CN115820652A - Nucleic acid aptamer group for specifically recognizing human chorionic gonadotropin and application thereof - Google Patents
Nucleic acid aptamer group for specifically recognizing human chorionic gonadotropin and application thereof Download PDFInfo
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- CN115820652A CN115820652A CN202211690092.1A CN202211690092A CN115820652A CN 115820652 A CN115820652 A CN 115820652A CN 202211690092 A CN202211690092 A CN 202211690092A CN 115820652 A CN115820652 A CN 115820652A
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Abstract
The invention belongs to the field of biomedicine, and particularly relates to a group of aptamers for specifically identifying human chorionic gonadotropin and application thereof. Specifically, the invention provides an aptamer, and the sequence of the aptamer is shown in any one of SEQ ID NO. 1-6. The aptamer is a DNA sequence, can be directly used for diagnosis, and can be used as a molecular probe to construct a biological detection sensor and the like.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a group of aptamers for specifically identifying human chorionic gonadotropin and application thereof.
Background
Human chorionic gonadotropin (hcg) is a glycoprotein hormone secreted by trophoblast cells of placental chorionic vesicles and consists of two distinct subunits, an alpha subunit and a beta subunit, and 244 amino acids, with a molecular weight of about 36.7kda. Structurally, the alpha subunit is similar to many hormones such as thyroid stimulating hormone, follicle stimulating hormone, etc., while the beta subunit is unique to hcg, so that the specificity of the beta subunit is mainly utilized in the hcg detection in clinic. The placenta can produce hcg, as can trophoblastoma, germ cell tumor containing trophoblastic tissue, and some non-trophoblastoma. Pregnant women have a predominant serum concentration of intact hcg molecules, which increases exponentially in the early stages of pregnancy and is time dependent, playing an important role in maintaining pregnancy.
If the change of the hcg value is irregular, the specific time is too high or too low, which indicates that the pregnancy is abnormal. An abnormally high detection may indicate choriocarcinoma, hydatidiform mole or multiple pregnancy, and a low detection may indicate threatened/early abortion, ectopic pregnancy, gestational toxicosis or intrauterine fetal death. The detection of hcg + beta is favorable for evaluating the risk of trisomy 21 syndrome in the middle of pregnancy by combining alpha-fetoprotein detection and accurate other parameters such as gestational age and weight of pregnant women, the serum alpha-fetoprotein concentration of the trisomy 21 pregnant women is reduced, and the hcg + beta concentration of maternal serum can reach twice of a normal median value. The monitoring of the human chorionic gonadotropin level can predict the occurrence of pregnancy-induced hypertension, and has important guiding significance for diagnosing the course of hypertensive diseases during pregnancy. hcg is also an important serum and urine tumor marker, and elevated hcg concentrations unrelated to pregnancy can also be seen in patients with germ cell, ovarian, bladder, pancreatic, gastric, lung and liver tumors. The detection methods commonly used at present are as follows: latex aggregation inhibition assay and hemagglutination inhibition assay, radioimmunoassay (RIA), adsorption assay (ELISA), monoclonal antibody colloidal gold assay.
The ligand phylogenetic evolution technology of index Enrichment, referred to as SELEX (Systematic volume of Ligands by expression engineering) technology, is a high-throughput screening technology for biological libraries that has been developed rapidly in recent decades. The method is characterized in that a random oligonucleotide library (ssDNA library and RNA library) with large capacity is applied, a PCR in-vitro amplification technology is combined, oligonucleotides which are specifically combined with target molecules are enriched in an exponential order, and the finally obtained aptamer (aptamer) is combined with the target molecules in a high specificity and high affinity manner based on a spatial structure through repeated in-vitro screening and amplification.
The aptamer has the advantages of accurate identification, no immunogenicity, easy in-vitro synthesis and modification and the like, is also called as an artificial substitute antibody, and has wide application prospects in aspects of basic medicine, clinical diagnosis, new drug research and development and the like.
Disclosure of Invention
The invention obtains a group of aptamers HCG-1, HCG-3, HCG-4, HCG-5, HCG-7 and HCG-15 for specifically recognizing Human Chorionic Gonadotropin (HCG) by screening by using the human chorionic gonadotropin as a target through SELEX technology and application thereof in recognizing the human chorionic gonadotropin. The aptamer is a DNA sequence, can be directly used for diagnosis, and can be used as a molecular probe to construct a biological detection sensor and the like. The nucleic acid aptamer and the truncated sequence thereof are identified to be capable of specifically recognizing the human chorionic gonadotropin without binding other unrelated proteins (BSA protein), and the control nucleic acid sequence is not bound with the human chorionic gonadotropin.
The specific technical scheme is as follows:
in one aspect, the invention provides an aptamer, wherein the sequence of the aptamer is shown in any one of SEQ ID NO. 1-6.
Preferably, the nucleic acid aptamer can also be a nucleic acid molecule specifically binding to hcg by adding or deleting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides relative to the sequence shown in any one of SEQ ID No. 1-6;
preferably, the aptamer can also be a nucleic acid molecule having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% homology with the sequence shown in any one of SEQ ID No. 1-6;
preferably, the sequence of the aptamer may also be reverse complementary to the sequence shown in any one of SEQ ID No. 1-6.
Preferably, the nucleic acid comprises DNA, RNA, or a hybrid of both.
Preferably, the aptamer is DNA.
The "homology" refers to sequence similarity, and homology can be evaluated by the naked eye or computer software. Using computer software, homology between two or more sequences can be expressed as a percentage (%), which can be used to assess homology between related sequences.
As used herein, the term "aptamer" refers to a single-stranded oligonucleotide that specifically binds to a target molecule. Principle of aptamer recognition of target molecules: the single-stranded oligonucleotide is adaptively folded by itself through various interaction forces such as nucleotide base complementary pairing, hydrogen bond, pi-pi accumulation, electrostatic action force and the like to form a specific three-dimensional structure, and the three-dimensional structure is specifically combined with a target molecule through intermolecular action force. The binding dissociation constant can reach nanomolar and picomolar levels, which is equivalent to that of monoclonal antibody. The target molecule of interest in the present invention is hcg.
In the present invention, the terms "HCG", "human chloronic gonadotropin" and "human chorionic gonadotropin" mean the same meaning and are used interchangeably.
As used herein, the term "specific binding" refers to a non-random binding reaction between an aptamer of the invention and hcg. The aptamers provided by the present invention do not bind to other proteins.
In another aspect, the present invention provides a derivative of an aptamer comprising an aptamer and a detectable label for labeling the aptamer.
Preferably, the detectable label comprises an enzyme (e.g., peroxidase, alkaline phosphatase, luciferase, etc.), a radionuclide (e.g., luciferase, etc.) 3 H、 125 I、 35 S、 14 C、 32 P, etc.), fluorescent dye (e.g., FITC, TRITC, PE, texas Red, cy7, alexa 750, VIC, JOE, TET, CY3, etc.), acridinium ester compound, magnetic bead, colloidal goldOr colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads, as well as avidin (e.g., streptavidin) for binding to the label modifications described above, biotin.
As used herein, the term "detectable label" refers to any substance that can be detected by fluorescent, spectroscopic, photochemical, biochemical, immunological, electrical, optical, or chemical means.
The detectable label as used in the embodiments of the present invention is biotin, which is a method of labeling aptamers that is conventional in the art.
Preferably, the aptamer or derivative thereof can be immobilized on a suitable solid support in daily storage to facilitate more convenient, visual detection, identification of hcg; alternatively, the aptamer, detectable label-labeled aptamer may be stored in a suitable liquid to maintain its stability, e.g., water, buffer.
In another aspect, the present invention provides a method of making a probe targeting hcg, the method comprising obtaining an aptamer of the invention and labeling the aptamer with a detectable label.
Preferably, the nucleic acid aptamer can be obtained by chemical synthesis and biological amplification methods.
Preferably, the bioamplification method comprises any one of the conventional nucleic acid amplification techniques in the art, and specifically, the bioamplification method comprises: temperature-variable amplification and temperature-constant amplification. The temperature-variable Amplification mainly includes a classical Polymerase Chain Reaction (PCR) and a Ligase Chain Reaction (LCR), and the Isothermal Amplification includes Strand Displacement Amplification (SDA), rolling Circle Amplification (RCA), loop-Mediated Amplification (Loop Mediated Amplification (LAMP), helicase-dependent Isothermal Amplification (HDA), nucleic acid sequence-dependent Amplification (NASBA), transcription-dependent Amplification System (TAS), and the like.
Preferably, the step of labeling the aptamer with a detectable label may use any alternative method in the art.
In another aspect, the present invention provides a method for detecting hcg, the method comprising contacting a test substance with an aptamer of the present invention or a derivative thereof.
Preferably, the analyte comprises a sample collected from a human body.
Preferably, the sample comprises peripheral blood, tissue, blood, serum, plasma, urine, saliva, semen, breast milk, cerebrospinal fluid, tears, sputum, mucus, lymph, cytosol, ascites, pleural effusion, amniotic fluid, bladder irrigation fluid and bronchoalveolar lavage fluid.
Preferably, the sample comprises urine and blood.
Preferably, the method is for non-diagnostic purposes.
Preferably, the aptamer or derivative thereof is denatured.
More preferably, the specific steps of the denaturation treatment are: dissolving the aptamer in a buffer solution, and cooling after denaturation at 100 ℃;
preferably, the buffer composition is 50mM HEPES,100mM NaCl,2mM MgCl 2 ，5mM KCl，1mM CaCl 2 。
Preferably, the contacting is maintained for at least 5, 10, 15, 20, 30, 40 minutes or more.
Preferably, the method further comprises the step of visualizing the test results using the reporting clique. Specifically, for example, when biotin is used as the detectable label, a reporter group HRP enzyme is used.
In another aspect, the invention also provides the use of the aptamers of the invention and derivatives thereof for specifically binding hcg.
Preferably, the specific binding occurs in vitro, for non-diagnostic purposes.
Preferably, the detection comprises a quantitative or qualitative detection, the result of which comprises the "presence" or "absence" of hcg in the test substance.
In another aspect, the invention also provides the use of the aptamers and derivatives thereof of the invention in the preparation of products for the diagnosis of symptoms associated with hcg.
Preferably, the hcg-associated symptoms comprise pregnancy, choriocarcinoma, hydatidiform mole, multiple pregnancy, threatened/early abortion, ectopic pregnancy, gestational toxicosis, intrauterine fetal death, trisomy 21 syndrome, hypertensive disorders of pregnancy, germ cell tumors, ovarian tumors, bladder tumors, pancreatic tumors, gastric tumors, lung tumors and liver tumors.
Preferably, the product comprises a kit, a test strip or a biosensor.
Drawings
FIG. 1 is a graph showing the results of EMSA experiments in which HCG-1 specifically binds to human chorionic gonadotropin hCG.
FIG. 2 is a graph showing the results of EMSA experiments in which HCG-3 specifically binds to human chorionic gonadotropin hCG.
FIG. 3 is a graph showing the results of EMSA experiments in which HCG-4 specifically binds to human chorionic gonadotropin hCG.
FIG. 4 is a graph showing the results of EMSA experiments in which HCG-5 specifically binds to human chorionic gonadotropin hCG.
FIG. 5 is a graph showing the results of EMSA experiments in which HCG-7 specifically binds to human chorionic gonadotropin hCG.
FIG. 6 is a graph showing the results of EMSA experiments in which HCG-15 specifically binds to human chorionic gonadotropin hCG.
FIG. 7 is a statistical chart of the results of the enzyme-linked assay.
Detailed Description
The present invention will be further described with reference to the following examples, which are intended to be illustrative only and not to be limiting of the invention in any way, and any person skilled in the art can modify the present invention by applying the teachings disclosed above and applying them to equivalent embodiments with equivalent modifications. Any simple modifications or equivalent changes made to the following embodiments according to the technical essence of the present invention, without departing from the technical spirit of the present invention, fall within the scope of the present invention.
Example 1 verification of aptamer specificity by EMSA experiment
1. Experimental Material
(1) Human chorionic gonadotropin: huayang Zhenglong goods number: 201215
(2) Bovine Serum Albumin (BSA): product number of okang bio-company, zhongsheng beijing: 01.10001D
(3) Biotin-labeled aptamers: the specific sequence of the synthetic gene is shown in Table 1
(4) HRP enzyme: solarbio goods number 898800
TABLE 1 sequences of nucleic acid aptamers
2. Experimental methods
2.1 separately, a concentration of the biotin-labeled aptamers HCG-1, HCG-3, HCG-4, HCG-5, HCG-7, HCG-15 and the biotin-labeled irrelevant control sequence AAAA were dissolved in an appropriate volume of buffer (50mM HEPES,100mM NaCl,2mM MgCl. RTM. AAAA) 2 ，5mM KCl，1mM CaCl 2 ) Immediately placing on ice for fully cooling after denaturation for 5min at 100 ℃;
2.2 co-incubating the biotin-labeled aptamer subjected to denaturation treatment with human chorionic gonadotropin (hCG) protein (or unrelated protein BSA) at 37 ℃ for 40min;
2.3 adding 10 XDNA sample buffer solution into the co-incubation system of the aptamer and the human chorionic gonadotropin hCG, and carrying out electrophoresis separation on 6% native PAGE gel;
2.4, rotating the die after unloading the glue, carrying out ultraviolet crosslinking for 2min, and then sealing the sealing liquid for 30min;
2.5 putting the membrane into HRP enzyme diluted according to 1;
2.6 addition of TMB substrate color development and remaining.
3. Results of the experiment
The results of EMSA experiments on specific binding of HCG-1, HCG-3, HCG-4, HCG-5, HCG-7 and HCG-15 to human chorionic gonadotropin hCG are shown in sequence in FIGS. 1-6.
Example 2 verification of aptamer specificity by enzyme-Linked assay
1. Experimental Material
The same as in example 1.
2. Experimental methods
2.1 melting a certain amount of human chorionic gonadotropin hCG in a carbonate buffer solution with the pH value of 9.7, adding the mixture into an enzyme-linked strip according to 100 mu l/hole, and coating the mixture overnight at the temperature of 4 ℃;
2.2 abandoning the coating solution, adding 100 mul of blocking solution containing 2% BSA into each hole, and blocking for 60min at room temperature;
2.3 separately, a concentration of the biotin-labeled aptamers HCG-1, HCG-3, HCG-4, HCG-5, HCG-7, HCG-15 and the biotin-labeled unrelated control sequence AAAA were dissolved in an appropriate volume of buffer (50mM HEPES,100mM NaCl,2mM MgCl. RTM. AAAA) 2 ，5mM KCl，1mM CaCl 2 ) Immediately placing on ice for fully cooling after denaturation for 5min at 100 ℃;
2.4 adding the biotin-labeled HCG aptamer subjected to denaturation treatment and an irrelevant control sequence Bio-AAAA into an enzyme-linked strip, and incubating the aptamer and the coated human chorionic gonadotropin hCG protein for 30min at 37 ℃;
2.5 discarding liquid in the holes, washing each hole by 200 mul of washing liquid, repeatedly washing for 3 times, and completely spin-drying the liquid in the holes after the last washing;
2.6 adding 100 μ l of HRP enzyme diluted according to 1;
2.7 adding 100 mul TMB chromogenic substrate into each hole, shading and developing at 37 ℃, adding 10 mul stop solution when obvious color changes, and reading by an enzyme-linked instrument.
3. Results of the experiment
Statistics of the enzyme-linked readout are shown in FIG. 7, which demonstrates that the HCG-1, HCG-3, HCG-4, HCG-5, HCG-7, HCG-15 aptamers can all specifically bind human chorionic gonadotropin compared to unrelated and control sequences.
Claims (10)
1. An aptamer, wherein the sequence of the aptamer is shown as any one of SEQ ID NO. 1-6.
2. A derivative of an aptamer comprising the aptamer of claim 1 and a detectable label that labels the aptamer.
3. The derivative of an aptamer according to claim 2, wherein the detectable label comprises an enzyme, a radionuclide, a fluorescent dye, an acridinium compound, a magnetic bead, colloidal gold or colored glass or plastic beads, avidin, biotin.
4. A method of making a probe targeting hcg, the method comprising obtaining the aptamer of claim 1 and labeling the aptamer with a detectable label.
5. The method of claim 4, wherein the method for obtaining the aptamer of claim 1 comprises a chemical synthesis method and a biological amplification method.
6. The method of claim 5, wherein the bioamplification method comprises temperature-variable amplification and temperature-constant amplification; the temperature-variable amplification comprises a polymerase chain reaction and a ligase chain reaction, and the constant-temperature amplification comprises strand displacement amplification, rolling circle amplification, loop-mediated amplification, helicase-dependent constant-temperature amplification, nucleic acid sequence-dependent amplification and transcription-dependent amplification systems.
7. A method for detecting hcg, the method comprising contacting a test substance with the aptamer of claim 1, or contacting a test substance with a derivative of the aptamer of claim 2.
8. The method of claim 7, wherein the test object comprises a sample taken from a human;
preferably, the sample comprises peripheral blood, tissue, blood, serum, plasma, urine, saliva, semen, milk, cerebrospinal fluid, tears, sputum, mucus, lymph, cytosol, ascites, pleural effusion, amniotic fluid, bladder irrigation fluid and bronchoalveolar lavage fluid;
preferably, the sample comprises urine and blood;
preferably, the method is for non-diagnostic purposes.
9. Use of the aptamer of claim 1 or a derivative of the aptamer of claim 2 for specifically binding hcg, detecting hcg;
preferably, the specific binding occurs in vitro, for non-diagnostic purposes.
10. Use of the aptamer of claim 1 or a derivative of the aptamer of claim 2 in the manufacture of a product for diagnosing a symptom associated with hcg;
preferably, the hcg-associated symptoms comprise pregnancy, choriocarcinoma, hydatidiform mole, multiple pregnancy, threatened/early abortion, ectopic pregnancy, gestational toxicosis, intrauterine fetal death, trisomy 21 syndrome, hypertensive disorders of pregnancy, germ cell tumors, ovarian tumors, bladder tumors, pancreatic tumors, gastric tumors, lung tumors and liver tumors.
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| CN102417920A (en) * | 2011-12-07 | 2012-04-18 | 浙江工业大学 | Method for preparing anti-human chorionic gonadotrophin (hCG) monoclonal antibody fragment |
| CN109081870A (en) * | 2018-09-21 | 2018-12-25 | 成都阿帕克生物科技有限公司 | A kind of anti-human nano antibody for promoting chorion gonadotrophic hormone beta subunit and nucleic acid molecules and application |
| CN113264985A (en) * | 2021-02-26 | 2021-08-17 | 长沙市信励致和科技有限责任公司 | Human chorionic gonadotropin peptide aptamer and preparation method and application thereof |
| CN114720527A (en) * | 2022-04-07 | 2022-07-08 | 广州大学 | Electrochemical aptamer detection method of glycoprotein |
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2022
- 2022-12-27 CN CN202211690092.1A patent/CN115820652B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5837456A (en) * | 1990-06-11 | 1998-11-17 | Nexstar Pharmaceuticals, Inc. | High affinity oligonucleotide ligands to chorionic gonadotropin hormone and related glycoprotein hormones |
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| CN102417920A (en) * | 2011-12-07 | 2012-04-18 | 浙江工业大学 | Method for preparing anti-human chorionic gonadotrophin (hCG) monoclonal antibody fragment |
| CN109081870A (en) * | 2018-09-21 | 2018-12-25 | 成都阿帕克生物科技有限公司 | A kind of anti-human nano antibody for promoting chorion gonadotrophic hormone beta subunit and nucleic acid molecules and application |
| CN113264985A (en) * | 2021-02-26 | 2021-08-17 | 长沙市信励致和科技有限责任公司 | Human chorionic gonadotropin peptide aptamer and preparation method and application thereof |
| CN114720527A (en) * | 2022-04-07 | 2022-07-08 | 广州大学 | Electrochemical aptamer detection method of glycoprotein |
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