CN112834740A - Peptide-like oligomer, preparation method thereof, pharmaceutical composition and microfluidic chip - Google Patents
Peptide-like oligomer, preparation method thereof, pharmaceutical composition and microfluidic chip Download PDFInfo
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- CN112834740A CN112834740A CN202011633232.2A CN202011633232A CN112834740A CN 112834740 A CN112834740 A CN 112834740A CN 202011633232 A CN202011633232 A CN 202011633232A CN 112834740 A CN112834740 A CN 112834740A
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
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- G—PHYSICS
- G01—MEASURING; TESTING
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
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- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
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- G01N2800/2814—Dementia; Cognitive disorders
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Abstract
The invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. The surface modification of the glass-based microfluidic chip is realized by assembling the peptide oligomer into a nanosheet layer, using the nanosheet layer for modifying the glass-based microfluidic chip, and further using GPTMS and 12-mercaptododecanoic acid to form covalent bonds with the peptoid oligomer nanosheet layer through reaction. The mode effectively reduces the nonspecific adsorption on the surface of the chip, provides the coupling groups of the antibody and the micromolecule, further improves the detection sensitivity and accuracy of the microfluidic chip, and provides a new choice for in vitro diagnosis. In addition, the modification method is simple, high in efficiency and low in manufacturing cost.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a micro-fluidic chip.
Background
The term microfluidic chip was originally derived from the micro total analysis system (μ TAS) proposed by Manz and Widmer in the 90 th of the 20 th century. Professor Manz successfully applies the MEMS technology to the field of analytical chemistry and realizes high-speed capillary electrophoresis on microchips in the near future, and the results are published in journal of Science and the like, and this field is rapidly receiving attention from the academia and becomes one of the leading Science and technology fields in the world. Lab-on-a-Chip (Lab-on-a-Chip) and Microfluidic Chip (Microfluidic Chip) are different names that have been proposed in this field, and as the application of this discipline expands from initial analytical chemistry to a number of research and application areas, and researchers's deep understanding of this discipline, Microfluidic chips have become a collective term for this area. Microfluidics is the processing and manipulation of microscale (10) in channel systems of tens to hundreds of micrometers-9To 10-18Liter) fluid science and technology. A key feature of microfluidic chip technology is the manipulation of fluids in microscale channels. It is because the micro-scale structure of the microfluidic chip significantly increases the specific surface area of the fluid, i.e. the ratio of the surface area to the volume, thereby causing a series of special effects related to the surface, such as laminar flow effect, surface tension, capillary effect, rapid thermal conduction effect, diffusion effect, etc., and thus bringing about superior performance that macro-scale laboratory devices do not have.
In the mainstream detection scheme at present, the surfaces of the microfluidic chips are modified by coupling antibodies or molecular probes, and the molecular probes comprise targeting molecules of specific receptor proteins of tumor parts such as antibodies, polypeptides, peptoids, nucleic acid aptamers and the like. However, the coupled functional molecules need to provide sufficient surface active groups, and blocking is also particularly important for the chip in order to reduce noise due to non-specific adsorption. The surface functionalization is carried out on the glass-based chip through chemical reaction, the surface modification of the glass-based chip can be effectively realized, the coupling effective duration of functional molecules is greatly prolonged, the activity of a natural living sample can be ensured, and new revelation is expected to be brought to in vitro diagnosis.
Disclosure of Invention
At least one embodiment of the present disclosure provides a peptide-like oligomer, comprising: beta-phenylethylamine subunit, 3-aminopropionic acid subunit, and ethylenediamine subunit.
For example, in at least one embodiment of the present disclosure, a peptoid oligomer is provided, which has a structure represented by formula I:
wherein, n1 is more than or equal to 10 and more than or equal to 3, n2 is more than or equal to 3, n1 is equal to n2, and n1 and n2 are natural numbers.
At least one embodiment of the present disclosure further provides a preparation method of the peptoid oligomer, wherein the preparation method comprises a solid phase synthesis method.
For example, in at least one embodiment of the present disclosure, a method for preparing includes the following steps:
(1) ligating the first subunit of the peptoid oligomer to a solid support according to the order of ligation of the subunits of the peptoid oligomer;
(2) reacting bromoacetic acid with an amino group of the first subunit attached to the solid support under activation by an activator to form an amide bond;
(3) reacting a donor of a second subunit of the peptoid oligomer with the product obtained in the step (2) to replace a bromine atom to complete the connection of the second subunit;
(4) repeating the connection of the bromoacetic acid and the subsequent subunits until the connection of all subunits is completed;
(5) and (3) cracking the synthesized peptoid oligomer from the solid phase carrier to obtain the peptoid oligomer.
At least one embodiment of the present disclosure also provides a pharmaceutical composition comprising: any of the peptoid oligomers described above; and pharmaceutically acceptable adjuvants.
For example, in the pharmaceutical composition provided in at least one embodiment of the present disclosure, the excipient is any one of or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, and a filler.
At least one embodiment of the present disclosure also provides a use of any one of the above pharmaceutical compositions in the preparation of a medicament for detecting or diagnosing a disease associated with alzheimer's disease.
At least one embodiment of the disclosure also provides a use of any one of the above pharmaceutical compositions in modification of a microfluidic chip.
For example, in uses provided by at least one embodiment of the present disclosure, the chip comprises a glass-based microfluidic chip.
At least one embodiment of the disclosure further provides a microfluidic chip, which contains the oligomer nanosheet layer and a functional layer, wherein the functional layer comprises GPTMS-guided epoxy modification and 12-mercaptododecanoic acid-guided blocking activation layer modification.
The invention has the following beneficial effects:
the invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. The surface modification of the glass-based microfluidic chip is realized by assembling the peptide oligomer into a nanosheet layer, using the nanosheet layer for modifying the glass-based microfluidic chip, and further using GPTMS and 12-mercaptododecanoic acid to form covalent bonds with the peptoid oligomer nanosheet layer through reaction. The mode effectively reduces the nonspecific adsorption on the surface of the chip, provides the coupling groups of the antibody and the micromolecule, further improves the detection sensitivity and accuracy of the microfluidic chip, and provides a new choice for in vitro diagnosis. In addition, the modification method is simple, high in efficiency and low in manufacturing cost.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below, and it is apparent that the drawings in the following description only relate to some embodiments of the present invention and are not limiting on the present invention.
FIG. 1 is a schematic diagram of a method for synthesizing a peptide-like oligomer according to an embodiment of the present invention;
fig. 2 is a schematic diagram of a forming process of a two-dimensional nanosheet material according to an embodiment of the present invention;
FIG. 3 is a fluorescence microscope image of a two-dimensional nanosheet layer provided in accordance with an embodiment of the present invention;
fig. 4 is a flowchart illustrating a process of performing an epoxy modification on a chip surface according to an embodiment of the present invention;
FIG. 5 is a schematic structural diagram of a surface modification and functional layer of a glass-based chip according to an embodiment of the present invention;
FIG. 6 is a graph showing the reduction of nonspecific binding signals for chip surface modification according to an embodiment of the present invention; and the number of the first and second groups,
FIG. 7 is a graph showing the results of affinity detection for Alzheimer's disease biomarker A β 42, according to an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The use of "first," "second," and similar terms in this disclosure is not intended to indicate any order, quantity, or importance, but rather is used to distinguish one element from another. The word "comprising" or "comprises", and the like, means that the element preceding the word covers the element listed after the word and its equivalent, but does not exclude other elements.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The SPRi instrument in the following examples is Plexar Kx5V2, Plexar Bioscience LLC, USA, which is mainly equipped with a 660nm LED light source, a CCD image collector and a sensor chip with a microfluidic channel, displays the intensity of reflected light at each monitoring point as a function of time and records it as an SPR curve.
As used herein, "nM" means "nmol/L" and "mM" means "mmol/L", unless otherwise specified.
The peptoid molecule has the characteristics of low immunogenicity, good tissue permeability, high stability, easy modification, low manufacturing cost and the like. However, in the application of molecular probes, the binding capacity of the peptoid micromolecules and the biosensor is not strong, so that the peptoid micromolecules cannot be used as probe molecules; the antibody has the characteristic of being tightly combined with the biosensor, but the arrangement direction of antibody molecules is random and difficult to control on the surface of the sensor, so that the specificity of the antibody is low, and the cost of the antibody is high. The inventor of the present disclosure finds that an oligomer formed by a peptoid small molecule and an antibody can well combine the peptoid small molecule and the antibody, that is, the peptoid oligomer has the characteristic that the antibody can be tightly combined with a biosensor, and can orderly form the peptoid small molecule on the surface of the sensor. In addition, the molecular probe formed by the oligomer has strong affinity with a target, and the oligomer can not be subjected to enzymolysis, so that the activity of a natural living sample can be ensured.
Compared with polypeptide, polypeptide (peptoid) takes alpha amino acid as a structural unit, and polypeptide (peptoid) takes N-substituted glycine as a structural unit. The peptoid compound has good biological activity and pharmacological properties, can effectively detect or inhibit deterioration in vivo experiments, and has good cell membrane penetrability. At present, mature peptide-like synthesis technology is known as "subunit synthesis" technology.
At least one embodiment of the present disclosure further provides a peptide-like oligomer, wherein the molecular structural formula of the oligomer is:
wherein, n1 is more than or equal to 10 and more than or equal to 3, n2 is more than or equal to 3, n1 is equal to n2, and n1 and n2 are natural numbers.
For example, the oligomer comprises: beta-phenylethylamine subunit, 3-aminopropionic acid subunit, and ethylenediamine subunit.
For example, the structural formula of each subunit is as follows:
for example, in at least one embodiment of the present disclosure, the oligomer comprises subunits arranged in the following order: [ beta-phenylethylamine subunit-3-aminopropionic acid subunit]n2-probe- [ beta-phenylethylamine subunit-ethylenediamine subunit]n1。
At least one embodiment of the present disclosure further provides a method for preparing an oligomer, which comprises synthesizing the subunit by a solid phase synthesis method.
For example, fig. 1 is a flow chart of a method for preparing a peptoid oligomer according to an embodiment of the present disclosure, the method comprising the following steps:
step S1: ligating the first subunit of the oligo to a solid support in the order of ligation of the subunits of the oligo;
step S2: reacting bromoacetic acid with an amino group of a first subunit attached to a solid support under activation by an activator to form an amide bond;
step S3: reacting the donor of the second subunit of the peptoid oligomer with the product obtained in step S2 to replace bromine atoms and complete the connection of the second subunit;
step S4: repeating bromoacetic acid and subsequent subunit ligation until all subunit ligations are completed;
step S5: and (3) cracking the synthesized oligomer from the solid phase carrier to obtain the peptide oligomer.
For example, the oligomer comprises the auxiliary chains formed by the left and right peptoid compounds, and also comprises various probes embedded in the peptoid compounds for detection, wherein the left auxiliary chain comprises amino groups, and the right auxiliary chain comprises carboxyl groups, and the auxiliary chains are helpful for the oligomer to form a two-dimensional layered structure, so that the middle probe is exposed on the surface of the sensor to detect various targets, and the auxiliary chains can further enable the oligomers to be arranged more orderly.
For example, in this oligomer, n1 ═ n2 ═ 3, n1 ═ n2 ═ 4, n1 ═ n2 ═ 6, n1 ═ n2 ═ 8, or n1 ═ n2 ═ 10.
It should be noted that when n1 and n2 are less than 3, the chain length is too short to assemble; when n1 and n2 are greater than 10, the formed chain is too long, the density of peptoid compounds inserted in the middle of the oligomer is too low, and affinity weakening occurs, so that specific binding to the target molecule cannot be achieved.
Example 1
The molecular structure is as follows:
the preparation method of the oligomer with n1 ═ n2 ═ 4, n1 ═ n2 ═ 6 or n1 ═ n2 ═ 8 specifically comprises the following steps:
(1) rink amide AM resin (starting resin for polypeptide synthesis, substitution level 0.3mmol/g) was swollen and deprotected with piperidine, and β -phenylethylamine was equimolar mixed with 1-hydroxybenzotriazole and coupled under activation of N-methylmorpholine.
(2) Adding 10mL of 2mol/L bromoacetic acid and 10mL of 3.2mol/L N, N' -Diisopropylcarbodiimide (DIC) into Rink amide AM resin, reacting at 38 deg.C for 30min, and acylating the amino group at the end of the resin;
(3) adding 2mol/L primary amine to react for 90min at 37 ℃, and replacing bromine atoms through nucleophilic substitution reaction to complete the synthesis of a subunit;
(4) repeating the steps (2) and (3) until the synthesis of the rest units is completed;
(5) after the synthesis is finished, the side chain protecting group is removed, and the oligomer is cracked from the resin by using trifluoroacetic acid with the mass percentage of 95%, ultrapure water with the mass percentage of 2.5% and triisopropylsilane with the mass percentage of 2.5% for standby.
In the process of forming the oligomer of the above structure, the subunit input sequence is:
beta-phenylethylamine, 3-aminopropionic acid, beta-phenylethylamine, 3-aminopropionic acid; beta-phenylethylamine, 3-aminopropionic acid, beta-phenylethylamine, 3-aminopropionic acid; beta-phenylethylamine, 3-aminopropionic acid, beta-phenylethylamine, 3-aminopropionic acid; beta-phenylethylamine, 3-aminopropionic acid, beta-phenylethylamine, 3-aminopropionic acid; amine acetate, butanediamine, alpha-methylbenzylamine, butanediamine, isobutylamine, piperonylamine, butanediamine; beta-phenylethylamine, ethylenediamine, diphenylethylamine, ethylenediamine; beta-phenylethylamine, ethylenediamine, diphenylethylamine, ethylenediamine; beta-phenylethylamine, ethylenediamine, diphenylethylamine, ethylenediamine; beta-phenylethylamine, ethylenediamine, diphenylethylamine and ethylenediamine.
For example, the oligomer can be dissolved in a ratio of the amount of the substance to the amount of dimethyl sulfoxide: 2:1 dimethyl sulfoxide (DMSO) and water (H)2O) was added to the mixed solution so that the concentration thereof was 2 mM.
The embodiment of the invention provides a preparation method of a two-dimensional nanosheet layer material, which specifically comprises the following steps:
(1) the peptoid oligomer is distributed on a gas-liquid interface through amphipathy;
(2) lateral pressure is applied to the quasi-peptide oligomer molecular chain to form a compact monomolecular layer;
(3) by further increasing the lateral applied pressure to the critical point, the monolayer collapses into an aqueous solution to form a bilayer.
For example, fig. 2 is a schematic diagram of a process for forming a two-dimensional oligomer according to an embodiment of the disclosure, and as shown in fig. 2, the process for forming a two-dimensional oligomer includes: placing an oligomer provided by the embodiments of the present disclosure in a langmuir trough, wherein the oligomer comprises a hydrophilic end and a hydrophobic end, and the oligomer is randomly arranged at an interface of gas and liquid without external force; then applying an external force to the oligomers which are arranged in a disordered way, wherein the oligomers are arranged in an orderly way at a gas-liquid interface; further, an external force is applied to the orderly arranged oligomers, the oligomers are squeezed to below the gas-liquid interface, under which the hydrophilic end is exposed to the outside and the hydrophobic end is formed on the inside, thereby forming a two-dimensional structure.
The oligomer nanosheet layer is formed as follows: the oligomer obtained in the first example above at a concentration of 2mM was dissolved in a solution containing 10mM 4-hydroxyethylpiperazine ethanesulfonic acid and 100mM sodium chloride at pH 8.0, diluted to a final concentration of 1 to 100 μ M, for example, 20 μ M, and then shaken by hand: the peptoid solution is stored stably for 22 hours at room temperature, then manually and lightly shaken for 30 seconds, then stabilized for 1 minute, and the shaking-stabilizing process is repeated for 5 times; or machine shaking method: the peptoid solution was slowly spun in the tube from horizontal to vertical (0.6rpm), once every 450 seconds; the obtained peptide-like nanosheet solution was added to nile red to a final concentration of 1 μ M, and the solution was placed on 1% agar and observed using a fluorescence microscope (vert. a1, Carl Zeiss Far East, Germany), with the result that a distinct nanosheet structure could be observed as shown in fig. 3.
The microfluidic chip is used for biomedical detection and diagnosis, and in addition to the fact that non-specific binding is one of the most main factors causing false positive or false negative, the shielding of non-specific adsorption has great scientific research and commercial significance. Although the traditional blocking reagents such as BSA, ethanolamine and the like can reduce part of non-specific binding, the effect is not ideal, and especially for targets with extremely low content, the requirements on sensitivity and specificity are more strict, so that the improvement of the sensitivity and specificity of detection by the chip surface modification technology has extremely important scientific significance.
The embodiment of the disclosure provides a complete functional molecular layer formed by three steps of reaction of 3-glycidyl ether oxygen propyl methyl diethoxy silane (GPTMS) and 12-mercapto dodecanoic acid, and the surface modification of the glass chip is completed by combining the peptide-like nano-sheet layer in a covalent connection mode.
Wherein, GPTMS structural formula is:
the structural formula of the 12-mercaptododecanoic acid is as follows:
as shown in fig. 4, the main steps of performing epoxy modification on the surface of the glass chip of the present invention are as follows:
(1) in an aqueous solution system, the methyl of GPTMS and water molecules undergo hydrolysis reaction to generate Si-OH;
(2) GPTMS molecules containing Si-OH and Si-OH on the surface of the glass chip are subjected to condensation reaction to form Si-O-Si bonds.
Performing dense monomolecular layer modification on the epoxy-modified glass chip by using 12-mercaptododecanoic acid to effectively seal the surface of the chip and provide-COOH required for coupling of the peptide-like nanosheets, and the method comprises the following specific steps of:
(1) placing the chip modified by the epoxy in pure water for fully cleaning;
(2) placing the chip in an aqueous solution of 1M 12-mercaptododecanoic acid for sufficient reaction for 24 hours to form a dense monomolecular layer;
(3) the chip was washed with 10 XPBS, 1 XPBS, and ultra pure water for use.
Functional layer modification is performed on the nanosheet layer assembled by the peptoid oligomer with the probe to form a complete chip structure, as shown in fig. 5, the specific steps are as follows:
(1) sequentially carrying out deep cleaning on the epoxy modified and sealed chip by using 10 multiplied by PBS, 1 multiplied by PBS and ultrapure water;
(2)1:1 adding EDC/NHS for carboxyl activation;
(3) and (4) carrying out peptide-like nanosheet layer spotting, fully incubating overnight, and then cleaning the chip.
The chip structure is as shown in fig. 5, and comprises an oligomer nanosheet layer, a GPTMS and 12-mercaptododecanoic acid modified functional molecular layer, a structural layer, a PVX layer, a Gate (integrated circuit layout) layer and a glass substrate layer from top to bottom in sequence. Wherein the structural layer, the PVX layer, the Gate layer and the glass substrate layer are basic structures of the biochip.
The oligomer provided by the embodiment of the disclosure has a simple synthesis process and strong binding capacity with A beta 42, and has extremely high affinity to modify the surface of a glass-based chip, so that the capture of the A beta 42 can be effectively realized, and further, the blood diagnosis of the Alzheimer disease can be realized.
For example, FIG. 6 is a graph showing the results of non-specific binding signals with time for chips according to examples and comparative examples of the present invention, wherein bio-chip is a chip comprising peptoid oligomers and a layer of modified functional molecules according to the above examples of the present invention, and control is a chip comprising peptoid oligomers without GPTMS and 12-mercaptododecanoic acid. It can be seen that the modified chip greatly reduces non-specific binding signals and improves specificity and signal-to-noise ratio. The test steps for the reduction of the nonspecific binding signal after the modification of the chip by using a microplate reader are as follows:
(1) carrying out deep cleaning on the modified chip by using 10 multiplied by PBS, 1 multiplied by PBS and ultrapure water in sequence;
(2)1:1 adding EDC/NHS for carboxyl activation;
(3) carrying out peptide-like nanosheet layer spotting, fully incubating overnight, cleaning the chip, and using the chip directly coated with the probe and the chip sealed by 2.5% BSA and 5% ethanolamine as a control;
(4) FITC-HSA in PBS was dispensed, and the fluorescence signal was collected every minute by feeding the test chip and the control chip of step (3) at a flow rate of 2. mu.L/s.
For example, the procedure of testing the binding ability between the oligomer and the A beta 42 by using the surface plasmon resonance imaging technology is as follows:
(1) dissolving oligomer-assembled nanosheets into ddH2O to an oligomer concentration of 1-1000. mu.M;
(2) dropping the oligomer solution on the surface of a sealed chip modified by epoxy, repeating 3 points for each sample, placing the chip at 4 ℃ for 12 hours, sequentially cleaning the chip by using 10 XPBS, 1 XPBS and ultrapure water, sealing the chip by using 1M hydrochloric acid aminoethanol for 30 minutes, cleaning the chip by using the ultrapure water for 5 times, and finally drying the chip by using nitrogen;
(3) installing the chip on an SPRi instrument, measuring an SPRi angle, adjusting to an optimal optical position, selecting related detection points including a sample point and a blank point in a detection area, and setting the experiment flow rate to be 3 mu L/s;
(4) PBS is selected as a buffer solution to be filled into a flow cell until a base line is stable, and then detection is sequentially carried out by the concentration of 5.68nM, 11.4nM, 22.8nM, 45.6nM and 91.2nM, the combination time is 300 seconds, the dissociation time is 300 seconds, and phosphoric acid is filled into each concentration for regeneration.
For example, fig. 7 is a graph of the resonance detection results of the surface plasmon resonance detection of oligomers and abeta 42 bound at concentrations of 5.68nM, 11.4nM, 22.8nM, 45.6nM and 91.2nM, respectively, in example one of the present disclosure, wherein a.u. represents the binding signal of the mobile phase after passing through the array minus the baseline signal of the initial PBS buffer, the curve is the test result of PlexArray HT, and the fitted straight line is obtained by biaevaluation 4.1, and from top to bottom, the test line of 91.2nM, the test line of 45.6nM, the test line of 22.8nM, the test line of 11.4nM and the test line of 5.68nM are sequentially. U. is a unit used to reflect the binding signal intensity in surface plasmon resonance imaging, and is a dimensionless unit. The equilibrium dissociation constant KD is 1.57X 10 by fitting-10Mole/liter, indicating that the probed peptoid nanosheets have a relatively high level of affinity for Α β 42.
For example, the oligomer is a two-dimensional nanosheet material, which enables the oligomer to be coupled to the sensor and display the peptoid oligomer with affinity on the surface of the sensor.
Two-dimensional peptide-like nanomaterials play increasingly important roles in biology and electronics, such as sensing, template growth and filtration, and testing proteins as mimetics for their molecular recognition and catalytic ability. Langmuir trough experimental apparatus revealed that the formation of the peptoid nanosheet is an unusual thermodynamic equilibrium process of self-assembly of a peptoid molecule and conversion of external mechanical energy into chemical energy of the peptoid molecule.
For example, the pharmaceutical composition further comprises: the peptoid oligomer of any one of the above; and pharmaceutically acceptable adjuvants.
For example, the excipients include any one or a combination of at least two of excipients, diluents, carriers, flavoring agents, binders and fillers.
For example, the excipient may be, for example, an emulsion or oily suspension, or polyalkylene glycols such as polypropylene glycol.
The embodiment of the invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. Has at least one of the following beneficial effects:
(1) in the peptide-like nanosheet layer provided in at least one embodiment of the present disclosure, the peptide-like nanosheet layer with the probe has a strong binding ability with the target molecule, and the equilibrium dissociation constant KD in the kinetic constants of binding of the nanosheet layer with the target molecule, obtained by the surface plasmon resonance technique, is 10-10On the order of moles/liter;
(2) in the chip modification technology provided by at least one embodiment of the present disclosure, chip epoxidation and carboxylation can be effectively performed;
(3) in the chip modification technology provided by at least one embodiment of the present disclosure, the chip based on the modification technology can effectively reduce the nonspecific binding to substances other than the target;
(4) the synthetic method of the peptoid oligomer provided by at least one embodiment of the disclosure is simple, the preparation efficiency is high, and the preparation cost is low;
(5) the assembling method of the peptide-like nano-sheet layer provided by at least one embodiment of the disclosure is simple, the preparation efficiency is high, and the manufacturing cost is low.
The following points need to be explained:
(1) the drawings of the embodiments of the invention only relate to the structures related to the embodiments of the invention, and other structures can refer to common designs.
(2) The thickness of layers or regions in the figures used to describe embodiments of the invention may be exaggerated or reduced for clarity, i.e., the figures are not drawn on a true scale.
(3) Without conflict, embodiments of the present invention and features of the embodiments may be combined with each other to arrive at new embodiments.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and the scope of the present invention should be subject to the scope of the claims.
Claims (10)
1. A peptide-like oligomer comprising: beta-phenylethylamine subunit, 3-aminopropionic acid subunit, and ethylenediamine subunit.
2. The peptoid oligomer of claim 1, wherein the peptoid oligomer has a structure represented by formula I:
wherein, n1 is more than or equal to 10 and more than or equal to 3, n2 is more than or equal to 3, n1 is equal to n2, and n1 and n2 are natural numbers.
3. A method of preparing a peptoid oligomer as described in claim 1 or 2, wherein the method comprises a solid phase synthesis method.
4. The method of manufacturing according to claim 3, comprising the steps of:
(1) ligating the first subunit of the peptoid oligomer to a solid support according to the order of ligation of the subunits of the peptoid oligomer;
(2) reacting bromoacetic acid with an amino group of the first subunit attached to the solid support under activation by an activator to form an amide bond;
(3) reacting a donor of a second subunit of the peptoid oligomer with the product obtained in the step (2) to replace bromine atoms and complete the connection of the second subunit;
(4) repeating the connection of the bromoacetic acid and the subsequent subunits until the connection of all subunits is completed;
(5) and (3) cracking the synthesized peptoid oligomer from the solid phase carrier to obtain the peptoid oligomer.
5. A pharmaceutical composition, comprising: the peptoid oligomer of claim 1 or 2; and pharmaceutically acceptable adjuvants.
6. The pharmaceutical composition of claim 5, wherein the excipient is any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, and a filler.
7. Use of the pharmaceutical composition of claim 5 or 6 for the manufacture of a medicament for detecting or diagnosing a disease associated with alzheimer's disease.
8. Use of the pharmaceutical composition of claim 5 or 6 for the preparation of a chip for detection or diagnosis.
9. Use according to claim 8, wherein the chip is a microfluidic chip.
10. A microfluidic chip comprising the oligomer nanosheet layer of claim 1 or 2 and a functional layer comprising GPTMS-directed epoxy modification and 12-mercaptododecanoic acid-directed blocking activation layer modification.
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