CN111678874A - 6-glucose phosphate dehydrogenase mutant and application thereof in preparation of cyclosporine A detection reagent - Google Patents
6-glucose phosphate dehydrogenase mutant and application thereof in preparation of cyclosporine A detection reagent Download PDFInfo
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- CN111678874A CN111678874A CN202010013174.7A CN202010013174A CN111678874A CN 111678874 A CN111678874 A CN 111678874A CN 202010013174 A CN202010013174 A CN 202010013174A CN 111678874 A CN111678874 A CN 111678874A
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- glucose
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title description 2
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- 239000007858 starting material Substances 0.000 description 1
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- 208000018556 stomach disease Diseases 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
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- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
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- 238000004879 turbidimetry Methods 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
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Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- 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
Abstract
The application relates to a 6-phosphoglucose dehydrogenase mutant and application thereof in preparing a cyclosporine A detection reagent. Specifically, the glucose-6-phosphate dehydrogenase mutant of the present application comprises one or a combination of mutations selected from the group consisting of: D306C, D375C, G426C. The detection kit prepared by using the glucose-6-phosphate dehydrogenase mutant has the advantages of strong specificity, high sensitivity, convenient operation, short detection time and accurate quantification, and is suitable for high-throughput detection.
Description
Priority of application No. 201910017764.4 filed on 1/9/2019 and 201910423122.4 "mutant glucose-6-phosphate dehydrogenase and use thereof in the preparation of test agents" filed on 5/21/2019, which are incorporated herein by reference.
Technical Field
The application relates to the field of biological detection, in particular to mutant enzyme 6-phosphoglucose dehydrogenase (G6 PDH for short) and application thereof in a cyclosporine A detection kit.
Background
Haptens, some small molecular substances (molecular weight less than 4000Da), alone cannot induce an immune response, i.e. are not immunogenic, but can acquire immunogenicity when crosslinked or conjugated with carriers such as macromolecular proteins or non-antigenic polylysine, and induce an immune response. These small molecule substances can bind to response effector products, have antigenicity, are immunoreactive only and are not immunogenic, and are also called incomplete antigens.
The hapten can be combined with a corresponding antibody to generate an antigen-antibody reaction, and can not singly stimulate the human or animal body to generate the antigen of the antibody. It is immunoreactive only, has no immunogenicity, and is also called incomplete antigen. Most polysaccharides, lipids, hormones, and small molecule drugs are haptens. If a hapten is chemically bound to a protein molecule (carrier), it will acquire new immunogenicity and will stimulate the production of corresponding antibodies in animals.
Small molecule antigens or haptens lack two or more sites that can be used in sandwich assays, and therefore cannot be measured using the double antibody sandwich assay, and often use a competition mode. The principle is that the antigen in the specimen and a certain amount of enzyme-labeled antigen compete to bind with the solid-phase antibody. The more the amount of the antigen in the specimen is, the less the enzyme-labeled antigen bound to the solid phase is, and the lighter the color develops. ELISA measurement of small molecule hormone, medicine, etc. is used in different methods.
Cyclosporine A (Cyclosporine A, CsA) has the following structural formula:
cyclosporin A is a lipid-soluble cyclic peptide consisting of a variety of amino acids secreted by fungi (Trichoderma polyspora or Trichoderma columbiatum). The CsA is used as an immunosuppressant with high selectivity and ultralow bone marrow toxicity, can selectively inhibit the proliferation and the release of T helper lymphocytes, and simultaneously has antifungal activity, and can effectively reduce the infection condition of patients. The cyclosporin A has important clinical application value in organ and tissue transplantation, blood diseases, ophthalmic diseases and other aspects, and can prevent rejection reaction caused by organ or tissue transplantation of allogeneic kidney, liver, heart, bone marrow and the like and prevent and treat graft-versus-host reaction caused by bone marrow transplantation in the aspect of organ and tissue transplantation; in the aspect of hematopathy, the medicine can be applied to diseases such as aplastic anemia, red blood cell aplastic anemia, myelodysplastic syndrome, autoimmune hemolytic anemia and the like; in the aspect of ophthalmic diseases, the eye drops are mainly used for diseases such as Behcet's syndrome, xerophthalmia, scleritis, allergic conjunctivitis and the like.
Cyclosporin a, a commonly used drug as a calcineurin inhibitor, has become one of the important choices for the treatment of many refractory renal diseases and organ transplantation, and is mainly distributed in human tissues other than the brain, and mainly distributed in red blood cells and plasma in blood. Cyclosporine A is mainly metabolized by liver, 15 metabolites are known, the elimination half-life period is about 10-27 hours, the metabolites are mainly excreted by bile through feces, and only 0.1% of urine is excreted in the form of original drug.
However, the medicament has narrow safety range and complicated metabolism influence factors, obvious individual difference exists in pharmacokinetics and pharmacodynamics, the correlation between the blood concentration and the dosage is poor, the difficulty is increased for clinical treatment, adverse reactions such as nephrotoxicity, hirsutism, gingival hyperplasia and the like are easy to generate, and the individual difference of the adverse reactions is serious.
For the reasons, cyclosporine A blood concentration monitoring is required in time in the treatment process, and the method is an effective mode for assisting clinical treatment, improving treatment effect and reducing toxicity risk.
The currently known detection methods of cyclosporine A mainly comprise: high Performance Liquid Chromatography (HPLC), luminescence immunity, enzyme-linked immunosorbent assay (ELISA), etc. The HPLC method needs complex sample pretreatment, has complex operation and long period and is expensive in cost; the reagent of the luminescence immunoassay method has high cost, is not suitable for the detection of conventional treatment drugs, and is not more beneficial to large-scale popularization.
The existing homogeneous enzyme immunoassay method and latex agglutination turbidimetry method are limited in application due to complex preparation process and large batch difference.
The prior art CN107782889A describes a cyclosporine a detection kit, which discloses a preparation method of a conjugate of glucose-6-phosphate dehydrogenase and cyclosporine a:
accurately weighing 240mg of cyclosporin A and 50mg of 4-benzoylbenzoic acid, putting into a quartz cuvette, adding 10mL of tert-butyl alcohol, and ultrasonically dissolving;
irradiating by ultraviolet light for 3 hours, fully reacting, and standing at room temperature to form lyophilized powder;
accurately weighing 4.5mg of 6-phosphoglucose dehydrogenase and dissolving in 0.5mL of 10mM PBS (pH 7.4), dissolving 15mg of the above powder (CsA-BBa) in 0.7mL of Dimethylformamide (DMF), and adding CsA-BBa dropwise into the PBS solution containing GDH at constant temperature of 25 deg.C under stirring;
adjusting the pH value of the solution to be 6.0-8.0, dropwise adding 120 mu L of 0.5% carbodiimide (EDC), and stirring overnight at 4 ℃;
purifying by G-25 gel chromatography column to obtain 6-phosphoglucose dehydrogenase-cyclosporine A conjugate, and storing at 2-8 deg.C.
However, the prior art methods rely on activation of a reactive group carried by the small molecule drug (cyclosporin A) itself, followed by reaction with an enzyme. In such a coupling method, a plurality of cyclosporins a are linked to the same glucose-hexametaphosphate dehydrogenase, and it is difficult to ensure consistency of coupling sites and orientation between the small molecule drug and the enzyme 1: 1, resulting in large batch-to-batch variation.
Disclosure of Invention
In view of the need in the art, the present application provides a novel glucose-6-phosphate dehydrogenase mutant and its use in the preparation of a cyclosporine a assay kit.
According to some embodiments, a glucose-6-phosphate dehydrogenase mutant is provided. In contrast to the previously published mutant of glucose-6-phosphate dehydrogenase of patent US006090567A (halogenated immunological systems using mutant glucose-6-phosphate dehydrogenes), the glucose-6-phosphate dehydrogenase mutant of the present application comprises a mutation selected from the group consisting of: D306C, D375C, G426C.
According to some embodiments, there is provided a glucose-6-phosphate dehydrogenase mutant, the glucose-6-phosphate dehydrogenase mutant being represented by a sequence selected from the group consisting of: SEQ ID No.2, SEQ ID No.3, SEQ ID No. 4.
According to some embodiments, there is provided a polynucleotide encoding a glucose-6-phosphate dehydrogenase mutant of the present application.
According to some embodiments, there is provided an expression vector comprising a polynucleotide of the present application.
According to some embodiments, there is provided a host cell comprising an expression vector of the present application. The host cell may be prokaryotic (e.g., bacteria) or eukaryotic (e.g., yeast).
According to some embodiments, there is provided a conjugate of a glucose-6-phosphate dehydrogenase mutant of the present application and a hapten in a molar ratio of 1: x is coupled. In some embodiments, x is 1 to 10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In some specific embodiments, the glucose-6-phosphate dehydrogenase mutant of the present application is preferably present in a molar ratio of 1: 1.
in some specific embodiments, the hapten has a molecular weight of from 100Da to 4000Da, for example: 100. 150, 200, 250, 300, 350, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 520, 550, 570, 600, 620, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000.
According to the present application, the skilled person will understand that "hapten" also comprises forms of its derivatives. To facilitate conjugation to glucose-6-phosphate dehydrogenase, haptens (e.g., cyclosporin A) that do not themselves bear a coupling group (e.g., a group that reacts with a sulfhydryl group) can be engineered to bear a linker for covalent attachment to a sulfhydryl group. Thus, in the present application, a hapten derivative refers to a hapten which has been engineered to carry a thiol-reactive group.
The hapten is selected from: small molecule drugs (e.g. antibiotics, psychotropic drugs), hormones, metabolites, sugars, lipids, amino acids.
Haptens are exemplified by, but not limited to: vancomycin, theophylline, phenytoin, vitamin D, 25 hydroxyvitamin D, 1, 25 dihydroxyvitamin D, folic acid, cardiac glycosides (including digoxin, digoxigenin), mycophenolic acid, rapamycin, cyclosporine A, amiodarone, methotrexate, tacrolimus, serum amino acids, bile acids, glycocholic acid, phenylalanine, ethanol, the metabolites cotinine of uretonidine, morphine, derivatives of uromonohydric phenol, neuropeptide tyrosine, plasma galanin, polyamines, histamine, thyroid stimulating hormone, prolactin, placental prolactin, growth hormone, follicle stimulating hormone, luteinizing hormone, adrenocorticotropic hormone, antidiuretic hormone, calcitonin, procalcitonin, parathyroid hormone, thyroxine, triiodothyronine, free thyroxine, free triiodothyronine, cortisol, Urinary 17-hydroxycorticosteroids, urinary 17-ketosteroids, dehydroepiandrosterone and sulfates, aldosterone, urinary vanillylmandelic acid, plasma renin, angiotensin, erythropoietin, testosterone, dihydrotestosterone, androstenedione, 17 α hydroxyprogesterone, estrone, estriol, estradiol, progesterone, human chorionic gonadotropin, insulin, proinsulin, C-peptide, gastrin, plasma prostaglandins, plasma 6-keto prostaglandin F1 α, prostacyclin, epinephrine, catecholamine, norepinephrine, cholecystokinin, nalin, cyclic adenosine monophosphate, cyclic guanosine monophosphate, vasoactive peptides, somatostatin, secretin, substance P, neurotensin, thromboxane a2, thromboxane B2, 5 hydroxytryptamine, neuropeptide Y, osteocalcin.
In a particular embodiment, the hapten is cyclosporine a or a derivative thereof.
In particular embodiments, the hapten is a cyclosporin a derivative bearing a thiol-reactive group, such as a maleimide, bromoacetyl, vinyl sulfone, or aziridine.
In a particular embodiment, the hapten is a cyclosporin a derivative, as shown in formula I:
In some embodiments, m is an integer from 1 to 10, preferably from 1 to 3, e.g., 1, 2, 3.
In a specific embodiment, the cyclosporin a derivative is represented by formula III:
According to some embodiments, there is provided a reagent comprising a conjugate of the present application.
According to some embodiments, there is provided the use of a glucose-6-phosphate dehydrogenase mutant of the present application in the preparation of a cyclosporine a detection reagent.
According to some embodiments, there is provided the use of a conjugate of the present application in the preparation of a cyclosporine a detection reagent.
In specific embodiments, the detection reagent is selected from the group consisting of: enzyme-linked immunosorbent assay reagent, chemiluminescence immunoassay reagent, homogeneous enzyme immunoassay reagent and latex enhanced immunoturbidimetry reagent.
In a specific embodiment, the detection reagent is preferably a reagent for detection based on a competition method.
According to some embodiments, there is provided the use of a conjugate of the present application in the preparation of a cyclosporine a detection device.
In particular embodiments, the detection device may be prepared in the form of a well plate (e.g., a 96-well plate), such as a plate coated with a reagent according to the present application.
In particular embodiments, the detection device may be prepared in the form of particles (e.g., latex, magnetic beads), such as particles coated with a reagent according to the present application.
According to some embodiments, there is provided a cyclosporine a detection kit comprising:
-a first reagent comprising a substrate, a buffer and a cyclosporine a antibody; the substrate is a substrate for glucose-6-phosphate dehydrogenase;
-a second agent comprising a conjugate of the present application and a buffer;
-optionally, a calibrator comprising 10mM to 500mM buffer, 0ng/ml to 1500ng/ml cyclosporin a; and
-optionally, a quality control comprising 10mM to 500mM buffer, 20ng/ml to 1400ng/ml cyclosporin a.
According to one embodiment, there is provided a cyclosporine a detection kit comprising:
a first reagent comprising:
10mM to 500mM buffer solution,
5mM to 50mM substrate,
0.1 to 10 mug/ml cyclosporin A antibody,
0.05% to 0.5% w/v stabilizer,
0.05% to 0.5% w/v of a surfactant,
0.05% to 0.5% w/v preservative;
a second reagent comprising:
10mM to 500mM buffer solution,
0.01. mu.g/ml to 1. mu.g/ml of a conjugate according to the present application,
0.05% to 0.5% w/v stabilizer,
0.05% to 0.5% w/v of a surfactant,
0.05% to 0.5% w/v preservative;
in some embodiments, the buffer is selected from one or a combination of: TAPS, tromethamine buffer solution, phosphate buffer solution, Tris-HCl buffer solution, citric acid-sodium citrate buffer solution, barbital buffer solution, glycine buffer solution, borate buffer solution and trimethylolmethane buffer solution; preferably, a phosphate buffer; the concentration of the buffer is 10mmol/L to 500mmol/L, preferably 50 to 100 mM; the pH of the buffer is 7 to 8.4.
In some embodiments, the stabilizing agent is selected from one or a combination of: bovine serum albumin, trehalose, glycerol, sucrose, mannitol, glycine, arginine, polyethylene glycol 6000, polyethylene glycol 8000; bovine serum albumin is preferred.
In some embodiments, the surfactant is selected from one or a combination of: brij23, Brij35, Triton X-100, Triton X-405, Tween20, Tween30, Tween80, coconut oil fatty acid diethanolamide, AEO7, preferably Tween 80.
In some embodiments, the preservative is selected from one or a combination of: azide, MIT, biological preservative PC (e.g. PC300), thimerosal; the azide is selected from: sodium azide and lithium azide.
In some embodiments, the substrate comprises: 6-phosphoglucose, beta-nicotinamide adenine dinucleotide.
In some specific embodiments, the cyclosporine a antibody is derived from: mouse, rat, cat, dog, primate, cow, horse, sheep, camelid, avian, human.
In some specific embodiments, the cyclosporin a antibody is selected from: monoclonal antibodies, polyclonal antibodies, recombinant antibodies, chimeric antibodies, antigen-binding fragments.
According to some embodiments, there is provided a method of preparing a conjugate comprising the steps of:
1) providing a cyclosporine a derivative according to the present application, in particular in an aprotic solvent (such as but not limited to acetonitrile, dimethylformamide, dimethylsulfoxide);
2) providing a glucose-6-phosphate dehydrogenase mutant, preferably in a buffer (which provides a reaction environment, such as, but not limited to, PBS, Tris, TAPS, TAPSO, buffer pH between 6.0 and 8.0);
3) contacting the cyclosporine A derivative and the glucose-6-phosphate dehydrogenase mutant at a molar ratio n:1 for 1 hour to 4 hours (preferably 2 hours to 3 hours) at 18 ℃ to 28 ℃ to couple the cyclosporine A derivative and the glucose-6-phosphate dehydrogenase mutant to obtain the seed conjugate;
4) the conjugate is optionally subjected to purification, such as desalting treatment or the like, as required.
In some embodiments, the contacting molar ratio of the enzyme to the hapten in the reaction system is 1: n, wherein n is 1 to 500, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 200, 300, 400, 500, and ranges between any of the foregoing values; preferably n is 20 to 60.
In some specific embodiments, steps 1) and 2) are interchangeable or concurrent.
In some specific embodiments, the glucose-6-phosphate dehydrogenase, prior to conjugation, comprises one or more free sulfhydryl groups, thereby allowing a targeted reaction with cyclosporine a.
Wild-type glucose-6-phosphate dehydrogenase does not contain a free sulfhydryl group, and thus in some embodiments, glucose-6-phosphate dehydrogenase is genetically engineered to have a free sulfhydryl group by mutating an amino acid at a specific site (306, 375, or 426) to cysteine.
Drawings
FIG. 1.G6PDH (wild type) amino acid sequence (SEQ ID No. 1); derived from Leuconostoc pseudomesenteroides.
FIG. 2.G6PDH (D306C) amino acid sequence (SEQ ID No. 2).
FIG. 3.G6PDH (D375C) amino acid sequence (SEQ ID No. 3).
FIG. 4.G6PDH (G426C) amino acid sequence (SEQ ID No. 4).
Detailed Description
Examples
Example 1 Synthesis of Cyclosporin A derivatives
1. Synthesis of Compound 2
Cyclosporin A (100mg,0.08mmol) was added to a round-bottomed flask, dissolved in dry dichloromethane (5mL), and triethylamine (25mg, 0.25mmol) was added to the reaction system, and stirred until all was dissolved.
Oxalyl chloride (52.8mg, 0.42mmol) was added to the reaction system, stirred at room temperature, checked by TLC, reacted at room temperature (18-28 ℃, preferably 20 to 25 ℃) for about 1 hour, the starting material substantially disappeared, the solvent was removed under reduced pressure, and excess oxalyl chloride was taken up repeatedly (2-3 times) using DCM and used in the next step without purification.
2. Synthesis of cyclosporin A derivatives
Compound 2 and compound 3(10mg, 0.05mmol) were dissolved in dry dichloromethane (5mL), to which triethylamine (12.4mg, 0.12mmol) was added dropwise, stirred at room temperature (18-28 ℃, preferably 20 to 25 ℃) and checked by TLC. After completion of the reaction, the reaction was directly purified using preparative plates (MeOH/DCM ═ 1:20) to give a cyclosporin a derivative of formula III (45mg, 38% yield).
3. The structure of the product was confirmed by a conventional method. This example allows cyclosporin A to carry a group that can bind to an enzyme.
Example 2 coupling of Cyclosporin A derivatives to G6PDH molecules
First, the coupling method of the present application
The coupling was carried out according to the G6 PDH-cyclosporine a conjugate of the present application in the following manner: a thiol-reactive group (such as, but not limited to, a maleimide group) on a cyclosporine a derivative molecule is covalently bound to a thiol on a G6PDH molecule.
1. The cyclosporine A derivative prepared in example 1 was dissolved in N, N-dimethylformamide (10 mg/ml);
g6PDH solution: g6PDH (mutant of the present application or of the prior art) was dissolved in 0.2M phosphate buffer, pH 8.0(2.5mg/ml enzyme);
3. adding 300 ul glucose 6 phosphate dehydrogenase mutant solution into 50 ul cyclosporine A derivative solution;
4. the mixed solution is shaken well for 2 to 3 hours at room temperature (18 to 28 ℃, preferably 20 to 25 ℃) and treated by molecular sieve chromatography, and the product, namely the G6 PDH-cyclosporine A conjugate (with the concentration of 0.1mg/mL to 2.5mg/mL) is obtained.
Two, control coupling method
The G6 PDH-cyclosporine a conjugate was prepared as disclosed in the example with reference to CN 107782889A.
Example 3 preparation of the kit
A kit for detecting cyclosporine a is prepared comprising:
reagent R1, comprising:
tris buffer 100mM, pH7.4
20mM glucose-6-phosphate
20mM beta-nicotinamide adenine dinucleotide
Cyclosporin A antibody 1. mu.g/ml (commercially available antibody)
0.5% w/v bovine serum albumin
0.1%w/v Tween80
0.1%w/v PC300;
Reagent R2, comprising:
tris buffer 100mM, pH8.2
0.05. mu.g/ml G6 PDH-Cyclosporin A conjugate
0.5% w/v bovine serum albumin
0.1%w/v Tween 80
0.1%w/v PC300;
Sample extraction liquid: 50mM of zinc sulfate, 50mM of Tris buffer solution, 3000.1% w/v of PC and 50% w/v of methanol;
calibration products: whole blood matrix, and 0ng/ml, 50ng/ml, 300ng/ml, 600ng/ml, 900ng/ml, 1500ng/ml cyclosporin A (or added as needed);
quality control product: whole blood matrix, and 100ng/ml, 750ng/ml, 1300ng/ml cyclosporin A (or added as needed).
And assembling the reagents (optionally containing quality control products and calibration products) into a detection kit.
The calibrator, the quality control product and the sample to be tested are physiological samples, such as serum, plasma, whole blood and the like. Preferably, the calibrator, the quality control material and the sample to be tested are all whole blood matrixes, and a sample extraction liquid is required to be pretreated before the test.
Example of detection
The kit adopts the enzyme amplification immunoassay EMIT principle, namely that the free CsA in the sample and the enzyme-CsA conjugate competitively bind to the CsA antibody, the more the free CsA in the sample is, the more the bound antibody is, the more the free conjugate is, the free conjugate catalyzes β -nicotinamide adenine dinucleotide oxidized form (NAD)+) Converting into β -nicotinamide adenine dinucleotide reduced form (NADH), wherein the CsA concentration in the sample is in direct proportion to the generation amount of NADH, and calculating the CsA content through the change of 340nm absorbance value.
TABLE 1 parameters of fully automatic biochemical analyzer
Model type | Hitachi 7180 parameter |
Sample size | 2.0μl |
Reagent R1 | 150μl |
Reagent R2 | 50μl |
Read point | 27-34 points |
Detecting wavelength (main) | 340nm |
Detecting wavelength (vice) | 410nm |
Curve fitting method | Spline |
Calibration article | 0.0、50.0、300.0、600.0、900.0、1500.0ng/ml |
Sample(s) | Samples to be tested, e.g. plasma, serum, whole blood, urine, etc |
Test example 1 Performance of the kit of the present application
1. Calibration of absorbance
TABLE 2 calibrated absorbances
2. Precision experiment
And measuring high, medium and low quality control products and clinical samples by using the calibration curve established above.
TABLE 3 Total inaccuracy
3. Repeatability of
And (4) measuring the low, medium and high-value quality control products for 20 times respectively to perform a repeatability experiment. As shown in the table below, the sample tests were repeated 20 times with CV within 2.35%.
TABLE 4 repeatability of the kit
4. Recovering
TABLE 5 recovery
5. Linearity of the detection kit
TABLE 6 linearity
Accelerated stability of reagent at 6.37 deg.C
TABLE 7.37 ℃ accelerated stability of reagents
7. Drug interference experiments
The following interferents were selected to produce a systematic bias of less than 10% at a cyclosporin A concentration of 200-1000 ng/ml.
TABLE 8 drug interference test
Medicine | Test concentration (μ g/mL) |
Aprazol cabin | 0.57 |
Digoxin | 0.015 |
Carbamazepine | 100 |
Gentamicin | 150 |
Rapamycin | 0.25 |
Tacrolimus | 0.25 |
Salicylic acid | 400 |
Theophylline | 200 |
Valproic acid | 600 |
Vancomycin | 500 |
Immunoglobulins | 8500 |
Isoproterenol hydrochloride | 0.4 |
Phenobarbital | 200 |
Aminopyralid | 5.0 |
Salbutamol | 0.15 |
Medicine for treating stomach disease | 4 |
Nitroglycerin | 3.5 |
Test example 2 antibody inhibition Rate
1. Detection principle of antibody inhibition rate
When the antibody is combined with the G6 PDH-cyclosporine A conjugate, the activity of G6PDH enzyme is influenced due to steric hindrance, so that the efficiency of catalyzing the conversion of NAD into NADH is reduced, and the difference between an experimental group with the antibody added and an experimental group without the antibody added is compared by detecting the change of NADH amount, wherein the difference is reflected in the inhibition capacity of the antibody on G6 PDH.
2. Reaction system
TABLE 9 preparation of reagents for detection of antibody inhibition
3. Results
And (3) comparing the added antibody with the unadditized antibody, and respectively detecting the absorbance value of the G6 PDH-cyclosporine A conjugate to obtain the inhibition condition of the antibody on G6 PDH.
Compared with the conjugate prepared from the published mutation sites (A45C and K55C), the mutant of the application has obviously improved antibody inhibition rate which can reach more than 44% (G426C: 44%; D375C: 50%) and reach 63% (D306C). Whereas the inhibition of previously published mutation sites (e.g. a45C, K55C) is 40% to 43%.
While not being bound to a particular theory, it may be partially explained as: compared with the G6PDH mutant (A45C, K55C) in the prior art, the mutation site (i.e. the site for introducing free sulfydryl) in the enzyme mutant of the application is the site for coupling with hapten (such as hormone, small molecule drug and the like). When the hapten binds to a hapten-specific antibody at this position, the steric hindrance formed has the greatest effect on the activity of the G6PDH enzyme, and after the introduction of the mutation, it cannot substantially affect the steric folding of the molecule. Therefore, the position of this mutation site is very important, and needs to be compatible with the activity of G6PDH enzyme, the spatial folding of the coupling molecule, and the sufficient exposure of the hapten epitope.
The enzyme mutant has obviously improved antibody inhibition rate. After the conjugate obtained by coupling the enzyme mutant and the cyclosporine A is prepared into the kit, the reagent has obvious performance improvement in the aspects of inter-batch variation coefficient, linearity, specificity and the like.
Sequence listing
<110> Beijing Jiuqiang Biotechnology Ltd
<120> 6-phosphoglucose dehydrogenase mutant and application thereof in preparation of cyclosporine A detection reagent
<130>300001CG
<150>201910017764.4
<151>2019-01-09
<150>201910423122.4
<151>2019-05-21
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Asp Leu Ala Lys Arg Lys Leu Tyr Pro Ser Val Phe Asn Leu Tyr Lys
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145 150 155 160
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165 170 175
Ile Asp His Tyr Leu Gly Lys Glu Met Val Gln Asn Ile Ala Ala Leu
180 185 190
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195 200 205
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225 230 235 240
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245 250 255
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260 265 270
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275 280 285
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290 295 300
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305 310 315 320
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325 330 335
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340 345 350
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355 360 365
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370 375 380
Asn Ala Lys Ser Val Glu Asp Ala Phe Asn Thr Arg Thr Ile Asp Leu
385 390 395 400
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405 410 415
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Asp Leu Ala Lys Arg Lys Leu Tyr Pro Ser Val Phe Asn Leu Tyr Lys
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145 150 155 160
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165 170 175
Ile Asp His Tyr Leu Gly Lys Glu Met Val Gln Asn Ile Ala Ala Leu
180 185 190
Arg Phe Gly Asn Pro Ile Phe Asp Ala Ala Trp Asn Lys Asp Tyr Ile
195 200 205
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225 230 235 240
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245 250 255
Phe Thr Asp Lys Asp Ile Arg Ala Ala Lys Asn Ala Ala Phe Asn Ala
260 265 270
Leu Lys Ile Tyr Asp Glu Ala Glu Val Asn Lys Tyr Phe Gly Arg Ala
275 280 285
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290 295 300
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305 310 315 320
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325 330 335
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340 345 350
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355 360 365
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370 375 380
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385 390 395 400
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405 410 415
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420 425 430
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435 440 445
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Ala Trp Val Phe Lys Gly
485
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485
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485
Claims (10)
1. A conjugate of a glucose-6-phosphate dehydrogenase mutant and a hapten in a molar ratio of 1: 1 is formed by covalent coupling;
the hapten is cyclosporine A or a derivative thereof;
preferably, the cyclosporin a derivative is represented by formula I:
wherein the content of the first and second substances,
m is an integer of 1 to 10, preferably 1 to 3;
preferably, the cyclosporin a derivative is represented by formula III:
2. the conjugate of claim 1, wherein:
the glucose-6-phosphate dehydrogenase mutant comprises a mutation selected from the group consisting of: D306C, D375C, G426C;
preferably, the glucose-6-phosphate dehydrogenase mutant is represented by a sequence selected from the group consisting of: SEQ ID No.2, SEQ ID No.3 and SEQ ID No. 4.
3. A reagent comprising the conjugate of claim 1 or 2.
4. Use of a conjugate according to claim 1 or 2 in the preparation of a detection reagent, wherein:
the detection reagent is a detection reagent of cyclosporine A;
preferably, the detection reagent is selected from: enzyme-linked immunosorbent assay reagent, chemiluminescence immunoassay reagent, homogeneous enzyme immunoassay reagent and latex enhanced immunoturbidimetry reagent.
5. Use of a conjugate according to claim 1 or 2 for the preparation of a detection device:
the detection device is a detection device for cyclosporine A;
the detection device is selected from any one of the following forms: orifice plate, particle, chip and test paper.
6. A cyclosporine a detection kit comprising:
a first reagent comprising a substrate, an anti-cyclosporin A antibody, a buffer;
a second reagent comprising the conjugate of claim 1 or 2, a buffer;
optionally, a calibrator comprising 0ng/ml to 1500ng/ml cyclosporin a; and
optionally, a quality control product comprising 20ng/ml to 1400ng/ml cyclosporin A.
7. The cyclosporine a detection kit of claim 6, comprising:
a first reagent comprising:
10mM to 500mM, preferably 50mM to 100mM, buffer,
5mM to 50mM, preferably 10mM to 20mM, glucose-6-phosphate,
5mM to 50mM, preferably 10mM to 20mM, oxidized form beta-nicotinamide adenine dinucleotide,
0.1 to 10. mu.g/ml, preferably 1 to 5. mu.g/ml, of an anti-cyclosporin A antibody,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v, of a stabilizer,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v, of a surfactant,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v preservative;
a second reagent comprising:
10mM to 500mM, preferably 50mM to 100mM, buffer,
The conjugate of claim 1 or 2, in an amount of 0.01 to 10. mu.g/ml, preferably 0.05 to 1. mu.g/ml,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v, of a stabilizer,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v, of a surfactant,
0.05% to 0.5% w/v, preferably 0.1% to 0.5% w/v preservative;
the buffer is selected from one or a combination of the following: TAPS buffer solution, phosphate buffer solution, glycine buffer solution, Tris buffer solution, boric acid buffer solution, MOPS buffer solution and HEPES buffer solution;
the pH of the buffer is 7 to 8.4;
the stabilizer is selected from one or a combination of the following: bovine serum albumin, trehalose, glycerol, sucrose, mannitol, glycine, arginine, polyethylene glycol 6000, polyethylene glycol 8000; preferably bovine serum albumin;
the surfactant is selected from one or a combination of the following: brij23, Brij35, Triton X-100, Triton X-405, Tween20, Tween30, Tween80, coconut oil fatty acid diethanolamide, AEO7, preferably Tween 80;
the preservative is selected from one or a combination of the following: azide, MIT, biological preservative PC, thimerosal;
preferably, the preservative is selected from: sodium azide, lithium azide and PC-300.
8. The cyclosporine a detection kit of claim 6, comprising:
a first reagent comprising:
tris buffer 100mM, pH7.4,
20mM glucose-6-phosphate,
20mM oxidized beta-nicotinamide adenine dinucleotide,
1 mu g/ml anti-cyclosporin A antibody,
0.5% w/v bovine serum albumin,
0.1%w/v Tween80、
0.1%w/v PC300;
A second reagent comprising:
100mM Tris buffer, pH8.2,
0.05 μ g/ml of the conjugate according to claim 1 or 2,
0.5% w/v bovine serum albumin,
0.1%w/v Tween80、
0.1%w/v PC300。
9. A method of preparing a conjugate comprising the steps of:
1) providing cyclosporine A or a derivative thereof;
2) providing a glucose-6-phosphate dehydrogenase mutant as defined in claim 2;
3) the glucose-6-phosphate dehydrogenase mutant is coupled with the cyclosporine A or the derivative thereof;
the cyclosporine A derivative is represented by formula I:
wherein the content of the first and second substances,
m is an integer of 1 to 10, preferably 1 to 3.
10. A method of preparing a conjugate according to claim 9, comprising the steps of:
1) providing a cyclosporin a derivative, preferably in an aprotic solvent;
2) providing a glucose-6-phosphate dehydrogenase mutant as defined in claim 2, preferably in a buffer;
3) contacting the glucose-6-phosphate dehydrogenase mutant and the cyclosporin A derivative at 18 ℃ to 28 ℃, preferably 20 ℃ to 25 ℃, for 1 hour to 4 hours, preferably 2 hours to 3 hours, such that the cyclosporin A derivative and the glucose-6-phosphate dehydrogenase mutant are coupled to obtain the conjugate;
4) optionally, purifying the conjugate, preferably desalting the conjugate;
step 1) and step 2) can be interchanged or in parallel;
the buffer is selected from: PBS, Tris, TAPS, TAPSO,
the pH of the buffer is 6.0 to 8.0;
the aprotic solvent is selected from one or a combination of the following: acetonitrile, dimethylformamide, dimethyl sulfoxide;
preferably, prior to step 3), said glucose-6-phosphate dehydrogenase mutant comprises a free thiol group; more preferably, the glucose-6-phosphate dehydrogenase mutant has a free thiol group at position 306, 375, or 426;
preferably, the cyclosporine A derivative and the glucose-6-phosphate dehydrogenase mutant are contacted at a molar ratio of n:1, n is 1 to 500, preferably 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500;
more preferably, n is 30 to 60.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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CN202310555230.3A CN116718761A (en) | 2019-01-09 | 2020-01-07 | Cyclosporine A detection kit |
CN202310554774.8A CN116679047A (en) | 2019-01-09 | 2020-01-07 | Method for preparing conjugate |
CN202310553479.0A CN116699125A (en) | 2019-01-09 | 2020-01-07 | Use of conjugates in the preparation of detection reagents |
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CN201910423122.4A CN110174363A (en) | 2019-01-09 | 2019-05-21 | Glucose-6-phosphate dehydrogenase mutant and its purposes in preparation detection reagent |
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CN202310555230.3A Division CN116718761A (en) | 2019-01-09 | 2020-01-07 | Cyclosporine A detection kit |
CN202310553479.0A Division CN116699125A (en) | 2019-01-09 | 2020-01-07 | Use of conjugates in the preparation of detection reagents |
CN202310554774.8A Division CN116679047A (en) | 2019-01-09 | 2020-01-07 | Method for preparing conjugate |
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CN201911365439.3A Active CN111239060B (en) | 2019-01-09 | 2019-12-26 | 6-phosphoglucose dehydrogenase mutant and application thereof in preparing theophylline detection reagent |
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CN201911372535.0A Active CN112285038B (en) | 2019-01-09 | 2019-12-27 | Glucose 6-phosphate dehydrogenase mutant and application thereof in preparation of digitoxin detection reagent |
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