CN105504014B - The polyethylene glycol derivative of beta-lactamase inhibitory peptide and its application - Google Patents
The polyethylene glycol derivative of beta-lactamase inhibitory peptide and its application Download PDFInfo
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- CN105504014B CN105504014B CN201510997793.3A CN201510997793A CN105504014B CN 105504014 B CN105504014 B CN 105504014B CN 201510997793 A CN201510997793 A CN 201510997793A CN 105504014 B CN105504014 B CN 105504014B
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention discloses the polyethylene glycol derivative of beta-lactamase inhibitory peptide and its application, the polyethylene glycol derivative of beta-lactamase inhibitory peptide by beta-lactamase inhibitory peptide the terminal modified NH of amino2‑(CH2CH2O)8‑CH2CH2COOH and obtain, the polyethylene glycol derivative of the beta-lactamase inhibitory peptide of acquisition is not easy hydrolyzed enzyme hydrolysis, and Half-life in vivo is long；Can be used for preparing beta-lactamase inhibitor, the antibacterial curative effect of beta-lactam antibacterials improved with beta-lactam combined antimicrobial agents, bacterial infection treatment field with good development and application prospects.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to the polyethylene glycol derivative of beta-lactamase inhibitory peptide, also
It is related to the application of the polyethylene glycol derivative of beta-lactamase inhibitory peptide.
Background technique
Bacterium is to there are many mechanism of beta-lactam antibiotic resistance, and wherein the generation of beta-lactamase is most important
With the most common mechanism, by with the carbonyl covalent bond on beta-lactam nucleus, hydrolyze amido bond make beta-lactam antibacterial
Drug inactivation.In recent years, with the extensive application of super wide spectrum beta-lactam antibacterials, the type of beta-lactamase, substrate
Spectrum and drug-resistant intensity develop at an amazing speed, have made bacterium to aztreonam, most third generation cephalosporin even the
Four generation cephalosporin drug resistances.The main method to solve the above problems first is that exploitation beta-lactamase inhibitor.It is clinical at present wide
The beta-lactamase inhibitor of general application has clavulanic acid, Sulbactam and Tazobactam etc., they are by inhibiting beta-lactamase
Activity and achieve the purpose that protect beta-lactam antibacterials.But with answering extensively for these beta-lactamase inhibitors
With also being gradually increased to the drug resistant zymogenic bacteria of these beta-lactamase inhibitors.Therefore, it is interior that novel, efficient other β-are developed
Lactamase inhibitor is necessary.
It is nineteen ninety from soil that beta-lactamase, which inhibits albumen (β-lactamase inhibitory protein, BLIP),
Isolated main protein in clavuligerus culture solution.Document report, it is interior that 2 fold domains of BLIP are inserted into β-
In the active site of amidase, the engagement of beta-lactamase and beta-lactam antibacterials is prevented.Although BLIP is by 165 ammonia
Base acid composition, molecular weight is larger, and antigenicity is stronger, is not suitable for the drug for being developed into clinical use, but it is beta-lactamase
The research and development of peptide for inhibiting provides new approach.The Chinese patent application of Publication No. CN1778916A discloses a kind of energy
Enough inhibit the polypeptide of beta-lactamase.The polypeptide is made of 24 amino acid, thus it is speculated that and molecular weight is 2600 dalton, although with
BLIP is compared in terms of molecular weight, antigenicity with some superiority, but still there are molecular weight is larger and potential antigenicity etc.
Problem；The polypeptide is prepared using Bacillus coli expression simultaneously, and complex process, the period is long, and cost is big, is not suitable for large-scale production.
(the activity research China antibiotic magazine of beta-lactamase inhibitory peptide, 2010,35 (4) such as Li Yong Chung:300-304) pass through meter
Calculation machine molecule three-dimensional simulation has designed and synthesized 6 beta-lactamase inhibitory peptides (amino acid sequence of each peptide for inhibiting is undisclosed),
But it is found during identified activity, 2. and 5. peptide for inhibiting can not dissolve, peptide for inhibiting is 4. most of during preservation to have dropped
Solution, although remaining 3 peptide for inhibiting have activity of inhibiting beta-lactamase, activity is weaker.Chen Yongchuan etc. application No. is
CN102212110A discloses beta-lactamase inhibitory peptide with stronger activity of inhibiting beta-lactamase, and molecular weight is small, no
It is also easy to produce antigenicity, but its easily hydrolyzed enzyme hydrolysis in vivo, half-life short, to maintain certain curative effect to need large dosage repeatedly
Medication.Therefore, beta-lactamase inhibitory peptide is chemically modified, increases its stability, change it in the intracorporal biology of people
Distribution, it is very necessary for extending its half-life period.
Summary of the invention
In view of this, one of the objects of the present invention is to provide the polyethylene glycol derivatives of beta-lactamase inhibitory peptide；
The second object of the present invention is that the polyethylene glycol derivative for providing beta-lactamase inhibitory peptide is preparing beta-lactamase suppression
Application in preparation；The third object of the present invention is to provide the polyethylene glycol derivative of beta-lactamase inhibitory peptide and β-is interior
Amides antibacterials combine the application in preparation antibacterials.
For achieving the above object, through many experiments, the present invention is provided the following technical solutions：
The Pegylation of the polyethylene glycol derivative of beta-lactamase inhibitory peptide, the beta-lactamase inhibitory peptide spreads out
Biology is the terminal modified NH of amino of beta-lactamase inhibitory peptide2-(CH2CH2O)8-CH2CH2The compound of COOH, the interior acyl of β-
The amino acid sequence of amine enzyme inhibition peptide is as shown in SEQ ID NO.1.
Preferably, the structural formula of the polyethylene glycol derivative of the beta-lactamase inhibitory peptide is as follows：
2, the polyethylene glycol derivative of the beta-lactamase inhibitory peptide is preparing answering in beta-lactamase inhibitor
With.
3, the polyethylene glycol derivative of the beta-lactamase inhibitory peptide is combined with beta-lactam antibacterials and is used for
Prepare the application in antibacterials.
The beneficial effects of the present invention are：It is derivative that the present invention provides a kind of Pegylations of beta-lactamase inhibitory peptide
Object can be prepared by solid phase polypeptide synthesis, simple and easy to do, production cost is low, be suitble to industrialization large-scale production；It is not easy by water
Enzyme hydrolysis is solved, Half-life in vivo is long；It can be used for preparing beta-lactamase inhibitor, with beta-lactam combined antimicrobial agents to mention
The antibacterial curative effect of high beta-lactam antibacterials, bacterial infection treatment field with good development and application prospects.
Detailed description of the invention
In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following attached drawing：
Fig. 1 is the polyethylene glycol derivative efficient liquid phase figure of beta-lactamase inhibitory peptide.
Fig. 2 is the polyethylene glycol derivative mass spectrogram of beta-lactamase inhibitory peptide.
Fig. 3 is that the polyethylene glycol derivative of beta-lactamase inhibitory peptide measures knot to the inhibitory activity of beta-lactamase
Fruit.
Fig. 4 is the polyethylene glycol derivative of beta-lactamase inhibitory peptide and the Drug-time curve of beta-lactamase inhibitory peptide
Figure.
Specific embodiment
Below in conjunction with attached drawing, a preferred embodiment of the present invention will be described in detail.It is not specified in embodiment specific
The experimental method of condition, usually according to conventional conditions or according to the manufacturer's recommendations.
Embodiment 1, solid phase polypeptide synthesis prepare the polyethylene glycol derivative of beta-lactamase inhibitory peptide
Solid phase polypeptide synthesis prepares the polyethylene glycol derivative of beta-lactamase inhibitory peptide, and specific step is as follows：
(1) resin swelling：Wang Shuzhi (wang resin) is put into reaction tube, n,N-Dimethylformamide (DMF) is added,
Vibrate 30min；
(2) first amino acid is connect：Solvent is leached out by husky core, addition is equivalent to 3 times moles of synthesis polypeptide of Fmoc-
O- tert-butyl-l-tyrosine (Fmoc-L-Tyr (Tbu)-OH) adds and is equivalent to 10 times moles of synthesis polypeptide of 4- diformazan ammonia
Yl pyridines (DMAP) and dicyclohexylcarbodiimide (DCC) are eventually adding DMF dissolution, vibrate 30min, closed with acetic anhydride；
(3) it is deprotected：Remove DMF, adding volume fraction is 20% Piperidine/DMF solution, is removed after 5min, then plus volume point
The Piperidine/DMF solution that number is 20%, 15min；
(4) it detects：Piperidine solution is taken out, more than ten grainy resins are taken, is washed three times with ethyl alcohol, ninhydrin, potassium cyanide, phenol is added
Each drop of solution, 105-110 DEG C of heating 5min, deepening blue is positive reaction；
(5) it cleans：It is respectively washed twice with DMF, methanol, DMF；
(6) it is condensed：The protected amino acid that will be equivalent to 3 times moles of synthesis polypeptide is equivalent to 3 times moles of synthesis polypeptide of O-
Benzotriazole-tetramethylurea hexafluorophosphate (HBTU), is dissolved with DMF, be added reaction tube, be added immediately be equivalent to synthesis it is more
10 times moles of peptide of 4- methyl morpholine (NMM) reacts 30min；
(7) it cleans：It is successively washed once using DMF (10ml/g), methanol (10ml/g) is washed twice, and DMF (10ml/g) washes two
It is secondary；
(8) operation of 2 to 6 steps is repeated, according to sequence C end to the N-terminal residue sequentially successively following amino acid of composition sequence：Thr
Thr Trp Ser Glu Tyr Tyr Pro Ala Tyr；
(9) Mass Spectrometer Method straight line peptide is main peak pair after the completion of straight line peptide, and addition is equivalent to 2 times moles of synthesis polypeptide of NH2-
(CH2CH2O)8-CH2CH2COOH is equivalent to 3 times moles of synthesis polypeptide of HBTU, is dissolved using DMF, is added immediately and is equivalent to conjunction
30min is reacted at 10 times moles of polypeptide of NMM；It is detected by the method for step (4), it is colourless for developing the color, removal Fmoc protection
Base；
(10) it drains, washes resin in following manner：It is successively washed twice using DMF (10ml/g), methanol (10ml/g) is washed
Twice, DMF (10ml/g) is washed twice, and DCM (10ml/g) is washed twice, drains 10min；
(11) polypeptide is cut from resin：Prepare cutting liquid (10ml/g) trifluoroacetic acid 95% (V/V)；Water 2% (V/V)；
1,2- dithioglycol 2% (V/V)；Tri isopropyl silane 1% (V/V)；120min is cut under cutting liquid effect.
(12) drying washing：Lysate is dried up as far as possible with nitrogen, is washed six times with ether, then room temperature (25 DEG C) volatilizes；
(13) by dry powder-shaped polypeptide crude product, (SHIMADZU high performance liquid chromatography is purified using high performance liquid chromatography
Instrument, 20 × 250mm of Kromasil C18120A chromatographic column, the trifluoroacetic acid and acetonitrile that mobile phase is 0.1% by volume fraction are pressed
It is 50 according to volume ratio:50 mix) to get the polyethylene glycol derivative sterling of beta-lactamase inhibitory peptide, structure such as formula 1
It is shown.
Formula 1
It is identified through high performance liquid chromatography, as a result as shown in Figure 1, the beta-lactamase inhibitory peptide obtained as the result is shown gathers
Glycation derivative sterling purity is greater than 98%；It is identified through mass spectrography, as a result as shown in Figure 2, the results showed that beta-lactamase
The polyethylene glycol derivative sterling molecular weight of peptide for inhibiting is consistent with theoretical molecular weight.
The preparation and activity identification of embodiment 2, beta-lactam enzyme extract
The production beta-lactam that picking is clinically separated and identifies through Nitrocefin (beta-lactamase specificity identification reagent)
The Klebsiella Pneumoniae single colonie of enzyme is inoculated in the fresh meat soup of 5ml, and 37 DEG C are incubated for 24 hours, then draw culture solution 2ml and add
Enter in the fresh meat soup of 200ml, 37 DEG C oscillation incubation 24 hours, 4 DEG C, 5000 × g be centrifuged 30 minutes, collect thallus, with 0.05M,
The phosphate buffer washing thalline of pH7.0 2 times, then thallus, ultrasonication bacterium under the conditions of ice-water bath is resuspended with buffer 5ml
Body, 4 DEG C, 20000 × g centrifugation 1 hour, collects supernatant to get beta-lactam enzyme extract, through -70 DEG C of protein quantification postposition
It is saved in refrigerator.
To final concentration of 10-430 μ l of beta-lactam enzyme extract is added in the cefaloridine solution 3ml of M, 37 DEG C of mixings are stood
I.e. with trap (OD value) variation at wavelength 260nm in the ultraviolet specrophotometer observation unit time, begun to decline from OD value
It rises, records an OD value at regular intervals, until OD value no longer changes or amplitude of variation is obviously reduced；It is vertical seat with OD value
Mark, time are abscissa, when calculating m- OD value regression equation, choose the point of related coefficient γ >=0.90, calculating Δ OD i.e. two
The mean value of the difference of the OD value of adjacent time calculates the activity of beta-lactamase according still further to following formula：Beta-lactam enzymatic activity (U)=Δ
OD value × protein quantification (mg/ml) before recording number × 1000/ hydrolysis of OD value in OD × 10 × 1 minute.The results show that this
Contain the beta-lactamase of 486U in beta-lactam enzyme extract made from embodiment.
Embodiment 3, beta-lactamase inhibitory peptide polyethylene glycol derivative the inhibitory activity of beta-lactamase is measured
Test is divided into 3 groups：1. ampicillin+enzyme group：β-is added into the ampicillin solution 2ml that concentration is 0.4mg/ml
Lactamase crude extract 40 μ l and water 8ml；2. ampicillin+enzyme+peptide for inhibiting group：It is molten to the ampicillin that concentration is 0.4mg/ml
40 μ l of beta-lactam enzyme extract and concentration are added in liquid 2ml as the Pegylation of the beta-lactamase inhibitory peptide of 0.1mg/ml
Derivative solution 8ml；3. ampicillin group：0.05M, pH7.0 is added into the ampicillin solution 2ml that concentration is 0.4mg/ml
Phosphate buffer 40 μ l and water 8ml；Each group is mixed in 37 DEG C, immediately with wave in the ultraviolet specrophotometer observation unit time
OD value variation at long 235nm investigates beta-lactamase and beta-lactamase suppression by the speed of ampicillin degradation rate
The influence that peptide processed degrades to ampicillin.As a result as shown in Figure 3, it is seen that the trap 3. organized has almost no change in 400 seconds；
1. the trap decline organized is most fast, show that beta-lactamase being capable of catalytic degradation ampicillin；2. the trap fall off rate organized
1. group obviously slows down, show that the polyethylene glycol derivative of beta-lactamase inhibitory peptide can obviously inhibit beta-lactamase pair
The degradation of ampicillin.
Embodiment 4, the polyethylene glycol derivative of beta-lactamase inhibitory peptide and beta-lactamase inhibitory peptide are in Beagle
The intracorporal pharmacokinetics comparative studies of dog
The experiment purpose of the present embodiment is analysis beta-lactamase inhibitory peptide polyethylene glycol derivative and beta-lactamase
The Pharmacokinetic Characteristics and difference of peptide for inhibiting, emphasis are the difference of Half-life in vivo, wherein the ammonia of beta-lactamase inhibitory peptide
Base acid sequence is as shown in SEQ ID NO.1.
1, the Chromatography/Mass Spectrometry condition of plasma sample measurement
Chromatographic column：SHISEIDO (3.0 × 100mm, 3 μm), the production of SHISEIDO company；Column temperature：30℃；Mobile phase：First
Alcohol (0.1% formic acid)：Water (0.1% formic acid)=80：20；Flow velocity：0.3mL/min；Sample volume：5μL.
Mass Spectrometry Conditions：Detection mode：Multiple-reaction monitoring (MRM)；Positive ion detection；Select ion pair：Beta-lactamase suppression
Peptide processed：641.2/350.1；Beta-lactamase inhibitory peptide polyethylene glycol derivative：852.8/350.2；Internal standard：764.6/
350.1；Gas curtain gas：25.0PSI；Ion source voltage：5000V；Ion source temperature：500℃；Remove cluster voltage (DP)：137.0V/
173.3V/120.0V；Impact energy (CE)：21V/25V/25.9V.
2. plasma sample processing method
It takes 100 μ l blood plasma that the 10 μ l of inner mark solution that concentration is 10 μ g/ml is added, adds 900 μ l of methanol, be vortexed and mix
2min；13000rpm is centrifuged 5min, and filtering with microporous membrane supernatant takes 5 μ l to carry out HPLC/MS/MS analysis.
3. standard curve
Beta-lactamase inhibitory peptide polyethylene glycol derivative is prepared respectively with beta-lactamase inhibitory peptide concentration is respectively
5, the blood plasma of 10,20,50,150,500,1500,5000ng/ml, sample introduction is surveyed after being handled according to plasma sample processing method
It is fixed, record chromatogram.Using testing concentration as abscissa, determinand and interior target peak area ratio are ordinate, are returned
Operation, the linear regression equation acquired.Beta-lactamase inhibitory peptide polyethylene glycol derivative and beta-lactamase inhibitory peptide mark
Directrix curve regression equation Tables 1 and 2.According to standard curve, beta-lactamase inhibitory peptide polyethylene glycol derivative and the interior acyl of β-
The range of linearity of amine enzyme inhibition peptide concentration is 5~5000ng/ml.
1 HPLC-MS/MS method of table measures beta-lactamase inhibitory peptide polyethylene glycol derivative standard curve in blood plasma
2 HPLC-MS/MS method of table measures beta-lactamase inhibitory peptide standard curve in blood plasma
4. relative recovery
Prepare the β-of basic, normal, high three concentration (10,150 and 4000ng/ml) respectively by the method under " standard curve " item
Lactamase peptide for inhibiting polyethylene glycol derivative and beta-lactamase inhibitory peptide plasma sample, at plasma sample processing method
Reason, each concentration carry out 5 sample analyses, and the ratio for bringing respective standard curve calculating gained concentration and theoretical concentration into respectively is
Relative recovery the results are shown in Table 3 and table 4.
3 Pegylation beta-lactamase inhibitory peptide relative recovery of table
4 beta-lactamase inhibitory peptide relative recovery of table
5. precision
Prepare the β-of basic, normal, high three concentration (10,150 and 4000ng/ml) respectively by the method under " standard curve " item
Lactamase peptide for inhibiting polyethylene glycol derivative and beta-lactamase inhibitory peptide plasma sample, at plasma sample processing method
Reason, each concentration carry out 5 sample analyses, calculate the precision of this law, the results are shown in Table 5 and 6.The suppression of Pegylation beta-lactamase
The precision (RSD) of basic, normal, high three concentration of peptide processed is respectively 6.50%, 2.61% and 2.21%, beta-lactamase inhibitory peptide
The precision (RSD) of basic, normal, high three concentration is respectively 6.70%, 2.15% and 7.48%, is all satisfied biological sample analysis and wants
It asks.
5 HPLC-MS/MS method of table measures the precision of Pegylation beta-lactamase inhibitory peptide in blood plasma
6 HPLC-MS/MS method of table measures the precision of beta-lactamase inhibitory peptide in blood plasma
6. pharmacokinetics
Reference《Chemicals Non-clinical Pharmacokinetics investigative technique guideline》Technical requirements carry out experimental design,
Using the random single-dose test of dual crossing, the cleaning phase is 1 week.6 Beagle dogs, half male and half female, be randomly divided into test group and
Control group, every group 3.Beagle dog fasting 12h (can't help water) before testing.The next morning intravenous (IV) drug beta-lactamase
The normal saline solution (2mg/ml) of peptide for inhibiting polyethylene glycol derivative or beta-lactamase inhibitory peptide, two groups of dosages are equal
For 1mg/kg.Every Beagle dog in administration before and administration after at once, 2,5,10,20,30,45,60,120,240,480,
720min takes blood 2ml in heparinised tubes respectively at forelimb cephalic vein, divides and takes blood plasma, to be measured in -70 DEG C of preservations.
The above plasma sample is handled by preceding method, and carries out HPLC/MS/MS analysis, brings respective mark into respectively
Directrix curve calculates drug concentration, and blood concentration-time data are handled through DAS 3.1.6 program, calculate its statistical moment parameter, blood
Concentration value is shown in Table 7 and table 8 respectively, and pharmacokinetic parameter is shown in Table 9, and Drug-time curve is shown in Fig. 4.The poly- second of beta-lactamase inhibitory peptide
Plasma half-life (the t of diolation derivative1/2), bioavilability (AUC), the main medicine such as mean residence time (MRT) is for power
It learns the more unmodified beta-lactamase inhibitory peptide of parameter values to obviously increase, shows that the modification of Pegylation promotes body pair
The producing level of beta-lactamase inhibitory peptide, extends Half-life in vivo, is conducive to the performance of beta-lactamase inhibitory peptide drug effect.
Plasma concentration (ng/ml) of the tested dog of table 7 to beta-lactamase inhibitory peptide polyethylene glycol derivative
Note：ND indicates to be lower than minimum detection limit
Plasma concentration (ng/ml) of the tested dog of table 8 to beta-lactamase inhibitory peptide
Note：ND indicates to be lower than minimum detection limit
The tested dog of table 9 administration after mean serum pharmacokinetic parameter (N=6)
Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (3)
1. the polyethylene glycol derivative of beta-lactamase inhibitory peptide is preparing the application in beta-lactamase inhibitor, feature
It is：The polyethylene glycol derivative of the beta-lactamase inhibitory peptide is the terminal modified NH of amino of beta-lactamase inhibitory peptide2-
（CH2CH2O）8-CH2CH2The compound of COOH, the amino acid sequence of the beta-lactamase inhibitory peptide such as SEQ ID NO.1 institute
Show.
2. the polyethylene glycol derivative of beta-lactamase inhibitory peptide according to claim 1, it is characterised in that：The β-is interior
The structural formula of the polyethylene glycol derivative of amide enzyme inhibition peptide is as follows：
。
3. the polyethylene glycol derivative of beta-lactamase inhibitory peptide is combined with beta-lactam antibacterials is preparing antimicrobial
Application in object, it is characterised in that：The polyethylene glycol derivative of the beta-lactamase inhibitory peptide is beta-lactamase inhibition
The terminal modified NH of the amino of peptide2-（CH2CH2O）8-CH2CH2The compound of COOH, the amino acid sequence of the beta-lactamase inhibitory peptide
Column are as shown in SEQ ID NO.1.
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| CN102212110A (en) * | 2011-05-04 | 2011-10-12 | 中国人民解放军第三军医大学第一附属医院 | Beta-lactamase inhibitory peptide and application thereof |
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| CN102212110A (en) * | 2011-05-04 | 2011-10-12 | 中国人民解放军第三军医大学第一附属医院 | Beta-lactamase inhibitory peptide and application thereof |
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| Title |
|---|
| 蛋白类药物聚乙二醇修饰的研究;旷瑜等;《中国煤炭工业医学杂志》;20080229;第11卷(第2期);第271-274页 * |
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