CN114507270A - Targeted PD-L1 polypeptide, preparation method, nanotube formed by assembly and application - Google Patents
Targeted PD-L1 polypeptide, preparation method, nanotube formed by assembly and application Download PDFInfo
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- CN114507270A CN114507270A CN202210011286.8A CN202210011286A CN114507270A CN 114507270 A CN114507270 A CN 114507270A CN 202210011286 A CN202210011286 A CN 202210011286A CN 114507270 A CN114507270 A CN 114507270A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a targeted PD-L1 polypeptide, a preparation method, an assembled nanotube and application, wherein the polypeptide has the following general formula: X1X2X3X4X5X6X7X8X9X 10; wherein X1, X2, X8, X9 and X10 are hydrophilic amino acids, X3 is basic or acidic amino acids, and X4, X5, X6 and X7 are hydrophobic amino acids; the polypeptide self-assembles to form a nanotube which can be used as a tumor treatment drug or an imaging reagent carrier and used for immune combination treatment and imaging of tumors; the polypeptide obtained by the invention is self-assembled to form a nanotube, and residues with recognition functions can be displayed on the surface of the nanotube, so that the polypeptide shows specific binding to PD-L1.
Description
Technical Field
The invention relates to the technical field of biological materials and medicines, in particular to a targeted PD-L1 polypeptide, a preparation method, an assembled nanotube and application.
Background
Malignant tumor seriously harms human health, and 1929 ten thousands of new cancers are discovered worldwide in 2020, and nearly 1000 thousands of cancers die. In recent years, with the rapid development of biological materials, immunology and other fields, the tumor immunization diagnosis and treatment has obtained great breakthrough. Unlike traditional chemotherapy, radiotherapy and surgical therapy, tumor immunotherapy kills tumor cells by activating the immune system of the human body, has many advantages of persistence, systematicness, pertinence, safety and the like, is known as the third revolution of cancer treatment, and is also considered as a new hope of overcoming tumors.
The tumor immunotherapy mainly comprises tumor vaccine, adoptive immune cell therapy and immune checkpoint therapy; among them, immune checkpoint therapy is a focus of attention. Immune checkpoints are a class of immunosuppressive molecules that reduce the intensity of the immune response and prevent over-immunization from damaging and destroying normal tissues. However, this mechanism is also used ingeniously in cancer development, resulting in immune escape by expressing immune checkpoint molecules on the surface of tumor cells. Immune checkpoint therapy is the process of killing tumor cells by using inhibitor molecules to bind to immune checkpoints, thereby blocking the binding of tumor cells to immune cells and activating immunity. Several immune checkpoints have now been discovered, such as cytotoxic T cell-associated protein-4 (CTLA-4), programmed death receptor (PD-1) and its ligand 1(PD-L1), T cell immunoglobulin and ITIM domain protein (TIGIT), and others. The therapy has been developed until now with a variety of inhibitor drugs on the market or in the clinical stage and has achieved satisfactory results. Such as ipilimumab and tremelimumab directed against CTLA-4 checkpoints, and pembrolizumab and nivolumab, and the like, which are PD-1 inhibitors.
At present, most of immune checkpoint inhibitors mainly use antibodies, the antibodies have the advantages of high inhibition efficiency, capability of remarkably prolonging the life cycle of tumor patients and the like, but the development of the inhibitors is limited by the defects of inherent immunogenicity, weak penetrating power, large side effect, low thermal stability, complex preparation, high price and the like.
Because PD-L1 participates in the process of generating and developing tumors and assists tumor cells to escape from the killing of the immune system of the body. Unlike conventional target proteins, PD-L1 has been a difficult point in inhibitor development due to its specific binding site. The polypeptide has the advantages of good biocompatibility, low immunogenicity, easy excretion and removal, chemical synthesis and the like, and plays a significant role in the development of immunosuppressive agents based on molecular recognition. In addition, different amino acids have unique physicochemical properties, such as chargeability, hydrophilicity and hydrophobicity, chirality and the like. The amino acid molecules with different properties can generate polypeptide chains containing abundant structural information and identification information according to different arrangement sequences and different residue numbers in the process of forming the polypeptide through dehydration condensation, which cannot be matched by other molecules. And the polypeptide shows strong superiority in the aspects of tumor immunity, diagnosis and the like by virtue of the advantages. The small molecule targeted polypeptide has the dilemma of univalent combination with a target spot, instability and easy enzyme degradation in a dynamic environment in vivo, and the polypeptide can form a supermolecular nanometer structure such as a nanometer tube, a nanometer fiber, a nanometer ball and the like through self assembly after being designed. The formation of the nano-assemblies greatly increases the enzymolysis resistance of the nano-assemblies on one hand, and on the other hand, the nano-assemblies can be used as carriers to efficiently carry anti-tumor drugs and imaging reagents to reach tumor sites to realize multi-method combined diagnosis and treatment. However, in the process of polypeptide self-assembly based on beta-sheet secondary structure, in order to form a stable self-assembly structure, polypeptide molecules are arranged in a manner of being perpendicular to the surface of the assembly body, so that the active sites of side chains are completely buried in the assembly body, and the structure-function connection cannot be established. In order to enable an assembly body to have a targeting function, the current common method is to splice a polypeptide unit with an identification function and a unit with an assembly function, and the assembly and identification are realized to a certain extent in this way, but the problem that the units cannot be coordinated exists; another way is to use a co-assembly method, in which the recognition sequence is designed to be longer than the assembly sequence, so that the recognition sequence is exposed outside the assembly body after co-assembly, but the method needs to strictly regulate the assembly density of the two polypeptides.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a targeted PD-L1 polypeptide which has high affinity to PD-L1 and can display residues with a recognition function on the surface of a nanotube formed by self-assembly, a preparation method, the nanotube formed by assembly and application.
The technical scheme adopted by the invention is as follows:
a targeted PD-L1 polypeptide having the general formula:
X1X2X3X4X5X6X7X8X9X10
wherein X1, X2, X8, X9 and X10 are hydrophilic amino acids, X3 is basic or acidic amino acids, and X4, X5, X6 and X7 are hydrophobic amino acids.
Further, X1 is one of threonine, serine, and cysteine; x2 is one of serine, glutamic acid, histidine and aspartic acid; x3 is one of lysine, arginine, glutamic acid, histidine and aspartic acid; x4 is one of phenylalanine, leucine and isoleucine; x5 is one of phenylalanine, tyrosine and glycine; x6 is one of leucine, valine, tryptophan, and phenylalanine; x7 is one of leucine, valine, tryptophan, and phenylalanine; x8 is one of serine, glycine and cysteine; x9 is one of asparagine and glutamine; x10 is one of lysine, glutamic acid, aspartic acid, histidine and arginine.
Further, the amino acid sequence of the polypeptide is: TSRFAAFSQK are provided.
Further, the amino acid sequence of the polypeptide is: TSRFVFFSQK are provided.
A polypeptide nanotube is formed by self-assembly of the polypeptide.
Furthermore, the thickness of the polypeptide nanotube wall is 2.4nm, and the polypeptide is assembled in an antiparallel manner by forming a beta-folding secondary structure in the self-assembly process; the active residues on both sides of the polypeptide chain are exposed at the surface of the nanotube.
A method of producing a polypeptide comprising the steps of:
taking resin as a solid phase carrier, and coupling the amino acid at each position to the carrier one by a mixed splitting method;
the polypeptide is cut off from the resin by lysate, separated and purified, and the needed polypeptide can be obtained.
The application of the polypeptide nanotube and the application of the polypeptide nanotube as a tumor treatment drug or an imaging reagent carrier.
Further, the tumor is a tumor positive for PD-L1 expression.
Further, the tumor is one of melanoma, non-small cell lung tumor, prostate tumor, colorectal tumor, pancreatic tumor, liver tumor, stomach tumor, esophageal tumor, breast tumor, and bile duct tumor.
The invention has the beneficial effects that:
(1) the polypeptide obtained by the invention has high affinity to PD-L1;
(2) the polypeptide obtained by the invention is self-assembled to form a nanotube, and residues with recognition functions can be displayed on the surface of the nanotube, so that the capacity of specifically binding PD-L1 and blocking PD-L1/PD-1 is shown;
(3) when the polypeptide obtained by the invention is self-assembled to form a nanotube, polypeptide molecules are inclined by about 40 degrees;
(4) the nanotube formed by self-assembly of the polypeptide has excellent capacity of loading antitumor drugs and imaging reagents, and can be used for immune combination therapy and imaging of tumors.
Drawings
FIG. 1 is a schematic diagram of a method for producing a polypeptide of the present invention.
FIG. 2 is a schematic diagram showing the mass spectrum and the HPLC purity of the polypeptide LY obtained in the present invention.
FIG. 3 is a schematic diagram of the affinity of polypeptide LY and nanotubes obtained by the present invention to PD-L1.
FIG. 4 is a schematic diagram showing the binding of the polypeptide obtained by the present invention to PD-L1.
FIG. 5 is a schematic diagram showing the binding of the polypeptide obtained by the present invention to MC38 and 293T cells.
FIG. 6 is a schematic diagram of nanotubes assembled by the polypeptide obtained by the present invention.
FIG. 7 is a schematic diagram of nanotubes obtained after 2 hours of sonication in an example of the present invention.
FIG. 8 is a schematic view of a circular dichroism spectrum of a nanotube formed by self-assembly of the polypeptide obtained by the present invention.
FIG. 9 is an SEM image of binding winding of the nanotubes formed by self-assembly of the polypeptide obtained by the invention on the surfaces of PD-L1 positive and PD-L1 negative cells.
FIG. 10 is a schematic diagram of a model mouse treated with the polypeptide nanotube drug of the present invention at different times.
Detailed Description
The invention is further described with reference to the following figures and specific embodiments.
A targeted PD-L1 polypeptide having the general formula:
X1X2X3X4X5X6X7X8X9X10
wherein X1, X2, X8, X9 and X10 are hydrophilic amino acids, X3 is basic or acidic amino acids, and X4, X5, X6 and X7 are hydrophobic amino acids.
X1 is one of threonine, serine and cysteine; x2 is one of serine, glutamic acid, histidine and aspartic acid; x3 is one of lysine, arginine, glutamic acid, histidine and aspartic acid; x4 is one of phenylalanine, leucine and isoleucine; x5 is one of phenylalanine, tyrosine and glycine; x6 is one of leucine, valine, tryptophan, and phenylalanine; x7 is one of leucine, valine, tryptophan, and phenylalanine; x8 is one of serine, glycine and cysteine; x9 is one of asparagine and glutamine; x10 is one of lysine, glutamic acid, aspartic acid, histidine and arginine.
The polypeptide is designed de novo based on the polypeptide with a Bola type structure, and the general formula of the polypeptide is shown as above. Wherein, four residues of X4, X5, X6 and X7 are hydrophobic residues, and form a hydrophobic core of the polypeptide. X1, X2, X3, X8, X9 and X10 are polar residues, and the whole molecule is symmetrical.
The synthetic polypeptides and the experimental instruments and materials used for the tests were as follows:
fluorescein Isothiocyanate (FITC), thioflavin T, 1 XPBS, 10 XPBS, skim milk, Tween-20, N-methylmorpholine, piperidine, trifluoroacetic acid (TFA), Dichloromethane (DCM), ninhydrin, vitamin C, phenol, tetramethyluronium Hexafluorophosphate (HBTU), piperidine, Triisopropylsilane (TIS), Ethanedithiol (EDT), N, N-Dimethylformamide (DMF), dehydrated ether, Tentagel resin, royal resin, cyanogen bromide, 20 Fmoc-amino acids, methanol, polypeptide synthesis tubes, shaker, cell incubator, Surface Plasmon Resonance Imager (SPRi), vacuum pump, rotary evaporator, confocal laser microscope (ZEISS LSM 710), scanning electron microscope, transmission electron microscope, atomic force microscope, all of which are commercially available.
Preparation of a solvent:
deprotection reagent-20% piperidine; the reaction solution-N-methylmorpholine, N-dimethylformamide: 1: 24. Lysate-trifluoroacetic acid (92.5%), triisopropylsilane (2.5%), ethanedithiol (2.5%), ultrapure water (2.5%);
The synthesis of peptide library is carried out by Fmoc solid phase synthesis, Tentagel resin is used as solid phase carrier, amino acid on each position is coupled to the carrier one by adopting a mixed splitting method, and finally peptide chain is cut off from the resin by strong acid and protective groups are removed, wherein the synthesis process is shown in figure 1.
0.2g of tentagel resin was weighed, cycled according to the above solid phase polypeptide synthesis procedure, according to amino acid: the resins are reacted one by one according to the mass ratio of 5:1, HBTU with the same amount as amino acid is added for coupling reaction, and ninhydrin color reagent is used for detection before and after the reaction. And finally, performing methanol replacement and shrinkage steps, and performing vacuum pumping to obtain dry resin for later use. The polypeptide is cut off from the resin by 95 percent TFA lysate, the polypeptide is precipitated by ethyl acetate, the obtained primary polypeptide is separated and purified by HPLC, and whether the synthesis is accurate or not is identified by mass spectrum.
Screening polypeptide with PD-L1 targeting property
After the peptide library synthesis was complete, the resin was collected, washed twice with 1 × PBS, blocked with 5% skim milk for 2 hours, and washed three times with PBS. Biotin-labeled PD-L1 protein was added, incubated at 37 ℃ for 2 hours, and then positive resin was selected using magnetic sorting. The polypeptides on the positive resin were cleaved with cyanogen bromide and the positive sequences were identified by second-order mass spectrometry using Maldi-TOF-MS. The polypeptide separated and purified by HPLC was identified by mass spectrometry to obtain a polypeptide sequence of TSRFAAFSQK (shown in SEQ ID NO: 1) designated as LY, which was synthesized by Fmoc solid phase synthesis and identified as pure as shown in FIG. 2. Identification of affinity of LY Polypeptides to PD-L1
The 1mg/mL polypeptide solution was printed on the chip, incubated overnight at 4 deg.C, and then washed 3 times with 10 XPBS, 3 times with 1 XPBS, and 2 times with ultrapure water. Blocked with 5% skim milk overnight, washed 3 times with 10 ×, 1 × PBS, and finally dried with nitrogen, mounted on a chip machine for testing. The mobile phase was a solution of PD-L1 in PBST at 192nM, 96nM, 48nM, 24nM, 12 nM. As shown in FIG. 3, the affinity of the finally obtained polypeptide for PD-protein was 2.6X 10- 8M, indicating a very high affinity.
Binding site of polypeptide LY on PD-L1 protein
The structure of polypeptide LY was generated using PEP-FOLD, the crystal structure of PD-L1 was obtained from the PDB database, and molecular docking and analysis were performed using the software ZDCK 3.0.2, the results are shown in FIG. 4. It can be seen from the figure that the polypeptide can be stably combined on a plane structure of PD-L1 contacted with PD-1, and the forces combined with PD-L1 mainly comprise hydrogen bonds, electrostatic interaction and pi-pi accumulation.
Selectivity of polypeptide LY at the cellular level for PD-L1-positive cells
The PD-L1 high expression colon cancer cell line MC38 uses 10% 1640 medium at a density of 1X 105The density of/mL was seeded in a confocal dish. Normal cells 293T were cultured in 10% DMEM medium at 1X 105The density of/mL was seeded in a confocal dish.
The cells were cultured at 37 ℃ under 5% carbon dioxide for 24 hours. The medium was discarded, 100. mu.L of FITC-LY solution prepared in serum-free medium was added, and incubated for 1 hour with exclusion of light. Then washed three times with 1 XPBS, 1 μ M Hoechst 3342 staining reagent, incubated for 15 minutes, washed three times with 1 XPBS, and observed the distribution of the polypeptide on both cells by confocal laser.
As a result, as shown in FIG. 5, there was bright fluorescence on the cell membrane of MC38 which is a PD-L1-positive cell, and no fluorescence was observed on 293T cells which are PD-L1-negative. The screened polypeptide LY has good targeting and selectivity to PD-L1 positive HMP.
Polypeptide LY is self-assembled to form nanotubes using the following method
The synthetically purified LY polypeptide was dissolved in hexafluoroisopropanol and incubated at room temperature for 6 hours, then the hexafluoroisopropanol was slowly evaporated clean with nitrogen. Dissolve well in water and adjust the pH to 7.0 with NaOH. The polypeptide was allowed to fully self-assemble by standing in a refrigerator at 4 ℃ for one week.
And sucking 10 mu L of the assembled polypeptide solution, dripping the polypeptide solution on a clean mica sheet, sucking the polypeptide solution for 20 minutes, sucking excessive liquid, and drying the polypeptide solution by using nitrogen. And observing the appearance of the assembly under an atomic force microscope, wherein the scanning parameters are as follows: 512 × 512, scanning speed: 1.0HZ, scan angle: 0 °, mode: tapping. The test results in FIG. 6, from which it can be seen that nanotubes of uniform diameter were formed with a wall thickness of 2.4 nm; the polypeptide is proved by a mechanism to have a molecular oblique assembly process, and residues with affinity to PD-L1 can be exposed on the surface of the nanotube.
After the assembly of the polypeptide is finished, the ultrasonic treatment is carried out for 2 hours under different powers, and the length of the nanotube can be controlled by the ultrasonic treatment method, so that the length of the nanotube can meet the requirement of the required length. As shown in fig. 7, the length of the nanotube is changed after 2 hours of ultrasound, and the length of the nanotube can be controlled by the method.
Polypeptide LY when assembled, the polypeptide molecule is tilted by approximately 40 ° and exposes the active site with affinity for PD-L1 to the surface of the assembly.
On the basis of polypeptide LY, the central two a residues of polypeptide LY were replaced by the more hydrophobic residue V, F. The hydrophobicity of the polypeptide is increased, so that the inclination angle of the beta-sheet is regulated and controlled by utilizing the solvation effect. The polypeptide sequence formed is: TSRFVFFSQK (shown as SEQ ID NO 2).
Secondary structure characterization of polypeptide LY nanotubes
The method for detecting the secondary structure of the assembly by using the circular dichroism spectrometer comprises the following specific steps: an MOS450 circular dichroism spectrometer is selected, a CD mode is selected, the scanning range is 190-260 nm, the interval time is set to be 0.5s, and the optical path of a cuvette used in the experiment is 0.1 mm. The results are shown in FIG. 8.
Targeting and selectivity of polypeptide LY assembly on cell surface
The method comprises the following steps:
MC38 and 293T cells were first grown on glass slides for 24 hours, then 100. mu.L of the assembled peptide solution was added and incubated at 37 ℃ for 1h and washed three times with PBS.
Cells were fixed overnight with 4% glutaraldehyde.
Critical point drying (absolute ethanol is replaced by carbon dioxide)
Spraying gold for 30s
And (5) imaging by a scanning electron microscope. The scanning results are shown in fig. 9.
As can be seen in FIG. 9, the surface of the 293T cell which is negative to PD-L1 is smooth, and no polypeptide assembly appears. On the surface of PD-L1 positive MC38 cells, a large number of assemblies were attached. The polypeptide assembly has good targeting ability and selectivity.
Polypeptide LY Assembly in situ treatment results
C57BL/6N mice 7 weeks old were injected subcutaneously with MC38 cells until tumors grew to 100mm3As a model mouse. Mice were divided into experimental and control groups.
Experimental groups: mice were injected intravenously with 100. mu.L of drug (where LY assemblies (nanotubes obtained as shown in FIG. 6): 4mg/kg, ce6 (chlorin): 3mg/kg) every other day tail.
Control group: mice were injected with 100 μ L PBS into the tail vein every other day, and 6 hours after injection, irradiated with 808nm laser for 10 minutes.
The results are shown in FIG. 10, from which it can be seen that the tumor size of the experimental group mice is significantly reduced, while the tumor size of the control group is gradually increased. The nano tube obtained by the invention has good treatment effect on carrying the anti-cancer drugs.
The polypeptide LY obtained by using the method of 'de novo design' and combinatorial chemistry peptide library screening can be self-assembled into a nanotube with the function of targeting and recognizing PD-L1 by manipulating the inclination of a polypeptide molecule. The excellent ability of loading anti-tumor drugs and imaging reagents can be used for immune combination therapy and imaging of tumors.
Claims (10)
1. A targeted PD-L1 polypeptide, wherein the polypeptide has the general formula:
X1X2X3X4X5X6X7X8X9X10
wherein X1, X2, X8, X9 and X10 are hydrophilic amino acids, X3 is basic or acidic amino acids, and X4, X5, X6 and X7 are hydrophobic amino acids.
2. The targeted PD-L1 polypeptide of claim 1, wherein X1 is one of threonine, serine, cysteine; x2 is one of serine, glutamic acid, histidine and aspartic acid; x3 is one of lysine, arginine, glutamic acid, histidine and aspartic acid; x4 is one of phenylalanine, leucine and isoleucine; x5 is one of phenylalanine, tyrosine and glycine; x6 is one of leucine, valine, tryptophan, and phenylalanine; x7 is one of leucine, valine, tryptophan, and phenylalanine; x8 is one of serine, glycine and cysteine; x9 is one of asparagine and glutamine; x10 is one of lysine, glutamic acid, aspartic acid, histidine and arginine.
3. The polypeptide of claim 1, wherein the amino acid sequence of the polypeptide is: TSRFAAFSQK are provided.
4. The polypeptide of claim 1, wherein the amino acid sequence of the polypeptide is: TSRFVFFSQK are provided.
5. A polypeptide nanotube formed by self-assembly of the polypeptide of any one of claims 1 to 4.
6. The polypeptide nanotube of claim 6, wherein the polypeptide nanotube has a wall thickness of 2.4nm, and the polypeptide is assembled in an antiparallel manner by forming a β -sheet secondary structure during the self-assembly process; the active residues on both sides of the polypeptide chain are exposed at the surface of the nanotube.
7. A method for preparing the polypeptide of claims 1-2, comprising the steps of:
taking resin as a solid phase carrier, and coupling the amino acid at each position to the carrier one by a mixed splitting method;
the polypeptide is cut off from the resin by lysate, separated and purified, and the needed polypeptide can be obtained.
8. The use of polypeptide nanotubes as claimed in claim 5, wherein the use of polypeptide nanotubes as a carrier for drugs for tumor therapy or imaging agents.
9. The use of claim 8, wherein the tumor is a tumor positive for PD-L1 expression.
10. The use of claim 9, wherein the tumor is one of melanoma, non-small cell lung tumor, prostate tumor, colorectal tumor, pancreatic tumor, liver tumor, stomach tumor, esophageal tumor, breast tumor, and biliary tract tumor.
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