CN110982843A - Application of tetrahydropyrimidine in regulating DNA (deoxyribonucleic acid) coagulation strength - Google Patents
Application of tetrahydropyrimidine in regulating DNA (deoxyribonucleic acid) coagulation strength Download PDFInfo
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Abstract
The invention belongs to the field of gene therapy, and particularly relates to application of tetrahydropyrimidine in regulating DNA (deoxyribonucleic acid) coagulation strength. The invention discovers that proper amount of tetrahydropyrimidine is added in the reaction of interaction between DNA and cations, low-concentration tetrahydropyrimidine plays a role in promoting DNA agglomeration, and high-concentration tetrahydropyrimidine plays a role in inhibiting DNA agglomeration. Namely, the strength of DNA agglomeration can be adjusted by controlling the concentration of tetrahydropyrimidine.
Description
Technical Field
The invention belongs to the field of gene therapy, and particularly relates to application of tetrahydropyrimidine in regulating DNA (deoxyribonucleic acid) coagulation strength.
Background
DNA is a carrier of genetic information, and a highly condensed and orderly arranged DNA structure keeps the stability of a genome, so that the replication is successfully completed. The gene therapy is to introduce the human health gene or the gene with therapeutic action into the pathogenic cells of human body through proper carrying medium to correct the pathogenic gene, so as to achieve the purpose of treating diseases. The tool which releases therapeutic genetic material into cells and protects the material from nuclease degradation during gene transfer is called gene vector, and the ideal gene vector should have the following characteristics: easy transmembrane entering into cells, specific targeting property, structural stability, safety, easy preparation and high transfection efficiency. The gene vector is divided into a virus vector and a non-virus vector, the virus vector has the advantage of higher transfection efficiency, but has high immunogenicity, small nucleic acid loading amount and potential carcinogenicity, and the non-virus gene vector makes up the defects of the virus vector compared with the virus vector, and has the advantages of low immunogenicity, low toxicity, easy preparation and the like. Non-viral gene vectors currently under investigation include polyamines, polyvalent metal cations, cationic liposomes, cationic polymers, nanomaterials, and the like. Non-viral gene vectors must satisfy some structural properties: the DNA coagulation reagent is a process that 1 or more DNA molecules collapse from a free extension state to a more compact ordered structure, so that a DNA complex can enter cells to further realize gene expression, and the research on the DNA coagulation has certain significance on gene therapy.
The paper, "dynamic light scattering analysis of DNA counterion agglomeration" (forest yog, poplars ginseng, royal brilliant great, acta phys.sin.vol.62, No.11 (2013)) 118702, studies the interaction between different valences of counterions and DNA, verifies that the counterions are adsorbed on the surface of DNA to shield the charges of DNA, so that the repulsive force between DNAs is reduced, and when the electrostatic repulsive force between DNAs is smaller than the electrostatic attractive force, DNA agglomeration occurs.
Tetrahydropyrimidine (ectoine), an osmotically compensating solute synthesized by certain microorganisms in response to environmental osmotic stress, is a small organic molecule that is electrically neutral and has low toxicity even at high concentrations. The currently known applications of tetrahydropyrimidines are as follows: 1. because of the functions of stabilizing and protecting macromolecules such as living cells and the like in an extremely severe environment and the characteristic of balanced osmotic pressure, the plant saline-alkali resistance can be improved, or the environment can be repaired by protecting other microbial cells and enzymes with bioremediation functions; 2. has enzyme activity protection effect; 3. the composition is applied to diseases with declined nerve function; 4. can be used as cosmetic additive for reducing UV damage to skin. At present, no research and report on the application of tetrahydropyrimidine to DNA condensation exists.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provides an application of tetrahydropyrimidine for promoting DNA agglomeration.
The technical scheme adopted by the invention is as follows: the tetrahydropyrimidine is used for regulating the strength of DNA condensation, low-concentration tetrahydropyrimidine plays a role in promoting the DNA condensation, and high-concentration tetrahydropyrimidine plays a role in inhibiting the DNA condensation.
Use of tetrahydropyrimidines for gene therapy, for the preparation of DNA aggregates.
A DNA coagulating agent comprising a cationic substance and tetrahydropyrimidine.
A DNA coagulation regulator comprising tetrahydropyrimidine
A DNA neutralization and coagulation regulation method comprising the process of: adding DNA and tetrahydropyrimidine to be coagulated into the solution containing cations.
The cation is a monovalent cation.
The cation is a multivalent cation.
The concentration of the tetrahydropyrimidine was 250 mM.
The invention has the following beneficial effects: the invention discovers that proper amount of tetrahydropyrimidine is added in the reaction of interaction between DNA and cations, low-concentration tetrahydropyrimidine plays a role in promoting DNA agglomeration, and high-concentration tetrahydropyrimidine plays a role in inhibiting DNA agglomeration. Namely, the strength of DNA agglomeration can be adjusted by controlling the concentration of tetrahydropyrimidine.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the examples or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on these drawings without inventive exercise.
In FIG. 1, (a) electrophoretic mobilities of DNA with Na at concentrations of 0mM, 100mM, 250mM and 500mM tetrahydropyrimidine+The curve of the concentration (b) at 2mM and 5mM Na+The change curve of the electrophoretic mobility of the DNA under the concentration along with the concentration of the tetrahydropyrimidine;
FIG. 2 shows Na concentrations+Particle size of DNA at (2mM, 5mM) versus tetrahydropyrimidine concentration;
in FIG. 3, (a) the electrophoretic mobility of DNA with Mg at concentrations of 0mM, 100mM, 250mM and 500mM tetrahydropyrimidine2+A change curve of concentration; (b) at 1mM and 3mM Mg2+The electrophoretic mobility of the DNA varies with the concentration of tetrahydropyrimidine under the concentration of (2);
FIG. 4 shows different concentrations of Mg2+Particle size of DNA at (1mM, 3mM) versus tetrahydropyrimidine concentration;
in FIG. 5, (a) the electrophoretic mobility of DNA and [ Co (NH) at tetrahydropyrimidine concentrations of 0mM, 100mM, 250mM and 500mM3)6]3+A concentration dependence; (b) at 0.01mM and 0.1mM [ Co (NH) ]3)6]3+The change curve of the electrophoretic mobility of the concentration DNA and the concentration of the tetrahydropyrimidine;
FIG. 6 shows different concentrations of [ Co (NH ]3)6]3+Particle size of DNA at (0.01mM, 0.1mM) versus tetrahydropyrimidine concentration;
FIG. 7 shows DNA in various concentrations of tetrahydropyrimidine and 0.01mM [ Co (NH) ]3)6]3+AFM imaging in (1). (a) No tetrahydropyrimidine; (b)50mM tetrahydropyrimidine; (c)200mM tetrahydropyrimidine; (d)300mM tetrahydropyrimidine; (e) a Buffer solution of 500mM tetrahydropyrimidine Tris (10mM, pH 7.5) was used for all samples measured.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Example 1 effect of tetrahydropyrimidine on DNA coagulation in monovalent counterion solution:
DNA was added to each of the mixed solutions (sodium chloride of different concentrations and tetrahydropyrimidine of different concentrations) and the measurement was carried out after standing at room temperature for 5 minutes. During the measurement, a 1mL volume of DNA solution was used and the sample temperature was maintained at 25 ℃.
The relationship between the electrophoretic mobility of DNA in solution and the concentration of sodium ions and the concentration of tetrahydropyrimidine under different concentrations of tetrahydropyrimidine is shown in FIG. 1. In FIG. 1(a), the Electrophoretic Mobility (EM) of DNA is plotted against the concentration of sodium ions. As the concentration of sodium ions in the solution increases, we can see that the electrophoretic mobility of the DNA complexes gradually increases as expected. The electrophoretic mobility gradually increased in the absence of tetrahydropyrimidine, and from-2.71X 10 at sodium ion concentrations from 1mM to 20mM-4cm2v-1s-1Increase to-1.78. 10-4cm2v-1s-1. When 100mM tetrahydropyrimidine was added to the solution, the Electrophoretic Mobility (EM) of the DNA showed the same tendency as that of the case without tetrahydropyrimidine, but the relation curve I was shifted upward as a whole.For example, at a sodium ion concentration of 5mM, the electrophoretic mobility was increased to-1.97 at 100mM tetrahydropyrimidine compared to-2.32 in a solution without tetrahydropyrimidine. When the concentration of tetrahydropyrimidine was further increased to 250mM, the effect of enhancing electrophoretic migration of DNA was still effective, but the effect was weak. For example, when we fixed the concentration of Na + to 10mM and added 100mM tetrahydropyrimidine to the solution, the electrophoretic mobility of the DNA increased from-2.00 to-1.68, with a lift value of about 0.32. Under the same ion condition, when the concentration of the tetrahydropyrimidine is increased from 100mM to 250mM, the electrophoretic mobility of the DNA is improved from-1.68 to-1.55, and the corresponding improvement value is only-0.13 and is obviously smaller than the change value of 100 mM. When we further added more tetrahydropyrimidine to the solution to a concentration of 500mM, we can see that the electrophoretic mobility of the DNA is almost restored to the original value without tetrahydropyrimidine. This effect can be seen more clearly in fig. 1 (b). Mixing Na+The concentration was fixed at 5mM while the concentration of tetrahydropyrimidine was varied from 0 to 500mM, wherein the electrophoretic mobility of the DNA initially rose, then reached its maximum value and finally dropped to about the original value. Mixing Na+A similar phenomenon was observed when the concentration of (2) was increased to 10 mM. In summary, in monovalent counterion solution, a proper amount of tetrahydropyrimidine has a promoting effect on the electrophoretic migration of DNA, while a high concentration of tetrahydropyrimidine has an inhibiting effect on the electrophoretic migration of DNA in solution.
DNA coagulation is closely related to its electrophoretic mobility, because the coulomb repulsion between electrophoretic fragments of DNA plays an important role in DNA coagulation. When the electrophoresis of DNA is neutralized by the counter ions in solution, it helps the DNA to condense more compactly.
Further measurement of the particle size of DNA under various conditions, as shown in FIG. 2, it can be seen that the particle size of DNA decreases and then approaches an almost constant value as the concentration of tetrahydropyrimidine increases under the same monovalent cation condition. Consistent with the change in electrophoretic mobility.
Example 2 effect of tetrahydropyrimidine on DNA coagulation in divalent counterion solution:
DNA was added to each of the mixed solutions (magnesium chloride of different concentrations and tetrahydropyrimidine of different concentrations), and the electrophoretic mobility was measured after standing at room temperature for 5 minutes. During the measurement, a 1mL volume of DNA solution was used and the sample temperature was maintained at 25 ℃.
The relationship between the electrophoretic mobility of DNA in solution and the concentration of magnesium ions and the concentration of tetrahydropyrimidine under different concentrations of tetrahydropyrimidine is shown in FIG. 3. In FIG. 3(a), the Electrophoretic Mobility (EM) of DNA is plotted against the concentration of magnesium ions. Similar to the case of the solution environment of the monovalent ions in example 1, we can see that the electrophoretic mobility of DNA is dependent on Mg in the solution2+The ion concentration increases. When no tetrahydropyrimidine is added to the solution, when Mg is present2+The electrophoretic mobility was gradually increased from-2.54 to-1.14 mM at ion concentrations from 0.1mM to 5 mM. When 100mM tetrahydropyrimidine was added to the solution, the electrophoretic mobility of the DNA showed the same tendency as that in the case of no tetrahydropyrimidine, but the change curve was shifted upward as a whole. For example, in Mg2+At an ionic concentration of 0.1mM, the DNA mobility in a 100mM tetrahydropyrimidine solution was increased from-2.45 to-2.27 compared to no tetrahydropyrimidine. When we increased the concentration of tetrahydropyrimidine further to 250mM, the promotion of electrophoretic migration of DNA was still effective, but the effect was weak. For example, when we associate Mg with2+When the concentration was fixed at 3mM and 100mM tetrahydropyrimidine was added to the solution, the electrophoretic mobility of the DNA rose from-1.33 to-1.14, with an increase of about 0.19. Under the same ion conditions, when the concentration of tetrahydropyrimidine is increased from 100mM to 250mM, the electrophoretic mobility is increased from-1.14 to-1.05. The corresponding lift value is only 0.10 lower than the previous value 0.19. When we further added more tetrahydropyrimidinyl to the solution to a concentration of 500mM, at Mg2+(<1mM), the electrophoretic mobility of the DNA is still promoted in the presence of tetrahydropyrimidine, but the promoting effect is gradually reduced, in the case of Mg2+Near zero at ± 1 mM. Crossing the critical point, when we further increase Mg2+At a concentration of (3), the electrophoretic mobility of the DNA is lower than that without tetrahydropyrimidine, which means that the electrophoretic mobility of the DNA is inhibited. This effect can be seen more clearly in FIG. 3(b), where the electrophoretic mobility of the DNA initially rises,then reaches its maximum value and finally drops around the original value at a certain concentration.
Further measurements of the particle size of DNA under different conditions, as shown in FIG. 4, under divalent cation conditions, it can be seen that the particle size of DNA decreases with increasing concentration of tetrahydropyrimidine and then approaches an almost constant value. Consistent with the change in electrophoretic mobility.
Example 3 effect of tetrahydropyrimidine on DNA coagulation in trivalent counterion solution:
DNA is respectively added into a plurality of groups of mixed solutions (trichlorohexamine complex cobalt with different concentrations and tetrahydropyrimidine with different concentrations), and the electrophoresis mobility is tested after the mixed solutions are stood for 5 minutes at room temperature. During the measurement, a 1mL volume of DNA solution was used and the sample temperature was maintained at 25 ℃.
Under the condition of different tetrahydropyrimidine concentrations, the electrophoretic mobility of DNA in solution is equal to that of [ Co (NH)3)6]3+The relationship between the concentration and the tetrahydropyrimidine concentration is shown in figure 5. In FIG. 5(a), the Electrophoretic Mobility (EM) of DNA and [ Co (NH) are plotted3)6]3+The concentration relationship curve of (1). With [ Co (NH) in solution3)6]3+With increasing ion concentration, we can see an increase in electrophoretic mobility of the DNA complex. For example, when no tetrahydropyrimidine is added to the solution, [ Co (NH) ]3)6]3+From 0.01mM to 2mM, the electrophoretic mobility gradually increases from-2.45 to-0.32. When 100mM tetrahydropyrimidine was introduced into the solution, the electrophoretic mobility of the DNA showed the same tendency as that in the case of no tetrahydropyrimidine, but the moving curve was shifted upward as a whole. For example, at 0.2mM [ Co (NH)3)6]3+Under the ion concentration, the electrophoresis mobility of the sample is 1.30 in 100mM tetrahydropyrimidine, and is obviously increased compared with the electrophoresis mobility of the sample which is-1.02 without tetrahydropyrimidine. When we increased the concentration of tetrahydropyrimidine further to 250mM, the promotion of electrophoretic migration of DNA was still effective, but weakened. For example, the amount of ectoine added is 100mM and [ Co (NH)3)6]3+At 0.1mM, the electrophoretic mobility of the DNA increased from-1.56 to-1.30, which was about 0.24. Under the same ion condition, when fourWhen the concentration of the hydropyrimidine is increased from 100mM to 250mM, the electrophoretic mobility is further increased from-1.30 to-1.28. The corresponding boost value is significantly less than the previous value. When we further added more tetrahydropyrimidine to the solution to a concentration of 500mM, it can be seen that the electrophoretic mobility of DNA is almost restored to the original value without tetrahydropyrimidine, which means that the accelerating effect of tetrahydropyrimidine is almost disappeared. This effect is more clearly seen in FIG. 5(b), where the mobility of the DNA initially rises, then reaches its maximum and finally gradually returns to about its original value.
Further measurements of the particle size of DNA under various conditions, as shown in FIG. 6, under divalent cation conditions, it can be seen that the particle size of DNA decreases with increasing concentration of tetrahydropyrimidine and then approaches an almost constant value. Consistent with the change in electrophoretic mobility.
Will [ Co (NH)3)6]3+The concentration of (2) was fixed to 0.01mM, and an image observed under an Atomic Force Microscope (AFM) with the tetrahydropyrimidine concentration as a control parameter is shown in FIG. 7. In FIG. 7(a), at 0.01mM [ Co (NH) ]3)6]3+At a concentration of (10mM Tris, pH 7.5), we can see that the mica surface exhibits a slightly contracted DNA morphology. As shown in FIG. 7(b), when 50mM tetrahydropyrimidine was added to the DNA solution, we can see that the structure of the DNA becomes more compact than without tetrahydropyrimidine. If we continue to increase the concentration of tetrahydropyrimidine, the morphology of the DNA becomes more compact, as shown in FIG. 7(c), which appears as a hairline ball at 200mM tetrahydropyrimidine. As shown in FIGS. 7(d) and (e), addition of tetrahydropyrimidine to a high concentration (300mM, 500mM) reduced the effect on DNA aggregation. In good agreement with the results of the electrophoretic mobility and size measurements. At low concentrations, tetrahydropyrimidines enhance the structural compactness of DNA agglomeration. There is a peak concentration, and if this number is exceeded, the effect becomes weaker when the tetrahydropyrimidine concentration is increased.
Based on the tests and analysis of the results of examples 1-3 on tetrahydropyrimidines, counterions and DNA coagulation, it can be concluded that proper amounts of tetrahydropyrimidines contribute to the neutralization of DNA by the counterions, promoting DNA coagulation. High concentrations of tetrahydropyrimidine slightly promote monovalent counterions, while for divalent and trivalent ions the electrophoretic mobility is slightly promoted in the low cation concentration range, but inhibition is achieved in the high cation concentration range.
In the above examples, the specific experimental procedures were as follows:
materials: Lambda-DNA was purchased from New England Biolabs at a primary concentration of 500 mg/L. Tetrahydropyrimidine with the purity of more than or equal to 95.0 percent; the purity of the trichloro hexa ammine complex cobalt is more than or equal to 99.0 percent; magnesium chloride hexahydrate with the purity of more than or equal to 99.0 percent; sodium chloride with purity more than or equal to 99.0%; hydroxyacetamidoethane (Tris, purity. gtoreq.99.8%), the reagents were purchased from Sigma. All buffers used in Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM) were Tris (10mM, pH 7). The final DNA concentration in the solution was 1 ng/. mu.L.
Electrophoretic mobility measurement (EM) and DLS sizing
Electrophoretic mobility measurements (EM) were performed using a Zetasizer Nano ZS90 instrument from Malvern using a helium neon gas laser (λ 633nm) at a probe angle of 90 °, using M3-PALS technology to measure electrophoretic mobility. We added DNA, cation (Na) to the mixed solution+，Mg2+，[Co(NH3)6]3+) And 0-500mM of various tetrahydropyrimidines. All samples measured after 5 min incubation at room temperature. During the measurement, a 1mL volume of DNA solution was used and the sample cells were maintained at 25 ℃.
In the dimensional measurement, the laser power is automatically attenuated to bring the sample's count rate within an acceptable range. Transparent disposable capillary cells were used. In sample preparation, we added DNA, including cations and tetrahydropyrimidines, to the mixed solution. All samples were measured for 10 min incubation at room temperature. During the measurement, a volume of 100. mu.L of DNA solution was used, and the sample cells were kept at 25 ℃.
Atomic Force Microscope (AFM)
The mica plate is cut into a square with the side length of 1cm, stuck on a glass slide and used as a substrate to adsorb DNA. In solution is added with DNA, and 0.01mM [ Co (NH)3)6]3+And 0-500mM tetrahydropyrimidine. 20 μ L of the solution was incubated on the freshly dissociated mica surface for 3min at room temperature. The mica surface was rinsed with distilled water and then dried with a gentle stream of nitrogen. The prepared test samples were scanned by AFM (JPK Nano wizard III, Berlin, Germany) in AC mode using a silicon AFM probe (NCHR-50, Nano World Corporation, Tokyo, Japan) 125 μm long by 30 μm wide by 4 μm thick with an aluminum coating attached, the cantilever spring constant was 42N/m and the resonance frequency was 320 kHz. The scan frequency of image acquisition was 1.0Hz and the sample viewing area was 5X 5 μm2The pixel is 512 × 512.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (8)
1. The tetrahydropyrimidine is used for regulating the strength of DNA condensation, low-concentration tetrahydropyrimidine plays a role in promoting the DNA condensation, and high-concentration tetrahydropyrimidine plays a role in inhibiting the DNA condensation.
2. Use of tetrahydropyrimidines for gene therapy, for the preparation of DNA aggregates.
3. A DNA coagulating agent characterized by: comprising a cationic species and tetrahydropyrimidine.
4. A DNA agglutination modulator characterized by: comprises tetrahydropyrimidine.
5. A method for regulating neutralization and coagulation of DNA, comprising the steps of: adding DNA and tetrahydropyrimidine to be coagulated into the solution containing cations.
6. The method for regulating neutralization and coagulation of DNA according to claim 5, wherein: the cation is a monovalent cation.
7. The method for regulating neutralization and coagulation of DNA according to claim 5, wherein: the cation is a multivalent cation.
8. The method for regulating neutralization and coagulation of DNA according to any one of claims 5 to 7, wherein: the concentration of the tetrahydropyrimidine was 250 mM.
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| CN1080172A (en) * | 1992-01-30 | 1994-01-05 | 耶达研究及发展有限公司 | The tetrahydropyrimidinederivatives derivatives of purification and comprise their Pharmaceutical composition |
| EP1127141A1 (en) * | 1998-11-07 | 2001-08-29 | Stefan Barth | Method for expressing recombinant proteins using the effect of stress and stress response mechanisms in the presence of compatible solutes |
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| WO2018206024A1 (en) * | 2017-05-11 | 2018-11-15 | Forschungszentrum Jülich GmbH | Pyruvate carboxylase and pyruvate carboxylase-encoding dna, plasmid containing said dna and microorganism for the production thereof, and methods for the production of products the biosynthesis of which includes oxaloacetate as precursor, and chromosome and screening method |
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| CN1080172A (en) * | 1992-01-30 | 1994-01-05 | 耶达研究及发展有限公司 | The tetrahydropyrimidinederivatives derivatives of purification and comprise their Pharmaceutical composition |
| EP1127141A1 (en) * | 1998-11-07 | 2001-08-29 | Stefan Barth | Method for expressing recombinant proteins using the effect of stress and stress response mechanisms in the presence of compatible solutes |
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