above-mentioned weak point, provide a kind of for clinical drug-resistant pathogenic bacterium, there is the new lipopeptide antibiotic that potential medical use is worth---preparation method and the application of ring nonapeptide rhzomorph.
According to technical scheme provided by the invention, a kind of cyclic lipopeptide microbiotic, skeleton symbol is as follows:
Wherein L-Dab is L-type 2,4-diamino-butanoic, and L-Ile is L-type Isoleucine, and D-Phe is D type phenylalanine, and L-Leu is L-type leucine, and D-Val is D type α-amino-isovaleric acid, and L-Thr is L-type Threonine.
Described bacterial strain is series bacillus (Paenibacillus ehirnensis strain B7), be preserved in Chinese Typical Representative culture collection center, preservation date: on June 24th, 2012, address: Wuhan, China Wuhan University, preserving number is CCTCC NO:M 2012244.
The antibiotic preparation method of cyclic lipopeptide, step is:
(1) cultivation and fermentation: series bacillus (Paenibacillus ehirnensis strain B7) is inoculated into fermention medium, obtain activating bacterial strain, activation bacterial strain twice of shaking culture in seed culture medium, obtain secondary seed solution, shaking culture fermentation in secondary seed solution access fermention medium, obtain fermented liquid, centrifugal, get fermented liquid supernatant, go precipitation, first, through absorption with macroporous adsorbent resin, fermentation supernatant is flowed through with distilled water balance chromatography column good, that be filled with macroporous adsorbent resin with appropriate speed;
(2) separation and purification: after complete on sample, first rinse with distilled water and methanol aqueous solution respectively, then use methanol aqueous solution wash-out; Collect each elution peak, survey and live, the concentrated evaporate to dryness of active ingredient is obtained to crude product; By crude product dissolve with methanol, centrifuging, is further purified with solid-phase extraction column; With preparative high performance liquid chromatography, carry out consummately again, collect active ingredient, concentrated, freeze-drying can obtain described ring nonapeptide rhzomorph;
The antibiotic preparation method of described cyclic lipopeptide, concrete steps are:
(1) series bacillus (Paenibacillus ehirnensis strain B7) being stored in the glycerine pipe of-80 ℃ of refrigerators is transferred on nutrient agar, cultivates 24～96h, obtain activating bacterial strain for 28～35 ℃;
Nutrient agar, prepares by following composition: extractum carnis 3g, peptone 10g, sodium-chlor 5g, agar 17g, distilled water 1000mL, pH7.2;
(2) access of activation bacterial strain is contained in the 50mL seed culture medium of 250mL triangular flask, in 28～35 ℃, 220rpm shaking culture 24h, is primary seed solution;
(3) the primary seed solution access of step (2) gained is contained in the 200mL seed culture medium of 500mL triangular flask, in 28～35 ℃, 220rpm shaking culture 24h, is secondary seed solution;
Seed culture medium is nutrient broth medium, prepares: extractum carnis 3g, peptone 10g, sodium-chlor 5g, tap water 1000mL, pH7.2 by following composition;
(4) 5%～10% the inoculum size access by volume of the secondary seed solution of step (3) gained is contained in the 2L triangular flask of 500mL fermention medium, in 28～35 ℃, 200rpm shaking culture 96h, obtains fermented liquid;
Fermention medium was prepared by following composition: glucose, 0～10g/L; CaCl
2, 0.01～0.7g/L; MgSO
47H
2o, 0.05～1g/L; ZnSO
4, 0.005～0.1g/L; NaCl, 0.05～0.5g/L; FeSO
4, 0.005～0.05g/L; (NH
4)
2sO
4, 0.5～4.0g/L; MnSO
4h
2o, 0.001～0.01g/L; KH
2pO
4, 0.5～5g/L; Solvent is distilled water, and pH 7.0～7.5;
(5) fermented liquid that step (4) obtains forwards in centrifugal bottle, after balance, in the centrifugal 30min of 6500 * g, removes precipitation, obtains clarification fermented supernatant fluid;
(6) supernatant liquor of step (5) gained is worn to the Amberlite XAD-16 chromatography column that distilled water balance is good with the flow velocity stream of 10～50mL/min, after complete on sample, with distilled water and containing the aqueous solution of the volume ratio methyl alcohol that is 45%, respectively rinse 5 bed volumes respectively, then with the aqueous solution wash-out that contains the methyl alcohol that volume ratio is 90%, collected volume is than the elution peak that is 90% methanol aqueous solution wash-out, 55～65 ℃ of concentrated evaporates to dryness, obtain crude product 1;
(7) by crude product 1 use dissolve with methanol, by loading after the membrane filtration of 0.45 μ m, extremely use the good C-18 solid-phase extraction column of acetonitrile solution balance of volume ratio 25%, the acetonitrile solution that is 25% by volume ratio again after sample adds rinses 5 bed volumes, then use the acetonitrile solution wash-out of volume ratio 65%, collect elution peak, concentrated evaporate to dryness, obtains crude product 2;
(8) by crude product 2 use dissolve with methanol, the centrifugal 10min of 12000rpm, and cross after 0.45 μ M filter membrane, with preparation HPLC, carry out separation; After separated, A liquid is the aqueous solution containing volume ratio 0.1% trifluoroacetic acid, and B liquid is trifluoroacetic acid aqueous solution; Gradient is: 40min in the time B liquid from volume ratio 15%, bring up to 60%; Collect active part, 55～65 ℃ of concentrated ,-50 ℃～-60 ℃ vacuum lyophilizations, obtain product cyclic lipopeptide microbiotic.
Described fermention medium is: glucose, 3.5g/L; CaCl
2, 0.05g/L; MgSO
47H
2o, 0.1g/L; ZnSO
4, 0.01g/L; NaCl, 0.3g/L; FeSO
4, 0.01g/L; (NH
4)
2sO
4, 2.5g/L; MnSO
4h
2o, 0.004g/L; KH
2pO
4, 2.5g/L; Solvent is water, and pH 7.0～7.2.
6, the antibiotic application of cyclic lipopeptide, is characterized in that: cyclic lipopeptide microbiotic can be used in prepares bacterial-infection resisting medicine.
Cyclic lipopeptide microbiotic is for the preparation of the medicine infecting due to anti-multidrug resistant bacterium.Cyclic lipopeptide microbiotic is for the preparation of the medicine infecting due to anti-multidrug resistant Gram-negative bacteria.
Preferred described macroporous adsorbent resin is Amberlite XAD-16, and solid-phase extraction column is C-18.Macroporous adsorbent resin has very strong specific adsorption performance, is widely used in the extraction of the materials such as microbiotic, VITAMIN and Effective Component of Chinese Medicine, concentrated and purifying.Macroporous adsorbent resin is generally White-opalescent spheroid, for microbiotic and small-molecule peptide, has very strong absorption, can be efficiently the specific target compound that is purified into from bulk fermentation liquid/extracting solution fast.In addition, macroporous adsorbent resin also can be used for removing non-polar compound from polar solvent.In a word, the absorption property of macroporous adsorbent resin is good, is a kind of desirable Solid-Phase Extraction material.
Tool of the present invention has the following advantages: the invention provides a kind of toxicity and be better than PXB, have ring nonapeptide rhzomorph of higher medical use value and its preparation method and application, this compound is to the Gram-positive of all tests and negative pathogenic bacterium and fungi, comprise multidrug resistant and super resistant organism, all there is significant restraining effect; In body, experiment shows that the mouse septicemia that this compound causes the false unit cell of super wide spectrum resistance verdigris has obvious prevention effect.
Accompanying drawing explanation
The ESI-MS collection of illustrative plates of the cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorph of Fig. 1 embodiment 1 preparation.
The ESI-MS-MS collection of illustrative plates of the cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorph of Fig. 2 embodiment 1 preparation.
Embodiment
Embodiment 1: the preparation of cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorph
(1) bacterial strain B7 is transferred on nutrient agar from be stored in the glycerine pipe of-80 ℃ of refrigerators, cultivates 24～72h for 32 ℃;
(2) access of activation bacterial strain is contained in the 50mL seed culture medium of 250mL triangular flask, in 32 ℃, 220rpm shaking culture 24h, is primary seed solution;
(3) primary seed solution access is contained in the 200mL seed culture medium of 500mL triangular flask, in 32 ℃, 220rpm shaking culture 24h, is secondary seed solution;
(4) by secondary seed solution by 5%～10%(v/v) inoculum size access containing in the 2L triangular flask of 500mL fermention medium, in 28 ℃, 200rpm shaking culture 96h, obtains fermented liquid.
Nutrient agar, prepares by following composition: extractum carnis 3g, peptone 10g, sodium-chlor 5g, agar 17g, distilled water 1000mL, pH7.2;
Seed culture medium is nutrient broth medium, prepares: extractum carnis 3g, peptone 10g, sodium-chlor 5g, tap water 1000mL, pH7.2 by following composition;
Fermention medium was prepared by following composition: glucose, glucose, 3.5g/L; CaCl
2, 0.05g/L; MgSO
47H
2o, 0.1g/L; ZnSO
4, 0.01g/L; NaCl, 0.3g/L; FeSO
4, 0.01g/L; (NH
4)
2sO
4, 2.5g/L; MnSO
4h
2o, 0.004g/L; KH
2pO
4, 2.5g/L; Tap water complements to 1L, and pH 7.0.
(5) fermented liquid forwards in centrifugal bottle, after balance, in the centrifugal 30min of 6500 * g, removes precipitation, obtains clarification fermented supernatant fluid;
(6) supernatant liquor is worn to the Amberlite XAD-16 chromatography column that distilled water balance is good with constant flow velocity stream, after complete on sample respectively with distilled water and containing 45%(v/v) aqueous solution of methyl alcohol respectively rinses 5 bed volumes, then with containing 90%(v/v) aqueous solution wash-out of methyl alcohol, collect the elution peak of 90% methanol aqueous solution wash-out, concentrated evaporate to dryness, is designated as crude product 1.
(7) by crude product 1 use dissolve with methanol, by loading after the membrane filtration of 0.45 μ m to 25%(v/v) C-18 solid-phase extraction column that acetonitrile solution balance is good, after sample adds, use again 25%(v/v) 5 bed volumes of acetonitrile solution flushing, then use 65%(v/v) acetonitrile solution wash-out, collect elution peak, concentrated evaporate to dryness, is designated as crude product 2.
(8) by crude product 2 use dissolve with methanol, centrifugal (12000rpm, 10min), and cross after 0.45 μ M filter membrane, with preparation HPLC, carry out separation.A liquid is for containing 0.1%(v/v) aqueous solution of trifluoroacetic acid, B liquid is trifluoroacetic acid aqueous solution, gradient is: 40min in the time B liquid from 15%(v/v) bring up to 60%.Collect active part, concentrated, vacuum lyophilization, obtain product sterling.
The mensuration of embodiment 2 cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorphs
This compound cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorph correlation parameter of product of embodiment 1 preparation is as follows:
Outward appearance: be white powder after lyophilize;
Molecular weight: 1100;
Molecular formula: C
54h
92n
12o
12;
ESI-MS collection of illustrative plates: see Fig. 1;
ESI-MS-MS collection of illustrative plates: see Fig. 2.
According to above-mentioned characteristic, this compound of deducibility is a kind of nine amino acid whose new cyclic lipopeptide microbiotic that contain, by its called after ring nonapeptide rhzomorph.This microbiotic is the another new cyclic lipopeptide microbiotic being separated to from series bacillus first both at home and abroad.This compound all has significant restraining effect to the Gram-positive of all tests (staphylococcus) and feminine gender (pseudomonas and colon bacillus) pathogenic bacterium and fungi (Candida albicans).In Mice Body, experiment shows, this compound has good provide protection to the mouse infection due to multi-resistant Pseudomonas aeruginosa.
Embodiment 3 cyclic lipopeptide antibiosis prime ring nonapeptide rhzomorph antibacterial activity in vitro are measured
With Mueller Hinton broth culture compound concentration, be the ring nonapeptide microbiotic of 256 μ g/mL, adopt doubling dilution that ring nonapeptide concentration is transferred to respectively to 256,128,64,32,16,8,4,2,1,0.5 μ g/mL.
In the 1st to the 10th hole of 96 hole polystyrene plates, add respectively the ring nonapeptide antibiotic solution after 50 μ L doubling dilutions, in the 11st hole, add 50 μ L Mueller Hinton broth culture (acid hydrolyzed casein 17.5g/L, beef extract powder 2g/L, starch 1.5g/L), as growth control, in the 12nd hole, add 100 μ L Mueller Hinton broth cultures as negative control.Contrast microbiotic is PXB.
Indicator is cultivated after 24h, with Mueller Hinton broth culture, is diluted to 10
6individual/mL, adds 50 μ L dilution bacterium liquid in the to the 1st to the 11st hole, seal 37 ℃ of cultivation 20h in rearmounted incubator, judged result.Now, the concentration of the 1st to the 10th hole Chinese style (I) new compound is respectively 128,64,32,16,8,4,2,1,0.5,0.25 μ g/mL.
By microplate reader, measure OD value, detection wavelength is 600nm.The minimum concentration that suppresses indicator growth is completely defined as to minimum inhibitory concentration (MIC).
The results are shown in Table 1.
Escherichia coli 5539 is clinical separated multiple antibiotic resistant strain with Pseudomonas aeruginosa 5215, wherein P.aeruginosa 5215 is general resistant organism bacterial strain, all insensitive to the common antibiotics of all tests (Amikacin Sulphate, cefepime, imipenum, Cefuroxime sodium, cefotaxime, Ampicillin Trihydrate, Kefzol, cefoxitin, Levofloxacin, cefuroxime axetil, ceftazime, gentamicin, Meropenem, Sulbactam/Cefoperazone and piperacillin/his azoles clings to).The lipopeptide antibiotics PXB similar with ring nonapeptide rhzomorph has anti-microbial effect to gram-negative bacterias such as Pseudomonas aeruginosa, intestinal bacteria, bacillus canalis capsulatuses.Be mainly used in clinically the severe infections due to aminoglycoside-resistant, resistance to third generation cephalosporin bacterium and Pseudomonas aeruginosa or other sensitive organism, as microbemia, endocarditis, pneumonia, burn postoperative infection etc.As shown in Table 1, the new lipopeptide antibiotic of the present invention all shows stronger bacteriostatic activity to the Gram-positive of all tests and negative pathogenic bacterium, wherein suitable to the fungistatic effect of Pseudomonas aeruginosa and PXB, to the fungistatic effect of escherichia coli a little less than PXB, but 3 strain staphylococcuses and Candida albicans to test have all shown more significant antibacterial effect, prompting ring nonapeptide rhzomorph has wider antimicrobial spectrum.
Table 1: ring nonapeptide rhzomorph and PXB antibacterial activity in vitro
PXB toxicity is larger, has limited the effect of its clinical application.Ring nonapeptide rhzomorph is to (iv) LD of the intravenous injection of Kunming mouse
50for 23.36mg/kg, apparently higher than PXB (7.35mg/kg), show that the toxicity of ring nonapeptide rhzomorph provided by the invention is significantly lower than the PXB of widespread use clinically, security is better.
In vivo in Protection; the ring nonapeptide microbiotic of intravenously administrable 4mg/kg has 90% protection effect to the fatal infection of the false unit cell 5215 of super wide spectrum resistant organism verdigris; as can be seen here, ring nonapeptide rhzomorph also has obvious antibacterial effect in animal body, can be applicable to prepare bacterial-infection resisting medicine.
The anxious poison experiment of embodiment 4 mouse
1, mouse
Mouse is Kunming kind, 6～8 weeks, weighs 18～22g.The processing of mouse is all carried out with reference to laboratory animal nursing and instruction manual (National Academy Press 1996).When finding mouse in dying state, adopt cervical vertebra dislocation execution method to alleviate the misery of mouse.Mouse is provided by Shanghai Si Laike laboratory animal responsibility company limited.
2, experimental technique
2.1 dosage setting: 40mg/kg, 32mg/kg, 25.6mg/kg, 20.5mg/kg, five groups of 16.38mg/kg.
2.2. test key step: adopt the test of Bliss method, get kunming mice random packet, every group of 20 mouse, male and female half and half.Adopt the method for vein single-dose to mouse tail vein injection, volume injected is 0.5mL/20 gram of mouse.Injection speed is strict controlled in 1mL/1 minute.Observe immediate reaction, statistics animal dead number.
3, experimental result
Ring nonapeptide rhzomorph vein single-dose is 23.36mg/kg to Kunming mouse acute toxicity LD50.Buck LD50 is 23.47mg/kg, and jenny LD50 is 23.24mg/kg, there was no significant difference between female tom.The LD50 of control drug PXB is 7.35mg/kg.
Embodiment 5: Mouse Protection Test
1, the best infection concentration of Pseudomonas aeruginosa 5215 trial test
Get 25 of ICR mouse, male, body weight 18-22g, is divided into 5 groups at random, and 5 every group, abdominal injection is pressed 5 kinds of concentration (2.5 * 10 of 1:10 proportional diluted by 1% sterilised yeast suspension respectively
7, 2.5 * 10
6, 2.5 * 10
5, 2.5 * 10
4, 2.5 * 10
3individual/mL) Pseudomonas aeruginosa 5215 bacterium liquid 0.5mL/ only, record the death condition in a week, the results are shown in Table 2.Determine that thus official test adopts 2.5 * 10
6the Pseudomonas aeruginosa bacterium liquid of individual/mL infects.
The best concentration trial test result that infects of table 2 Pseudomonas aeruginosa 5215
2, the impact of ring nonapeptide rhzomorph on abdominal cavity infection Pseudomonas aeruginosa 5215 mouse death rates
Get 50 of ICR mouse, body weight 18～22g, male, the Pseudomonas aeruginosa 5215 suspensions (concentration 2.5 * 10 of 1% sterilised yeast suspension dilution for abdominal injection
6individual/ml), be divided at random control group, PXB 2mg/kg positive controls, nonapeptide rhzomorph 1,2,4mg/kg Three doses group, 10 every group, intravenous injection gives relative medicine respectively.Administering mode is respectively every day 1 time, for three days on end.Each administration volume is 0.2mL/10g body weight, and control group gives equal-volume physiological saline; The death condition in mouse one week respectively organized in record, calculates mortality ratio, the results are shown in Table 3.
Result shows, encircles nonapeptide rhzomorph with 2mg/kg and above dosed administration, all can make the mortality ratio of infecting mouse obviously reduce (P<0.01, with control group comparison), shows that this dosage range has obvious vivo bacteria corrosion action to Pseudomonas aeruginosa.
Table 3: the impact of ring nonapeptide rhzomorph on abdominal cavity infection Pseudomonas aeruginosa mouse death rate
Note: by the accurate stochastic method of Fisher, carry out X
2check,
*p<0.01(and control group comparison).
Claims (3)
1. the antibiotic bacterial strain of cyclic lipopeptide is produced in a strain, it is characterized in that: described bacterial strain is series bacillus (Paenibacillus ehirnensis) B7, be preserved in Chinese Typical Representative culture collection center, preservation date: on June 24th, 2012, address: Wuhan, China Wuhan University, preserving number is CCTCC NO:M2012244; Described bacterial strain can produce the cyclic lipopeptide microbiotic as shown in formula I:
Wherein L-Dab is L-type 2,4-diamino-butanoic, and L-Ile is L-type Isoleucine, and D-Phe is D type phenylalanine, and L-Leu is L-type leucine, and D-Val is D type α-amino-isovaleric acid, and L-Thr is L-type Threonine.
2. utilize bacterial strain described in claim 1 to prepare the antibiotic method of cyclic lipopeptide, it is characterized in that the step of described method is:
(1) cultivation and fermentation: described series bacillus is inoculated into fermention medium, obtain activating bacterial strain, activation bacterial strain twice of shaking culture in seed culture medium, obtain secondary seed solution, shaking culture fermentation in secondary seed solution access fermention medium, obtains fermented liquid, centrifugal, get fermented liquid supernatant, go precipitation, first through absorption with macroporous adsorbent resin, fermentation supernatant is flowed through with distilled water balance chromatography column good, that be filled with macroporous adsorbent resin with appropriate speed;
(2) separation and purification: after complete on sample, first rinse with distilled water and methanol aqueous solution respectively, then use methanol aqueous solution wash-out; Collect each elution peak, survey and live, the concentrated evaporate to dryness of active ingredient is obtained to crude product; By crude product dissolve with methanol, centrifuging, is further purified with solid-phase extraction column; With preparative high performance liquid chromatography, carry out consummately again, collect active ingredient, concentrated, freeze-drying can obtain described cyclic lipopeptide microbiotic.
3. method as claimed in claim 2, is characterized in that: described fermention medium is: glucose, 3.5g/L; CaC1
2, 0.05g/L; MgSO
47H
2o, 0.1g/L; ZnSO
4, 0.01g/L; NaCl, 0.3g/L; FeSO
4, 0.01g/L; (NH
4)
2sO
4, 2.5g/L; MnSO
4h
2o, 0.004g/L; KH
2pO
4, 2.5g/L; Solvent is water, pH7.0～7.2.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616484A (en) * | 2004-09-27 | 2005-05-18 | 沈阳药科大学 | Novel cyclopeptide anti-tumor, anti-virus antibiotic active compound |
| CN101519435A (en) * | 2009-04-09 | 2009-09-02 | 中国人民解放军第二军医大学 | Cyclic nonapeptide compound in Hsisha sponge and application thereof |
| CN101962401A (en) * | 2010-09-01 | 2011-02-02 | 浙江大学 | Polypeptin and preparation and application thereof |
| CN102030819A (en) * | 2010-11-22 | 2011-04-27 | 浙江大学 | Broad spectrum polypeptin and application thereof |
| CN102432674A (en) * | 2010-09-29 | 2012-05-02 | 上海天伟生物制药有限公司 | Method for purifying cyclic lipopeptide compound or salt thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616484A (en) * | 2004-09-27 | 2005-05-18 | 沈阳药科大学 | Novel cyclopeptide anti-tumor, anti-virus antibiotic active compound |
| CN101519435A (en) * | 2009-04-09 | 2009-09-02 | 中国人民解放军第二军医大学 | Cyclic nonapeptide compound in Hsisha sponge and application thereof |
| CN101962401A (en) * | 2010-09-01 | 2011-02-02 | 浙江大学 | Polypeptin and preparation and application thereof |
| CN102432674A (en) * | 2010-09-29 | 2012-05-02 | 上海天伟生物制药有限公司 | Method for purifying cyclic lipopeptide compound or salt thereof |
| CN102030819A (en) * | 2010-11-22 | 2011-04-27 | 浙江大学 | Broad spectrum polypeptin and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Sogn J..Structure of the Peptide Antibiotic Polypeptin.《Journal of Medicinal Chemistry》.1976,第19卷(第10期),第1228-1231页. |
| Structure of the Peptide Antibiotic Polypeptin;Sogn J.;《Journal of Medicinal Chemistry》;19761030;第19卷(第10期);第1228-1231页 * |
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