CN114292332B - Gold nanoparticle-based artificial antibody for specifically targeting MDM2 protein and application thereof - Google Patents
Gold nanoparticle-based artificial antibody for specifically targeting MDM2 protein and application thereof Download PDFInfo
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- CN114292332B CN114292332B CN202111596238.1A CN202111596238A CN114292332B CN 114292332 B CN114292332 B CN 114292332B CN 202111596238 A CN202111596238 A CN 202111596238A CN 114292332 B CN114292332 B CN 114292332B
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- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 title claims abstract description 48
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 title claims abstract description 48
- 229910052737 gold Inorganic materials 0.000 title claims abstract description 47
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000010931 gold Substances 0.000 title claims abstract description 45
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 41
- 230000008685 targeting Effects 0.000 title claims abstract description 11
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 44
- 229920001184 polypeptide Polymers 0.000 claims abstract description 38
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 38
- 239000012634 fragment Substances 0.000 claims description 15
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- 230000027455 binding Effects 0.000 description 10
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- 238000000034 method Methods 0.000 description 4
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- 238000000978 circular dichroism spectroscopy Methods 0.000 description 3
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- 238000012827 research and development Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 230000033616 DNA repair Effects 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
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- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
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- Peptides Or Proteins (AREA)
Abstract
The invention discloses an artificial antibody of a specific targeting MDM2 protein based on gold nanoparticles and application thereof, wherein the artificial antibody is composed of gold nanoparticles and a section of specially designed polypeptide sequence, the synthesized nano-gold artificial antibody can specifically recognize MDM2 protein, and the polypeptide can stabilize the natural conformation of a natural protein p53 after being grafted on the gold nanoparticles in a regulating and controlling way. The artificial antibody aims at being capable of specifically acting with MDM2 protein and realizing the same cancer inhibiting capability as the natural p53 protein, so that the artificial antibody has potential application value in MDM2 analysis and detection and cancer treatment.
Description
Technical Field
The invention relates to the field of biomedicine, and particularly provides a gold nanoparticle-based specific targeting MDM2 protein artificial antibody, and preparation and application thereof, wherein the prepared and synthesized nano-gold artificial antibody can specifically identify MDM2 protein, and the polypeptide can reconstruct and stabilize the alpha-helix conformation of a natural protein p53 by regulating and grafting on gold nanoparticles.
Background
In order to endow the nano-particles with biomedical functions, a common method for solving the problem is to covalently modify some functional groups on the nano-particles, but to covalently modify nonfunctional groups on the nano-particles for reconstructing functions and conformations, which cannot be realized at present. The design method of conformational engineering disclosed in the patent documents with publication numbers CN105884888A and CN106699890a can graft non-functional groups onto nanoparticles and complete reconstruction of conformations and functions, but the polypeptide fragment is a fragment containing only a single element of Loop region, and does not contain an alpha-helical conformation, and it is unclear whether the technology can be applied to conformational reconstruction of alpha-helical polypeptides.
p53 is one of the most widely studied oncogenes, the p53 protein acting as a keeper of the genome in cells, as it contributes to the integrity of the genome. Tumor suppressor protein p53 acts as a transcription factor to induce the expression of several downstream targets, which have great roles in regulating cell cycle, apoptosis, DNA repair, cell senescence, and other cellular mechanisms. Normal intracellular p53 maintains equilibrium with the target protein MDM 2; however, in many tumor cells, MDM2 is overexpressed. The p53 protein can be released by introducing the inhibitor specifically combined with the MDM2 to play a role in inhibiting the growth of tumors, so that the research and development of the inhibitor specifically combined with the MDM2 is an important direction for the research and development of tumor therapeutic drugs at present.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to overcome the defects in the prior art and provide an artificial antibody for specifically targeting MDM2 protein based on gold nanoparticles and application thereof, the artificial antibody synthesized by the invention can specifically target MDM2, can realize the same cancer inhibition capability as that of natural p53 protein, and can reconstruct and stabilize the alpha-helical conformation of the natural protein p53 by modulating and grafting polypeptide on the gold nanoparticles through a conformation engineering technology. The artificial antibody reduces steric hindrance when the gold nanoparticles bind polypeptide and MDM2 protein, so that the formed artificial antibody has stronger binding force with MDM2 protein.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an artificial antibody of a specific targeting MDM2 protein based on gold nanoparticles is used as a nano-gold artificial antibody for specifically recognizing the MDM2 protein, and consists of gold nanoparticles and conformationally controlled polypeptide fragments, wherein the polypeptide fragments comprise alpha-helix and Loop region mixed structural elements.
Preferably, both ends of the polypeptide are grafted to the surface of the gold nanoparticle by using Au-S bond, every 1nm 2 And fixing 0.05-3 polypeptides on the surface of the gold nanoparticle, and utilizing the fluidity of gold atoms to enable polypeptide chains to be in proper space positions, thereby constructing an alpha-helical conformational structure.
Further preferred, the polypeptide sequence is SP20: LSQETFCDLWKLLCEN or SP30: SQDTFSCLWCLLPEN or SP40: SQDTFSCLWACLPEN.
According to the invention, an alpha-helix fragment on p53 protein is selected, two cysteines are respectively introduced at the positions i and i+7 (SP 20), i and i+3 (SP 30) and i and i+4 (SP 40) on the basis of the original amino acid sequence LSQETFSDLWKLLPEN according to the rule that each 3.6 amino acid residues in the alpha-helix structure are spirally increased by one circle, and a new polypeptide sequence is designed: SP20, SP30 and SP40; and utilizing sulfhydryl groups of cysteine and gold atoms to form Au-S bonds, grafting two ends of the polypeptide to the surfaces of gold nanoparticles, and performing conformation regulation. Meanwhile, the selection principle of the site i is that the site i is far away from the binding interface of the polypeptide and MDM2, so that the steric hindrance of the gold nanoparticle is reduced as much as possible, and the synthetic artificial antibody has stronger binding force with MDM2 protein.
The invention relates to an application of an artificial antibody based on gold nanoparticles and specifically targeting MDM2 protein, wherein the artificial antibody of MDM2 protein can specifically identify MDM2 protein, and the application of the artificial antibody of MDM2 protein in an analysis and detection method of MDM2 protein or in a medicament for treating cancers.
Compared with the prior art, the invention has the following obvious prominent substantive features and obvious advantages:
1. the invention refers to the design method of conformational engineering disclosed in patent documents with publication numbers CN105884888A and CN106699890A, a nonfunctional group can be grafted on the nanoparticle, and reconstruction of conformation and function is completed, but the invention is different from the method in that the designed fragment is a fragment containing mixed elements of alpha-helix and Loop region, but not only the Loop region;
2. the polypeptide of the invention has no structure when independently existing, but through redesigning the fragment, the two ends of the polypeptide are grafted to the surface of gold nano particles by utilizing the Au-S bond formed by the sulfhydryl group of cysteine and the gold atom, the polypeptide chain is positioned at a proper space position by utilizing the fluidity of the gold atom, so that the alpha-helical conformation of the polypeptide is restored, and the prepared synthetic artificial antibody can replace the p53 protein to be specifically combined with MDM2, thereby having potential application value in cancer treatment.
Drawings
FIG. 1 is a schematic diagram of an artificial antibody of MDM2 protein based on gold nanoparticles.
FIG. 2 is a schematic representation of the conformational reconstruction of the artificial antibody AuNP-SP20 according to the preferred embodiment.
FIG. 3 is a preferred embodiment for characterizing the conformational reconstitution of the artificial antibody AuNP-SP 30.
FIG. 4 is a preferred embodiment for characterizing the conformational reconstitution of the artificial antibody AuNP-SP 40.
FIG. 5 is a graph showing the specific binding properties of the artificial antibodies AuNP-SP20 and AuNP-SP40 to MDM2 according to the preferred embodiment.
Detailed Description
Examples are given below to further illustrate the invention. It should be noted that the following examples should not be construed as limiting the scope of the present invention, and if those skilled in the art make some insubstantial modifications and adjustments to the present invention, such as partial adjustments or mutations to the designed polypeptide sequences, adjustments to the particle size or shape of gold nanoparticles, etc., based on the above disclosure, the present invention still falls within the scope of the present invention.
The foregoing aspects are further described in conjunction with specific embodiments, and the following detailed description of preferred embodiments of the present invention is provided:
in this embodiment, an artificial antibody of specific targeting MDM2 protein based on gold nanoparticles is composed of gold nanoparticles and a segment of polypeptide fragment, which is used as a nano-gold artificial antibody for specifically recognizing MDM2 protein, wherein the fragment contains a fragment of mixed elements of alpha-helix and Loop region.
1. Design of polypeptide fragments
According to the region of the p53 protein that binds to MDM 2: the alpha-helical fragment of 15-29 amino acids mutates part of amino acids into cysteine, and the two cysteines form Au-S bonds with gold atoms of gold nanoparticles to graft onto the gold nanoparticles, so that polypeptide SP20 is designed: LSQETFCDLWKLLCEN, SP30: SQDTFSCLWCLLPEN, SP40: SQDTFSCLWACLPEN.
2. Preparation of anti-MDM 2 artificial antibodies
According to the gold nanoparticle area of 1nm 2 Fixing the proportion of 0.05-3 polypeptides, grafting the polypeptides on the surface of the nano gold ball through Au-S bond, thereby obtaining the anti-MDM 2 artificial antibody.
3. Conformational reconstruction of artificial antibody AuNP-SP20
To demonstrate the conformational reconstruction of the artificial antibodies, we examined the structure of the pure peptide SP20, auNP-SP20 and AuNP-SP20-TFE by circular dichroism spectroscopy, as shown in FIG. 2, pure peptide SP20 had no structure, and AuNP-SP40-TFE had structure, because SP20 was restored to its original conformation after grafting to AuNP. TFE is a typical alpha-helix inducer, and conformation after TFE induction can be used as a positive control, and the conformation change before and after TFE induction is small for an artificial antibody AuNP-SP20, so that the success of polypeptide conformation reconstruction is indicated.
4. Conformational reconstruction of artificial antibody AuNP-SP30
To demonstrate the conformational reconstruction of the artificial antibody, we examined the structure of the pure peptide SP30, auNP-SP30 and AuNP-SP30-TFE by circular dichroism spectroscopy, as shown in FIG. 3, the pure peptide SP30 had no structure, and the AuNP-SP30 and AuNP-SP30-TFE had structure, because the original conformation was restored after grafting of SP30 to AuNP. TFE is a typical alpha-helix inducer, and conformation after TFE induction can be used as a positive control, and the conformation change before and after TFE induction is small for an artificial antibody AuNP-SP30, so that the success of polypeptide conformation reconstruction is indicated.
5. Conformational reconstruction of artificial antibody AuNP-SP40
To demonstrate the conformational reconstruction of artificial antibodies, we examined the structure of pure peptide SP40, auNP-SP40, and AuNP-SP40-TFE by circular dichroism spectroscopy, as shown in FIG. 4, pure peptide SP40 had no structure, and AuNP-SP40-TFE had structure, because SP40 was grafted to AuNP, restoring its original conformation. TFE is a typical alpha-helix inducer, and conformation after TFE induction can be used as a positive control, and the conformation change before and after TFE induction is small for an artificial antibody AuNP-SP40, so that the success of polypeptide conformation reconstruction is indicated.
6. Characterization of specific binding Properties of Artificial antibodies AuNP-SP20 and AuNP-SP40 to MDM2
In order to characterize the specific binding capacity of the artificial antibodies AuNP-SP20 and AuNP-SP40 to MDM2, the present invention measured the binding of AuNP-SP20 and AuNP-SP40, auNP-SP40m to MDM2, and as shown in FIG. 5, it can be seen that the binding of the AuNP-SP40 artificial antibody to MDM2 was strongest, and that the AuNP-SP20 artificial antibody was second, because SP40 was grafted to the gold nanoparticle surface at a different angle from SP20, resulting in that the steric hindrance was smaller than SP20 when the polypeptide SP40 on the gold nanoparticle surface bound to the MDM2 protein, and thus the binding force was stronger than SP 20. AuNP-SP40m was single-headed anchored to the gold nanoparticle surface as a control group, and was weak in binding compared to the other two artificial antibodies, indicating that we designed the synthetic artificial antibodies AuNP-SP20 and AuNP-SP40 to specifically recognize MDM2 protein. Because the gold antibody designed by the embodiment has strong binding force with protein, is not easy to dissociate, and the chip is not completely regenerated, the binding error of each AuNP-SP20, auNP-SP40 and protein MDM2 is larger, and the AuNP-SP40m gold antibody and the MDM2 protein are non-specifically bound, the binding value is small, and the dissociation is easy, so the error is small.
The embodiment is based on the artificial antibody of the specific targeting MDM2 protein of the gold nano particles, and the preparation and the application thereof. The artificial antibody is composed of gold nanoparticles and a section of specially designed polypeptide sequence, the synthesized nano-gold artificial antibody can specifically identify MDM2 protein, and the polypeptide can stabilize the natural conformation of natural protein p53 by regulating grafting on the gold nanoparticles. The artificial antibody aims at being capable of specifically acting with MDM2 protein and realizing the same cancer inhibiting capability as the natural p53 protein, so that the artificial antibody has potential application value in MDM2 analysis and detection and cancer treatment.
The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the embodiments described above, and various changes, modifications, substitutions, combinations or simplifications made under the spirit and principles of the technical solution of the present invention can be made according to the purpose of the present invention, and all the changes, modifications, substitutions, combinations or simplifications should be equivalent to the substitution, so long as the purpose of the present invention is met, and all the changes are within the scope of the present invention without departing from the technical principles and the inventive concept of the present invention.
Claims (2)
1. An artificial antibody of specific targeting MDM2 protein based on gold nano particles is characterized in that: the nano-gold artificial antibody for specifically recognizing MDM2 protein consists of gold nano-particles and conformationally controlled polypeptide fragments, wherein the polypeptide fragments comprise alpha-helix and Loop region mixed structural elements;
grafting two ends of polypeptide onto gold nanoparticle surface with Au-S bond at each 1nm 2 Fixing 0.05-3 polypeptides on the surface of the gold nanoparticle, and utilizing the mobility of gold atoms to enable polypeptide chains to be in proper space positions, so as to construct an alpha-helical conformational structure;
the polypeptide sequence is SP20: LSQETFCDLWKLLCEN or SP40: SQDTFSCLWACLPEN.
2. Use of an artificial antibody specifically targeting MDM2 protein based on gold nanoparticles according to claim 1, characterized in that: the application is the application of the artificial antibody specifically recognizing the MDM2 protein in preparing a reagent for detecting the MDM2 protein.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884888A (en) * | 2016-04-14 | 2016-08-24 | 上海大学 | Artificial antibody construction method based on gold nanoparticles |
| CN110184265A (en) * | 2019-05-22 | 2019-08-30 | 上海大学 | The preparation method and applications of nano enzyme based on gold nanoparticle |
| CN112062841A (en) * | 2020-06-16 | 2020-12-11 | 上海大学 | Polypeptide, preparation method thereof, anti-p 53 protein artificial antibody and application thereof |
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- 2021-12-24 CN CN202111596238.1A patent/CN114292332B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884888A (en) * | 2016-04-14 | 2016-08-24 | 上海大学 | Artificial antibody construction method based on gold nanoparticles |
| CN110184265A (en) * | 2019-05-22 | 2019-08-30 | 上海大学 | The preparation method and applications of nano enzyme based on gold nanoparticle |
| CN112062841A (en) * | 2020-06-16 | 2020-12-11 | 上海大学 | Polypeptide, preparation method thereof, anti-p 53 protein artificial antibody and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Qi Liu et al..A Potential MDM2 Inhibitor Formed by Restoring the Native Conformation of the p53 α-Helical Peptide on Gold Nanoparticles.《ChemMedChem》.2022,第17卷第4页左栏第4段. * |
| 李博等.订书肽的合成与活性研究进展.《药学学报》.2017,第52卷(第5期),第688页第1.1.3节，第689页第1.2.1节. * |
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