WO2011054290A1 - Procedes et kits de reactifs pour determiner l'activite de la thioredoxine reductase et leurs utilisations - Google Patents

Procedes et kits de reactifs pour determiner l'activite de la thioredoxine reductase et leurs utilisations Download PDF

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Publication number
WO2011054290A1
WO2011054290A1 PCT/CN2010/078369 CN2010078369W WO2011054290A1 WO 2011054290 A1 WO2011054290 A1 WO 2011054290A1 CN 2010078369 W CN2010078369 W CN 2010078369W WO 2011054290 A1 WO2011054290 A1 WO 2011054290A1
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Prior art keywords
sample
activity
thioredoxin reductase
reductase
determining
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PCT/CN2010/078369
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English (en)
Chinese (zh)
Inventor
曾慧慧
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凯熙医药(武汉)有限公司
武汉尚宜康健科技有限公司
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Priority to CN201080049877.XA priority Critical patent/CN102695805B/zh
Publication of WO2011054290A1 publication Critical patent/WO2011054290A1/fr
Priority to HK13103743.9A priority patent/HK1176097A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/90212—Oxidoreductases (1.) acting on a sulfur group of donors (1.8)

Definitions

  • the invention belongs to the field of enzyme activity detection, and particularly relates to a method, reagent and application for measuring thioredoxin reductase activity in a sample. Background technique:
  • TM Tumor marker
  • TM is a type of substance produced by tumor tissue, present in the tumor tissue itself, or secreted into blood or other body fluids, or produced by host cells by tumor tissue stimulation, which is significantly higher than the normal reference value.
  • TM has certain application value in the treatment monitoring and prognosis of tumors.
  • tumor markers are mainly antibodies or proteins formed after tumor formation.
  • the spirulina reductase system includes Thioredoxin reductase (TrxR), thioredoxin (Trx) and nicotinamide adenine dinucleotide phosphate (NADPH), which is a wide range.
  • TrxR Thioredoxin reductase
  • Trx thioredoxin
  • NADPH nicotinamide adenine dinucleotide phosphate
  • Trx is a growth factor that can be produced by many cells and secreted by lymphocytes, hepatocytes and fibroblasts, as well as many cancer cells.
  • the thiol redox activity of Trx has a general and important role in the maintenance of cellular physiological activity.
  • TrxR under oxygen stress, Trx and TrxR in lymphocytes and tumor cells, as well as some normal cells, can rapidly regulate and slow down the stress of oxygen stress.
  • TrxR reduces the oxidation state of Trx.
  • the reduced form of Trx acts as an electron donor for PRDX to reduce hydrogen peroxide to water.
  • Hydrogen peroxide generated by ultraviolet light or the like induces the production of TrxR.
  • persistent hydrogen peroxide induces a high level of tumor suppressor p53, which in turn negatively regulates TrxR, so that TrxR activity is better under the control of hydrogen peroxide.
  • TrxR the level of tumor suppressor p53 in the body
  • the higher the level of p53 the easier the body can make tumor cells tend to apoptosis, so the ability to fight tumors is stronger. Therefore, the level of TrxR activity reflects the anti-tumor level in vivo to some extent.
  • TrxR activity is determined by the inhibition method of Aurothioglucose (see formula a).
  • the working principle is: using 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) Total reduction ability in the sample; After inhibiting the activity of TrxR in the sample with thioglucose gold, the reducing ability was measured by DTNB; the difference between the two reducing powers before and after the sample was calculated to determine the activity of TrxR in the sample.
  • glucosinolate gold lacks specificity and can also block other sulfhydryl substances in the sample, and is not suitable for direct determination of TrxR activity in blood or tissue samples. 1" Column, KE, etc.
  • TrxR activity was determined by adding thioglucose gold. It can be seen that other small molecule sulfhydryl substances (such as glutathione) can interfere with the thioglucose gold pair.
  • TrxR Activity assay of TrxR. Another study showed that glucosinolate gold increased the rate of reaction of thiol-based substances with DTNB in blood (Hu ML, Dillard CJ, Tappel AL In vivo effects of aurothioglucose and sodium thioglucose on rat tissue sulfhydryl levels and plasma sulfhydryl reactivity. Agents Actions 1988, Aug; 25(l-2): 132-8).
  • TrxR TrxR
  • a reagent for determining thioredoxin reductase activity in a sample comprising separately present separately:
  • Thioredoxin reductase specifically inhibits compounds.
  • Another object of the present invention is to provide a kit for determining thioredoxin reductase activity in a sample, the kit comprising the above reagent for determining thioredoxin reductase activity in a sample.
  • Another object of the present invention is to provide a method for determining thioredoxin reductase activity in a sample, the method comprising:
  • Another object of the invention is a method for determining thioredoxin reductase activity in a sample, the method comprising:
  • Another object of the present invention is to provide a method for assessing the level of disease resistance in vivo, the method comprising:
  • the anti-disease level is high in the body; when the activity of the spirulina reductase is from about 1 or more to about 10 or less, and The ratio of the oxidative stress level to the oxidoreductin reductase activity is 5 to 10 or more, such as 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more, and preferably 5 or more, the in vivo anti-disease level is high; When the activity of the thioredoxin reductase is from about 1 or more to about 10 or less, and the ratio of the oxidative stress level to the thioredoxin reductase activity is 5 or less, the in vivo anti-disease level is low; The activity of the reoxygenase reductase is 10-20 or more, such as 9 or more, 10 or more, 11 or more, 12 or more, or 15 or more
  • the present invention provides the use of the above agent for the preparation of a medicament for evaluating an anti-disease level in vivo.
  • the TrxR activity in the sample can be effectively determined without any pretreatment of the sample, and the measurement result is more accurate and reliable than the measurement using thioglucose gold.
  • Figure 2 is the effect of glutathione on the inhibition of ethaneselenase. Detailed ways:
  • TrxR activity is inhibited by a specific inhibitor of TrxR, and the activity or content of TrxR in the sample is determined by measuring the TrxR activity in the biological sample by background subtraction.
  • the inventors have further found that by measuring the TrxR activity or content in a sample, and combining the ratio of oxidative stress (OS) level in the sample to the measured activity (TR) of TrxR, ie, OS/TR can be evaluated in vivo.
  • the specific measurement principle is: 5,5-Dithiobis(2-nitrobenzoic acid) (DTNB) can be reduced by the -SH group to produce 2-nitro-5-mercaptobenzoic acid (TNB), while TNB is at 405-412 nm.
  • DTNB 5,5-Dithiobis(2-nitrobenzoic acid)
  • TNB 2-nitro-5-mercaptobenzoic acid
  • TNB 2-nitro-5-mercaptobenzoic acid
  • the compound of Formula 1 or Formula 2 especially the organic selenium compound I-XI in Table 1, can specifically react with the sulfhydryl group in TrxR as a specific inhibitor of TrxR, and it is difficult Reacts with sulfhydryl groups other than TrxR.
  • the use of the compounds of the invention enables the determination of TrxR activity in complex systems, including blood and tissue extract samples.
  • the accuracy of evaluating the level of disease resistance by measuring a single test index is very limited, in order to further improve the prediction of anti-disease, such as anti-tumor levels.
  • the reliability of the present invention was first proposed by calculating the ratio of oxidative stress level to thioredoxin reductase activity in the sample, that is, OS/TR to the disease resistance in the body.
  • the reagent for determining the activity of streptohol reductase in the sample of the present invention contains at least an agent for determining the total thiol content in the sample and the above-mentioned thioredoxin reductase specific inhibitory compound, wherein the 'oxygen reductase specific enzyme "Suppressor compound” (hereinafter sometimes referred to as “inhibitor”) refers to a compound highly selective for thioredoxin reductase, which is capable of specifically binding to thioredoxin reductase and inhibiting sulfhydryl groups therein.
  • the preferred thioredoxin reductase specific inhibitory compound is a compound having the structure represented by the following Formula 1 or Formula 2, and it has been found that the compound of Formula 1 or Formula 2 used in the present invention is particularly It is a strong inhibitory effect of selenoline compound I-XI on TrxR.
  • this kind of compound is the only inhibitor with specific targeting of TrxR, which can effectively bind to SeCys/Cys activity in TrxR.
  • the site acts as a suppressor to suppress TrxR with a high degree of selectivity, see Figure 1.
  • Formula 1 where:
  • Xo is C or N
  • X ⁇ Se is hydrogen, dC 6 alkyl, C 3 -C 7 cycloalkyl, R ; 1 -
  • R a , R b , R e , R f , R g are each independently: dC 6 alkyl;
  • R c , R d are each independently: Hydrogen, halogen, nitrile group, C Ce alkyl group, dC 6 alkoxy group, hydroxyl group, S0 3 R, COOR, polyethylene glycol, 0-S0 3 R or 0-P0 3 RR, wherein R can be hydrogen, dC 6 alkyl or aryl;
  • R 2 and R 3 are each independently selected from the group consisting of: hydrogen, halogen, nitrile group, dC 6 alkyl group, dC 6 alkoxy group, hydroxyl group, S0 3 R, COOR, polyethylene glycol, 0 -S0 3 R or 0-P0 3 RR, wherein R may be hydrogen, dC 6 alkyl or aryl,
  • Xo is C or N; X ⁇ Se;
  • ⁇ is alkylene, phenylene, biphenylene, cyclohexane, cyclopentane, -(CH 2 ) m SS(CH 2 ) m - , -((CH 2 ) m O) n (CH 2 ) m - ,
  • R' 2 , R' 3 , R'4 and R' 5 are each independently: hydrogen, [3 ⁇ 4], nitrile group, dC 6 alkyl group, dC 6 alkoxy group, hydroxyl group, S0 3 R, COOR, polyethyl b A diol, 0-S0 3 R or 0-P0 3 RR, wherein R can be hydrogen, dC 6 alkyl or aryl, wherein the aryl group can be phenyl or benzo.
  • the selenium-based compound used in the present invention in particular, the inhibitory effect of the organic selenium compound I-XI on TrxR is not interfered by other sulfhydryl substances in the system, and has high selectivity. Studies have shown that even in the presence of high concentrations of other sulfhydryl species in the sample system, such as 0.5 mM reduced glutathione, the selenium compounds used in the present invention, especially the organic selenium compound I-XI, still exhibit high selectivity for TrxR. For strong inhibition, see Figure 2.
  • the most preferred thioredoxin reductase specific inhibitory compound in the present invention is the following compound I-XI.
  • the "reagent for determining the total thiol content in the sample” in the present invention is not particularly limited as long as it can react with the thiol group and indicates the content in the sample. Preferred
  • the "reagent for determining the total thiol content in the sample” is 5,5-dithiobis(2-nitrobenzoic acid) (DTNB).
  • the reagent for determining the total thiol content in the sample and the thioredoxin reductase specific inhibitory compound may be provided in any form such as a solid, a powder, a solution or the like. These two components may be provided in the form of a composition, but are preferably provided in a form which is independently present.
  • the reagent for thioredoxin reductase activity or the thioredoxin reductase specific inhibitory compound in solution form is not particularly limited in concentration, and is preferably formulated into a concentration of 1 X working solution, more preferably formulated.
  • the concentration of the 5 X working solution is most preferably formulated to a concentration of 10 Torr of working fluid.
  • the reagent for determining the activity of thioredoxin reductase in the sample may further contain other components, for example, may contain NADPH, and may also contain other components required for measuring thioredoxin reductase activity, such as maintenance.
  • activity stabilizing buffer components including K 2 HP0 4 and the like KH 2 P0 4, EDTA and / or the like BSA.
  • sample in the present invention means any tissue derived from a living organism or a portion separated therefrom, and the “sample” is preferably blood, body fluid, tissue tumbling liquid, and most preferably blood, wherein the blood may be serum, plasma, or the like. Component.
  • the thioredoxin reductase activity (TR) described in the present invention refers to an activity expressed by a thiol content in a thioredoxin reductase, wherein a thiol content in a sample is obtained by reacting a thiol group with a D TNB to produce a TNB at 405 nm.
  • the absorbance at the place The calculation method of thioredoxin reductase activity (TR) is as follows:
  • the kit for measuring thioredoxin reductase activity in a sample of the present invention contains at least the reagent for determining the total thiol content in the sample and the thioredoxin reductase inhibiting compound, and may further contain other reagents.
  • a component necessary for measuring the activity of the enzyme such as a buffer or the like.
  • the above various components may be packaged in a kit in any form, such as a bottle-shaped container or the like each containing the above-described different reagents or compounds.
  • the kit may be provided in any form including, but not limited to, in the form of a square package.
  • the total thiol content in the sample can be determined by any known method capable of indicating the total thiol content, including direct measurement of the thiol content.
  • the method, or an indirect method capable of indicating an index of thiol content, the indicator includes an absorbance value or the like.
  • the oxidative stress level can be determined by any known measurement method, such as the barbituric acid method, and the measurement TrxR of the present invention can also be utilized.
  • the total ⁇ A in the sample measured in the method without the addition of the gram-reducing enzyme-specific inhibitor was calculated by ⁇ A sample X 224 .
  • the OS/TR described in the present invention can be calculated by ( ⁇ sample x224)/TR.
  • the level of anti-disease in vivo is high; when the activity of the thioredoxin reductase is near 1 or above 1 to 10 or below 10, and the ratio of the oxidative stress level to the oxydoxin reductase activity is around 5 Or 5 or more, the anti-disease level in the body is high; when the activity of the strepto-reoxygenase reductase is 10 or more, the anti-disease level in the body is low.
  • the "disease” as used in the present invention includes, but is not limited to, diseases such as abnormal hyperplasia, wherein the abnormal proliferation described herein includes a tumor, and includes diseases associated with abnormal hyperplasia, such as benign hyperplasia of medicine, atypical hyperplasia, and malignant hyperplasia.
  • diseases such as abnormal hyperplasia, wherein the abnormal proliferation described herein includes a tumor, and includes diseases associated with abnormal hyperplasia, such as benign hyperplasia of medicine, atypical hyperplasia, and malignant hyperplasia.
  • abnormal proliferation may also include combined abnormal proliferation.
  • Wavelength 405 certificate.
  • each analysis batch (Run) establishes a standard curve for calculating the concentration of the analyte in the analysis batch.
  • the blood sample stored at -20 °C was thawed into liquid at 4 °C, and the working solution and inhibitor working solution stored at 4 °C were placed on a shaker and mixed.
  • Example 1 The same sample was measured in the same manner as in Example 1 except that the compound I in Example 1 was changed to the compound ⁇ - ⁇ shown in Table 1, and the results are shown in Table 1.
  • Table 1 Results of TrxR activity in blood samples determined using various inhibitors
  • TrxR activity is less than 0, indicating that there is almost no TrxR activity in the body.
  • TrxR activity in the blood of the above subjects was measured under the same conditions using the gram-deoxyglucose inhibition method and the inhibitory compound I of the present invention, respectively, and the results are shown in Table 2.
  • TrxR activity measured by the present invention is significantly lower than that of TrxR activity measured by thioglucose gold, and the TrxR activity is related to the level of abnormal proliferation in vivo.
  • the higher the degree of normality, the inhibitor of the present invention is more realistic and more reliable because it can specifically inhibit TrxR.
  • Kit for the determination of thioredoxin reductase activity in blood :
  • the kit of the present invention (100 test) may contain:
  • TrxR inhibitor solution (containing 2.5 mM inhibitor selected from one of compounds I-XI), lOOuL, stored at -20 ° C;
  • TrxR inhibitor working solution (25 ⁇ ): Take 10 ⁇ inhibitor stock solution (2.5 mM), add 1 ⁇ working solution, dilute to 1 mL, and test for 50 wells. Use at room temperature.
  • the kit can be prepared as a 200 Test or 50 Test package.
  • the 10 X buffer in the kit should be a colorless and transparent liquid. After a long period of time, a small amount of visible protein can be precipitated, which is precipitated and precipitated by bovine serum albumin. It can be dissolved after ultrasonication and does not affect the determination.
  • the TrxR activity inhibitor is a pale yellow, yellowish or colorless, clear, clear solution at room temperature, which is solid when stored at a temperature below the melting point of DMSO, and is used after melting.
  • DTNB is a dry, pale yellow powder with no wet agglomerates and uniform powder particles.
  • NADPH Na 4 is a dry white or off-white amorphous powder.
  • Electrocardiogram left ventricular high electricity, no swelling
  • ALT 52U/L
  • B-ultrasound pathological lesions
  • the inventors also compared the consistency of the evaluation method of the present invention with the clinical diagnosis results, specifically: screening out of 300 subjects with absolute clinical normality (44 cases), absolute clinical evaluation of abnormal hyperplasia (17 cases) In the three groups of patients who have been diagnosed as tumors (20 cases), the anti-tumor levels in vivo in the three groups were evaluated by the kit of the present invention. The specific results are shown in Table 5. Table 5 Comparison of the consistency between this evaluation method and clinical diagnosis results
  • the ratio of TR value and 0 S / T R measured by the kit of the present invention is clearly consistent with the physical examination condition, and the consistency thereof is more than 80%. Therefore, the ratio of TR to OS/TR can be used as an indicator of anti-tumor levels in vivo, which can effectively evaluate the anti-tumor level in the body.
  • the TR measuring method and kit of the present invention it is possible to detect a sample, particularly a TR in a complex sample such as blood, with excellent sensitivity, and is very useful for measuring an antitumor level in vivo, and the reagent or method of the present invention. It can also be used for the assessment of the risk of tumorigenesis in vivo, as well as in the medical field such as tumor prognosis.

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Abstract

L'invention concerne des procédés et des kits de réactifs pour déterminer l'activité de la thiorédoxine réductase dans un échantillon et leurs utilisations. Les procédés consistent à déterminer la teneur en sulphydryle de composés de sélénium avant et après traitement individuel d'un échantillon, et par conséquent à mesurer l'activité de la thiorédoxine réductase dans l'échantillon au moyen de la différence de teneur en sulphydryle avant et après traitement de l'échantillon. L'invention concerne également des procédés pour évaluer le niveau de résistance à la maladie in vivo, qui consistent à déterminer l'activité de la thiorédoxine réductase dans un échantillon, et à mesurer le niveau de stress oxydatif et l'activité de la thiorédoxine réductase. DRWAING:
PCT/CN2010/078369 2009-11-03 2010-11-03 Procedes et kits de reactifs pour determiner l'activite de la thioredoxine reductase et leurs utilisations WO2011054290A1 (fr)

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CN201080049877.XA CN102695805B (zh) 2009-11-03 2010-11-03 用于测定样品中硫氧还蛋白还原酶活性的方法和试剂盒及应用
HK13103743.9A HK1176097A1 (en) 2009-11-03 2013-03-25 Methods and reagent kits for determining the activity of thioredoxin reductase and the uses thereof

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CN200910207455.X 2009-11-03
CN200910207455XA CN102051406A (zh) 2009-11-03 2009-11-03 一种用于预报人体发生异常增殖或肿瘤发生风险的检测方法

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CN113372296A (zh) * 2020-03-10 2021-09-10 杭州汉菁生物科技有限公司 用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途

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WO2018171619A1 (fr) * 2017-03-21 2018-09-27 南京凯熙医学科技有限公司 Procédé de détection d'activité de thiorédoxine réductase, dispositif de détection et son procédé de fonctionnement
CN108627469B (zh) * 2017-03-21 2021-04-02 凯熙医药（武汉）股份有限公司 一种用于协同检测设备的硫氧还蛋白还原酶活性检测方法
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CN111748604A (zh) * 2020-07-06 2020-10-09 兰州大学 一种检测硫氧还蛋白还原酶活性的方法
CN115260260A (zh) * 2021-04-29 2022-11-01 杭州健昵福生物科技有限公司 具有kga抑制活性的含硒核糖类化合物及其合成方法的应用
CN116891443B (zh) * 2023-09-08 2023-12-01 潍坊医学院 一种异吲哚-1-酮衍生物及其制备方法、应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105277699A (zh) * 2014-07-21 2016-01-27 凯熙医药（武汉）股份有限公司 测试试剂在制备评价临床肿瘤患者临床治疗监测的药品中的应用
CN113372296A (zh) * 2020-03-10 2021-09-10 杭州汉菁生物科技有限公司 用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途

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