CN103074403A - Method for converting echinocandin B by using microbial enzyme - Google Patents
Method for converting echinocandin B by using microbial enzyme Download PDFInfo
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Abstract
The invention provides a method for converting echinocandin B (ECB) by using microbial enzyme. The method comprises the steps that: (1) microbes are fermented, such that echinocandin B deacylase is obtained; (2) when fermentation is finished, phosphate is added into the fermentation broth; ultrasonic processing is carried out; and supernatant is obtained by centrifugation, and the supernatant is echinocandin B deacylase crude enzyme solution; (3) the crude enzyme solution is purified, such that echinocandin B deacylase enzyme solution is obtained; (4) echinocandin B is dissolved in ethanol, and is mixed with the deacylase enzyme solution; mixing and stirring are carried out, such that the material is converted into echinocandins B nucleus; when conversion is finished, filtering is carried out; and the filtrate is obtained; and (5) the filtrate is processed by using macroporous adsorption resin; echinocandins B nucleus is absorbed on resin; and echinocandins B nucleus is eluted by using an organic solvent. According to the invention, a molar conversion rate is high, a conversion time is short, an obtained product is easy to separate and to purify, and ECB deacylase can be repeatedly used.
Description
Technical field
The present invention relates to field of biological pharmacy, more specifically, the present invention relates to by microbial enzyme ECB is converted into the method for ECB parent nucleus.
Background technology
Since the seventies in last century, fungi infestation is its occurrence frequency or infecting kind is all constantly increasing, and particularly comprises that at immunosuppressed patient HIV the infected, organ transplantation person, tumour patient and those suffer from Other diseases and just carry out among the patient of immunotherapy.Until late 1980s and the nineties imidazoles and the research and development of antifungal drug in triazole class success, clinically can effectively and safely control fungi infestation.Although these medicines play an important role to the control deep fungal infections, but the appearance of, drug resistance fungal poor owing to these drug selectivities and to reasons such as the susceptibility of fungies such as aspergillus and Candida albicans are not strong, the mortality ratio of deep fungal infection disease is still high.Therefore, seek a kind of new safely and effectively antifungal drug and just seem particularly important.
As everyone knows, the fungal cell has cell walls and mammalian cell does not have cell walls.Therefore, fungal cell wall is the desirable target spot of novel antifungal drugs.The echinocandin class medicine is one group of natural product that 20 century 70s are found, formed with different fatty acid side chains by similar ring type polypeptide core, this lipid side chain suppresses β-(1 by the noncompetitive mechanism of action, 3)-D-dextran synthetic, thereby cause the cell walls dextran emptying, osmotic transient fixed and fungal cell's dissolving and bring into play its antifungic action.Its mechanism of action is unique, and bad should rate low, and the fungi of some azoles and amphotericin B resistance is had very strong anti-microbial activity, and the fungi that especially trend such as the infection such as aspergillus and Candida albicans is risen has good killing action.The echinocandin class microbiotic mainly contains three types: B, C and D.Wherein ECB (Echinocandin B, ECB) is topmost type.ECB be to produce in being fermented by Eurotium Aspergilus nidulans and Aspergilusrugulosus of the people such as Nyfeler R. discovery in 1974, but because the existence of acyl side-chain makes it have certain hemolytic toxicity.Carry out structure of modification take ECB as lead compound, can obtain the compound that some have clinical value, such as Cilofungin (Cilofungin), Caspofungin (Caspofungin, MK991), MFG (Micafungin, FK463), anidulafungin (Anidulafungin, LY303366).Cilofungin is because toxicity and formulation problem have stopped research and development, but rear three is successively in U.S.'s (calendar year 2001), Japan (2002), the U.S. (2006) Initial Public Offering.
Wherein anidulafungin is to come company and the joint research and development exploitation of Vicuron Pharmaceuticals company by gift, and route of administration is intravenous drip.Animal experiment study shows, compares with MFG with Caspofungin, and anidulafungin is stronger to the aspergillus fumigatus activity, to the Candida albicans activity relatively a little less than.Its preparation process comprises following two steps: (1) is by microbial transformation---and the deacylation enzyme that the actinoplanes fermentation produces is to ECB (Echinocandin B; ECB) carry out catalysis; make the side chain fracture; generate parent nucleus (EchinocandinB Nucleus, ECBN) and unsaturated fatty acids side chain.(2) adopt the method for chemosynthesis to add new side chain---penta oxygen-triphen carboxyl on the basis of parent nucleus.Wherein the preparation of parent nucleus is committed step.Present preparation for the ECB parent nucleus, the chemical process cost is higher, and microbial transformation has the following advantages: reaction conditions is gentle, product is single, chemo-selective, regioselectivity and the enantio-selectivity of height, be easy to purifying, free from environmental pollution and can finish some chemosynthesis and be difficult to the reaction carried out.
US Patent No. 7785826B2 describes the technique of ECB Transformed E CBN in detail.The main flow process of this technique comprises: after the ECB fermentation was finished, then centrifugal acquisition mycelium added deacylase to the mycelium Eddy diffusion and transforms in water.But this technique transforms 20～30h consuming time, and the ECB deacylase only utilizes once.
Therefore, still need develop the method that microbial enzyme transforms ECB.
Summary of the invention
In view of the above-mentioned condition of prior art, the invention provides a kind of method that simply ECB (ECB) is changed into ECB parent nucleus (ECBN), the method may further comprise the steps:
1) microbial fermentation obtains the ECB deacylase;
2) after fermentation is finished, add phosphoric acid salt in fermented liquid, carry out ultrasonicly, the centrifuging and taking supernatant liquor is ECB deacylase crude enzyme liquid;
3) purifying crude enzyme liquid obtains ECB deacylase enzyme liquid;
4) ECB is dissolved in the ethanol, mixes and stir making it be converted into the ECB parent nucleus with deacylase enzyme liquid, after conversion is finished, filter, get filtrate;
5) filtrate is crossed macroporous adsorbent resin, and the ECB parent nucleus is adsorbed on the resin, with organic solvent the ECB parent nucleus is eluted.
Below describe each step of the inventive method in detail:
The step 1 of aforesaid method) in, the fermentation bacterial strain uses therefor can be natural zymogenic bacteria, for example actinoplanes utahensis; Also can be genetic engineering bacterium, for example streptomyces albus engineering strain.Can adopt condition well known to those skilled in the art to carry out the fermentation of ECB deacylase.
The ECB deacylase is a kind of salting-in protein, and is combined on the cytolemma.After the fermentation of ECB deacylase is finished, in fermented liquid, add a certain amount of phosphoric acid salt to form acid-base buffer system, so that phosphatic concentration is 0.05M-0.15M, thereby provide certain ionic strength and stable pH environment, be beneficial to the dissolving of ECB deacylase and stable.Therefore, in a preferred embodiment of the present invention, the step 2 of aforesaid method) in, the pH that regulates described buffer system is 6-7.In another preferred embodiment of the present invention, ultrasonic this acid-base buffer system 1-2 hour.The ultrasonic deacylase that is conducive to separates from cytolemma.The centrifuging and taking supernatant liquor namely gets ECB deacylase crude enzyme liquid.
After obtaining ECB deacylase crude enzyme liquid, need this crude enzyme liquid is carried out purifying.According to the present invention one preferred embodiment, described purifying comprises makes crude enzyme liquid revolve the contract step of suction filtration of inspissation.Have the foreign protein precipitation to occur after revolving steaming, suction filtration is to remove foreign protein, and gained filtrate is ECB deacylase enzyme liquid.Therefore the Main Function step 3 of aforesaid method) is the foreign protein of removing in the ECB deacylase crude enzyme liquid, and makes enzyme liquid obtain to a certain degree concentrated, improves enzymatic conversion efficient.Preferred embodiment describedly revolve that to steam temperature be 45-50 ℃ according to one of the present invention, revolving the steaming time is 1-2 hour; Described simmer down to is reduced to volume the 50-80% of original volume.
Because the water-soluble extreme difference of ECB, it is solubility promoter that published method for transformation adopts DMSO more, the step 4 of the inventive method) in substitute DMSO as the ECB solubility promoter with ethanol.Ethanol is compared the advantage such as have environmental friendliness, nontoxic, cheap with DMSO, and unexpected the discovery utilizes ethanol higher as ECB solubility promoter transformation efficiency.The ECB that is dissolved in ethanol added in the deacylase enzyme liquid to being made into reaction system, usually the reaction system for preparing placed in the conversion reactor, fully stir, transform finish after, suction filtration, filtrate is the ECB parent nucleus.Content with ECB parent nucleus in the HPLC detection by quantitative filtrate.According to of the present invention one preferred embodiment, described transformation time can be 6-12 hour.According to of the present invention another preferred embodiment, the concentration of described ethanol is more than or equal to 95% (volume).
Final step, filtrate is crossed macroporous adsorbent resin, and the ECB parent nucleus is adsorbed on the resin, then with organic solvent the ECB parent nucleus is eluted.Converted product ECB parent nucleus can be adsorbed on the resin fully, and the larger impurity of some polarity then can not adsorb.In a preferred embodiment of the present invention, the step 5 of aforesaid method) be that the methanol aqueous solution (volume) of 30-60% can resolve the ECB parent nucleus get off fully with concentration behind the upper prop in, liquid phase purity reaches more than 90%.According to of the present invention one preferred embodiment, described macroporous adsorbent resin can be selected from HP20 or XAD18.
According to a preferred embodiment of the present invention, deacylase enzyme liquid is by step 4 behind the upper prop)-5) reusable 2-4 time.The ECB deacylase can reuse be in other published techniques report, reusing the ECB deacylase can effectively reduce production costs, and reduces energy consumption.
The present invention is high with the molar yield that ECB is converted into the ECBN method, and transformation time is short, and product is easy to separation and purification, yield and purity that can the separation and purification of Effective Raise later stage, and the ECB deacylase can be reused.Therefore be fit to large-scale industrial production, have good commercial value.
Description of drawings
Fig. 1 is HPLC collection of illustrative plates after embodiment 1 transforms for the 1st time;
Fig. 2 is HPLC collection of illustrative plates after embodiment 1 the 4th transforms;
Fig. 3 is HPLC collection of illustrative plates after embodiment 2 transforms for the 1st time;
Fig. 4 is HPLC collection of illustrative plates after embodiment 2 transforms for the 3rd time;
Fig. 5 is HPLC collection of illustrative plates after embodiment 3 transforms for the 1st time;
Fig. 6 is HPLC collection of illustrative plates after embodiment 3 the 4th transform;
Fig. 7 is that conversion fluid was crossed HPLC collection of illustrative plates behind the post after embodiment 1 the 1st time transformed;
Fig. 8 is that conversion fluid was crossed HPLC collection of illustrative plates behind the post after embodiment 2 the 1st time transformed;
Fig. 9 is that conversion fluid was crossed HPLC collection of illustrative plates behind the post after embodiment 3 the 1st time transformed.
Embodiment
Unless refer else, the % among the embodiment is weight percentage.
In following examples, the condition of HPLC detection method is as follows:
Moving phase: 0.2% ammonium acetate solution: acetonitrile=95: 5;
Post model: C18,150 * 4.60mm, 3 μ m;
Column temperature: 40 ℃;
Flow velocity: 0.7ml/min;
Detect wavelength: 222nm.
Agents useful for same all can be from commercially available acquisition in the embodiment of the invention.Wherein yeast powder (Yeastextract) is available from Britain Oxoid company; Peptone (Trypton) is available from Britain Oxoid company, and Fructus Hordei Germinatus soaks powder available from source, Shanghai consor thing Science and Technology Ltd.; Sucrose is available from upper sea blue plain industry company limited; Glucose is available from west, Shanghai king's β-amylose company limited; The peanut meal powder is available from Beijing Kang Mingwei substratum technology limited liability company; Oatmeal is available from Tianjin chemical industry sales department; All the other biochemical reagents are all available from Chemical Reagent Co., Ltd., Sinopharm Group.The HP20 resin is produced by Mitsubishi chemical company, and the XAD18 resin is available from Rhom and Hass.
Embodiment 1:
1), the fermentation of ECB deacylase
Bacterial classification: actinoplanes utahensis (Actinoplanes utahensis NRRL12052), available from american agriculture research DSMZ.
Culture medium prescription:
Slant medium: yeast powder 0.3%, Fructus Hordei Germinatus soak powder 0.3%, peptone 0.5%, and glucose 1.0%, agar 2.5%, pH 7.0-7.2 cultivated 5-7 days for 30 ℃
Seed culture medium: sucrose 2.5%, oatmeal 2%, yeast powder 0.25%, K
2HPO
40.1%, KCl 0.05%, MgSO
47H
2O 0.05%, FeSO
47H
2O 0.0002%, and pH=6.8 cultivated 4-5 days for 30 ℃
Fermention medium: sucrose 2.5%, peanut meal powder 1.2%, K
2HPO
40.1%, MgSO
47H
2O0.3%, pH=6.8 cultivated 3-4 days for 30 ℃
2), the fermentation finish after, add Na in the fermented liquid
2HPO
412H
2O and NaH
2PO
42H
2O concentration is respectively 6.10g/L and 5.8g/L, and regulating pH with HCl is 6.0, ultrasonic 1h, and the centrifuging and taking supernatant is ECB deacylase crude enzyme liquid.
3), crude enzyme liquid revolves inspissation and is reduced to original volume 80%, revolving and steaming temperature is 45 ℃, revolving the steaming time is 1h.Have the foreign protein precipitation to occur after revolving the inspissation contracting, suction filtration is removed the part foreign protein, and gained filtrate is ECB deacylase enzyme liquid.
4), ECB is dissolved in 95% ethanol, add in the deacylase enzyme liquid being made into reaction system to, ECB concentration is controlled at 4mg/ml in the system.The reaction system for preparing is placed in the conversion reactor, fully stir, 28 ℃, 150rpm transforms 12h.After conversion was finished, suction filtration was got filtrate HPLC detection by quantitative ECB parent nucleus content, and the molar yield of calculating substrate ECB is 93%.
Molar yield %=generates ECBN mole number/substrate ECB mole number * 100%
5), transform rear filtrate and cross macroporous adsorbent resin HP20, the ECB parent nucleus is adsorbed on the resin fully, is that 40% methanol aqueous solution is concentrated ECBN and eluted with concentration, reaches 93.3% by the liquid phase purity of Fig. 7 calculating.
6), behind the upper prop enzyme liquid by step 4)～5) reuse 3 times, molar yield is respectively 94%, 90%, 86%.
Embodiment 2
1), the fermentation of ECB deacylase
Bacterial classification: actinoplanes utahensis (Actinoplanes utahensis NRRL12052), available from american agriculture research DSMZ.
Culture medium prescription:
Slant medium: yeast powder 0.3%, Fructus Hordei Germinatus soak powder 0.3%, peptone 0.5%, and glucose 1.0%, agar 2.5%, pH 7.0-7.2 cultivated 5-7 days for 30 ℃
Seed culture medium: sucrose 2.5%, oatmeal 2%, yeast powder 0.25%, K
2HPO
40.1%, KCl 0.05%, MgSO
47H
2O 0.05%, FeSO
47H
2O 0.0002%, and pH=6.8 cultivated 4-5 days for 30 ℃
Fermention medium: sucrose 2.5%, peanut meal powder 1.2%, K
2HPO
40.1%, MgSO
47H
2O0.3%, pH=6.8 cultivated 3-4 days for 30 ℃
2), the fermentation finish after, add Na in the fermented liquid
2HPO
412H
2O and NaH
2PO
42H
2O concentration is respectively 18.20g/L and 15.15g/L, and it is 7.0 that NaOH transfers pH, ultrasonic 2h, and the centrifuging and taking supernatant is ECB deacylase crude enzyme liquid.
3), crude enzyme liquid revolves inspissation and is reduced to original volume 50%, revolving and steaming temperature is 45 ℃, revolving the steaming time is 2h.Have the foreign protein precipitation to occur after revolving the inspissation contracting, suction filtration is removed the part foreign protein, and gained filtrate is ECB deacylase enzyme liquid.
4), ECB is dissolved in the dehydrated alcohol, add in the deacylase enzyme liquid being made into reaction system to, ECB concentration is controlled at 2mg/ml in the system.The reaction system for preparing is placed in the conversion reactor, fully stir, 28 ℃, 150rpm transforms 6h.After conversion was finished, suction filtration was got filtrate HPLC detection by quantitative ECB parent nucleus content, and the molar yield of calculating substrate ECB is 86%.
Molar yield %=generates ECBN mole number/substrate ECB mole number * 100%
5), transform rear filtrate and cross macroporous adsorbent resin, the ECB parent nucleus is adsorbed on the resin fully, is that 60% methanol aqueous solution is concentrated ECBN and eluted with concentration, reaches 90.7% by the liquid phase purity of Fig. 8 calculating.
6), enzyme liquid is reused 2 times by step 4～5 behind the upper prop, the molar yield of ECB is 90%, 86%.
Embodiment 3
1), the fermentation of ECB deacylase
Bacterial classification: actinoplanes utahensis (Actinoplanes utahensis NRRL12052), available from american agriculture research DSMZ.
Culture medium prescription:
Slant medium: yeast powder 0.3%, Fructus Hordei Germinatus soak powder 0.3%, peptone 0.5%, and glucose 1.0%, agar 2.5%, pH 7.0-7.2 cultivated 5-7 days for 30 ℃
Seed culture medium: sucrose 2.5%, oatmeal 2%, yeast powder 0.25%, K
2HPO
40.1%, KCl 0.05%, MgSO
47H
2O 0.05%, FeSO
47H
2O 0.0002%, and pH=6.8 cultivated 4-5 days for 30 ℃
Fermention medium: sucrose 2.5%, peanut meal powder 1.2%, K
2HPO
40.1%, MgSO
47H
2O0.3%, pH=6.8 cultivated 3-4 days for 30 ℃
2), the fermentation finish after, add Na in the fermented liquid
2HPO
412H
2O and NaH
2PO
42H
2O concentration is respectively 12.20g/L and 10.15g/L, and regulating pH is 6.8, ultrasonic 1.5h, and the centrifuging and taking supernatant is ECB deacylase crude enzyme liquid.
3), crude enzyme liquid revolves inspissation and is reduced to original volume 70%, revolving and steaming temperature is 50 ℃, revolving the steaming time is 1.5h.Have the foreign protein precipitation to occur after revolving the inspissation contracting, suction filtration is removed the part foreign protein, and gained filtrate is ECB deacylase enzyme liquid.
4), ECB is dissolved in the dehydrated alcohol, add in the deacylase enzyme liquid being made into reaction system to, ECB concentration is controlled at 3mg/ml in the system.The reaction system for preparing is placed in the conversion reactor, fully stir, 28 ℃, 150rpm transforms 12h.After conversion was finished, suction filtration was got filtrate HPLC detection by quantitative ECB parent nucleus content, and the molar yield of calculating substrate ECB is 93%.
Molar yield %=generates ECBN mole number/substrate ECB mole number * 100%
5), transform rear filtrate and cross macroporous adsorbent resin XAD18, the ECB parent nucleus is adsorbed on the resin fully, is that 50% methanol aqueous solution is concentrated ECBN and eluted with concentration, reaches 92.6% by the liquid phase purity of Fig. 9 calculating.
6), enzyme liquid is reused 3 times by step 4～5 behind the upper prop, the molar yield of ECB is 90%, 85%, 85%.
Claims (15)
1. ECB is changed into the method for ECB parent nucleus, may further comprise the steps:
1) microbial fermentation obtains the ECB deacylase;
2) after fermentation is finished, add phosphoric acid salt in fermented liquid, carry out ultrasonicly, the centrifuging and taking supernatant liquor is ECB deacylase crude enzyme liquid;
3) purifying crude enzyme liquid obtains ECB deacylase enzyme liquid;
4) ECB is dissolved in the ethanol, mixes and stir making it be converted into the ECB parent nucleus with deacylase enzyme liquid, after conversion is finished, filter, get filtrate;
5) filtrate is crossed macroporous adsorbent resin, and the ECB parent nucleus is adsorbed on the resin, with organic solvent the ECB parent nucleus is eluted.
2. the fermentation bacterial strain uses therefor method according to claim 1, wherein said step 1) is natural zymogenic bacteria or genetic engineering bacterium.
3. the fermentation bacterial strain uses therefor method according to claim 1, wherein said step 1) is actinoplanes utahensis (Actinoplanes utahensis).
4. method according to claim 1, wherein said step 2) described ultrasonic lasting 1-2h.
5. in fermented liquid, add phosphoric acid salt method according to claim 1, wherein said step 2), so that phosphatic concentration is 0.05M-0.15M.
6. the pH regulator with described fermented liquid method according to claim 1, wherein said step 2) is 6-7.
7. method according to claim 1, wherein said step 3) described purifying comprises and makes crude enzyme liquid revolve the contract step of suction filtration of inspissation.
8. revolving method according to claim 7, wherein said step 3) and steaming temperature is 45-50 ℃, and revolving the steaming time is 1-2 hour.
9. simmer down to is reduced to volume the 50-80% of original volume method according to claim 7, wherein said step 3).
10. macroporous adsorbent resin is selected from HP20 or XAD18 method according to claim 1, wherein said step 4).
11. method according to claim 1, wherein said step 4) transformation time is 6-12 hour described in.
12. method according to claim 1, wherein said step 4) concentration of ethanol is more than or equal to 95% described in.
13. method according to claim 1, wherein said step 5) organic solvent is methanol aqueous solution described in.
14. method according to claim 13, the concentration of wherein said methanol aqueous solution are 30-60%.
15. method according to claim 1, wherein deacylase enzyme liquid is pressed step 4 behind the upper prop)-5) reusable 2-4 time.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447961A (en) * | 2013-09-13 | 2015-03-25 | 浙江震元制药有限公司 | Method for extracting echinocandin B mother nucleus |
| CN105648000A (en) * | 2014-11-19 | 2016-06-08 | 重庆乾泰生物医药有限公司 | A microbial enzymatic conversion method for echinocandin B |
| CN107779487A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method that ECB is converted using actinoplanes utahensis |
| CN108410929A (en) * | 2018-05-30 | 2018-08-17 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of anidulafungin precursor |
| CN108676831A (en) * | 2018-05-30 | 2018-10-19 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of echinocandin B parent nucleus |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447961A (en) * | 2013-09-13 | 2015-03-25 | 浙江震元制药有限公司 | Method for extracting echinocandin B mother nucleus |
| CN104447961B (en) * | 2013-09-13 | 2018-05-15 | 浙江震元制药有限公司 | The extracting method of echinocandin B parent nucleus |
| CN105648000A (en) * | 2014-11-19 | 2016-06-08 | 重庆乾泰生物医药有限公司 | A microbial enzymatic conversion method for echinocandin B |
| CN105648000B (en) * | 2014-11-19 | 2019-08-13 | 重庆乾泰生物医药有限公司 | A kind of echinocandin B microbial enzyme method for transformation |
| CN107779487A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of method that ECB is converted using actinoplanes utahensis |
| CN108410929A (en) * | 2018-05-30 | 2018-08-17 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of anidulafungin precursor |
| CN108676831A (en) * | 2018-05-30 | 2018-10-19 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of echinocandin B parent nucleus |
| CN108410929B (en) * | 2018-05-30 | 2024-01-26 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of anidulafungin precursor |
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| CN103074403B (en) | 2014-07-09 |
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