CN112851759B - Screening of polypeptide capable of crossing blood-cerebrospinal fluid barrier by phage display technology - Google Patents
Screening of polypeptide capable of crossing blood-cerebrospinal fluid barrier by phage display technology Download PDFInfo
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- CN112851759B CN112851759B CN202110201329.4A CN202110201329A CN112851759B CN 112851759 B CN112851759 B CN 112851759B CN 202110201329 A CN202110201329 A CN 202110201329A CN 112851759 B CN112851759 B CN 112851759B
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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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- A—HUMAN NECESSITIES
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A—HUMAN NECESSITIES
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention discloses a polypeptide capable of crossing a blood-cerebrospinal fluid barrier screened by a phage display technology, and relates to the technical field of protein polypeptides. The bioactive peptides of the invention are capable of crossing the blood-cerebrospinal fluid barrier via blood circulation, penetrating into the cerebrospinal fluid and enriching in the cerebrospinal fluid. The present invention relates to a method for obtaining peptides spanning the blood-cerebrospinal fluid barrier by means of phage display technology. The amino acid sequence of the polypeptide is shown in SEQ ID No.1-4, and is CMRTHHMQC, CMWTHHHYQC, CMRTHHYQC and CMWTHHHMQC respectively. The peptide is used for constructing a targeting drug carrier, so that the drug carrier is enriched in cerebrospinal fluid and can be used for diagnosing and treating brain diseases.
Description
Technical Field
The invention relates to the technical field of protein polypeptides, in particular to a method for screening polypeptides capable of crossing a blood-cerebrospinal fluid barrier by using a phage display technology.
Background
With the aging problem of the human society becoming more and more serious, the incidence of brain diseases is on an increasing trend, and the brain diseases, especially the diseases of the central system, threaten the life and health of human beings. Generally, the brain diseases refer to the general term of inflammation, vascular diseases, tumor, degeneration, malformation, genetic diseases, immunological diseases, nutritional metabolic diseases, poisoning, trauma, parasitic diseases, etc. of intracranial tissue organs (meningeal blood vessels, brain, cerebellum, brainstem, cranial nerves, etc.). Different conditions may cause direct life-threatening diseases. Disorders such as consciousness, sensation and movement or vegetative nerve dysfunction are often manifested. There may also be fever, headache, vomiting, etc. and mental symptoms.
The blood-brain barrier (BBB) is the regulation interface between blood and nerve parenchyma, not only has the function of passive mechanical protection barrier, but also can selectively pump the surplus substances in the brain out of the brain, regulate the physiological balance of the central nervous system and keep the internal environment of the brain constant. Previous studies have shown that the structural basis of the BBB is the brain capillary endothelial cells and choroid plexus epithelium. The brain capillary endothelial cell membrane has a unique enzyme system, and the choroid plexus also has an actively transported enzyme system. Can degrade certain drugs, and the enzymes form an enzyme barrier of the BBB, prevent corresponding substrates from entering the brain, and have a non-negligible effect on the permeability of the BBB. For example, dopamine decarboxylase can decarboxylate L-dopa and L-5-hydroxytryptophan to produce L-dopamine and L-5-hydroxytryptophan which are not easy to permeate BBB, and monoamine oxidase inhibitor can permeate BBB; p-glycoprotein on the endothelial cell membrane of the brain capillary has the function of an efflux pump, can selectively pump harmful substances or surplus substances in the brain out of the brain, and limits the delivery of certain substances in the brain. The structure and function of the enzyme barrier and the efflux pump of the blood brain barrier play a certain role in maintaining the relatively constant internal environment of brain tissues, but the medicine is limited from entering the brain in the treatment of brain diseases. According to relevant statistics, due to the existence of blood brain barrier, after the current clinical conventional preparation is used, about 98 percent of chemical drugs and almost 100 percent of protein polypeptide or gene drugs are difficult to enter the brain, which greatly limits the treatment of brain diseases.
The blood cerebrospinal fluid barrier (BCSFB) is a selective regulatory interface between the vascular system and the central nervous system that can maintain homeostasis of the brain environment by regulating the chemical environment of the brain, the transport of immune cells, etc., while it can also handle foreign substances. The blood cerebrospinal fluid barrier is a functional cell complex composed of Central Nervous System (CNS) capillary endothelial cells, pericytes, astrocytes and neurons. Wherein the endothelial cells are capable of forming a physical barrier that controls the transport of drugs, xenobiotics, endogenous peptides and other compounds. The capillary vessel endothelial cells of the choroid plexus are provided with window holes, so that the blood-cerebrospinal fluid barrier has certain permeability compared with the blood-brain barrier, and the possibility of the medicine entering the brain to exert curative effect is provided.
There are currently methods to increase the likelihood of drug entry into the brain by temporarily opening the blood-cerebrospinal fluid barrier by physical or chemical means, but such methods are invasive and non-targeted and increase the risk of large amounts of potential neurotoxins and other chemicals entering the brain, adversely affecting the homeostasis of the central nervous system and increasing the likelihood of adverse side effects. In contrast, nanocarriers, such as liposomes and nanoparticles, have very good targeting selectivity. There have been an increasing selection of nanoparticle and liposome species for treatment. The liposome or nanoparticle after surface modification can target the central nervous system through a specific mechanism. Screening peptides capable of crossing blood-cerebrospinal fluid barrier, improving the precise selectivity of the medicine, achieving better treatment effect and reducing the systemic toxicity caused by the medicine.
The phage display peptide library technology is characterized in that a gene engineering means is utilized to insert exogenous gene fragments into specific protein genes of phage, the protein or polypeptide coded by the exogenous genes is expressed by the phage, the relative spatial structure and biological activity of recombinant fusion protein are maintained and are presented on the surface of the phage, phage which are not combined in a targeted manner are washed away by biopanning, high-affinity and high-specificity phage monoclonals are obtained by 3-5 rounds of collection, amplification and enrichment, and the protein sequences coded by the phage clones are identified by gene sequencing and can be used for further research. The polypeptide specifically bound with endothelial cells is screened out by a phage display technology, wherein the most representative is an arginine-glycine-aspartic acid (RGD) tripeptide sequence specifically bound with endothelial cells of tumor vessels, and the screened RGD shows good targeting property to the tumor cells by a long-circulating nano drug delivery system formed by binding a nano carrier. Barati et al obtained the HER 2-derived polypeptide AE37, and at the same time, AE37 and lambda phage coat protein gpD constructed a novel nanoparticle fusion peptide and were able to produce effective prevention and treatment of HER2 positive breast cancer. Studies have shown that initial antibodies obtained from phage display libraries of antibodies are generally of lower affinity, and that high affinity monoclonal antibodies can be obtained by increasing diversity through recombinant mutation and affinity screening.
The prior art to which the present invention relates is also: jingwei Li, liang Feng, xinguo Jiang. In virtual phase Display screen for peptide sequences through cross the block-parallel barrier. 2015 47 (2): 401-405. Jingwei Li, qizhi Zhang, zhiqiing Page, et al, identification of peptide sequences through target to the bridge using In virtual phase Display. 2012 42 (6): 2373-2381. Akinori Wada, tomoya Terasima, sumum Kageyama, et al, efficie Protate Cancer filter screen with Tissue sample Display screen, 138-19. Technique.
In conclusion, the invention designs a phage display technology for screening polypeptides capable of crossing the blood-cerebrospinal fluid barrier.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a method for screening polypeptide capable of crossing the blood-cerebrospinal fluid barrier by using a phage display technology,
in order to achieve the purpose, the invention is realized by the following technical scheme: the polypeptide capable of crossing the blood-cerebrospinal fluid barrier is screened by a Phage display technology, and is a polypeptide sequence which can cross the blood-cerebrospinal fluid barrier and is screened by a Phage display heptapeptide library (Ph.D. -C7C TM Phage display peptide library). The amino acid sequence of the polypeptide is shown as SEQ ID No.1-4, and is CMRTHHMQC, CMWTHHHYQC, CMRTHHYQC and CMWTHHHMQC respectively.
The method for screening the polypeptide capable of crossing the blood-cerebrospinal fluid barrier by the phage display technology comprises the following steps: a) Administering the phage randomly displayed peptide library intravenously, followed by recovery of phage from cerebrospinal fluid; amplifying the recovered phages and repeating the step a) until a consensus peptide sequence capable of crossing the blood-cerebrospinal fluid barrier is obtained.
The phage display technology screens the application of the polypeptide capable of crossing the blood-cerebrospinal fluid barrier in a targeting preparation; the targeting preparation is, for example, drug-loaded nanoparticles, liposomes, vesicles or micelles. Polypeptide modification is carried out on the surfaces of the nanoparticles, the liposomes, the vesicles or the micelles, so that the targeting preparation of the peptide is obtained. Performing polypeptide modification on the surface of the preparation by electrostatic adsorption, affinity connection or covalent connection.
The application of the phage display technology to screening the polypeptide capable of crossing the blood-cerebrospinal fluid barrier in treating neurodegenerative diseases, preferably Alzheimer disease,
the polypeptide capable of passing through the blood-cerebrospinal fluid barrier is screened by the phage display technology and is used for treating cerebral diseases such as hypoxic ischemic brain injury, depression after stroke and the like.
The invention has the following beneficial effects:
1. the polypeptide obtained by screening has the advantages of small relative molecular mass, good stability, good activity, strong biological penetration, high affinity and specificity, low toxicity and the like.
2. The polypeptide obtained by screening can be used for constructing a brain targeting drug carrier system.
Drawings
The invention is described in detail below with reference to the drawings and the detailed description;
FIG. 1 is a schematic representation of the brain-entry validation of monoclonal phages according to the invention;
FIG. 2 is a schematic diagram of in vivo imaging of a Pep-1 peptide animal of the present invention;
FIG. 3 is a schematic diagram of the live imaging of a Pep-2 peptide animal of the present invention;
FIG. 4 is a schematic diagram of the live imaging of a Pep-3 peptide animal of the present invention;
FIG. 5 is a schematic diagram of the live imaging of a Pep-4 peptide animal of the present invention;
FIG. 6 is a schematic diagram showing the determination of TChE activity in hippocampus of mouse brain according to the present invention;
FIG. 7 is a schematic diagram of the determination of TChE activity in the homogenate of the cerebral cortex of a mouse according to the present invention;
FIG. 8 is a schematic diagram of the determination of ChAT activity in the hippocampus of the mouse brain according to the present invention;
FIG. 9 is a schematic diagram showing the determination of ChAT activity in the homogenate of the brain cortex of a mouse in accordance with the present invention.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Referring to fig. 1 to 9, the following technical solutions are adopted in the present embodiment: the polypeptide capable of crossing the blood-cerebrospinal fluid barrier is screened by a Phage display technology, and is a polypeptide sequence which can cross the blood-cerebrospinal fluid barrier and is screened by a Phage display heptapeptide library (Ph.D. -C7C TM Phage display peptide library). The amino acid sequence of the polypeptide is shown in SEQ ID No.1-4, and is CMRTHHMQC, CMWTHHHYQC, CMRTHHYQC and CMWTHHHMQC respectively.
The method for screening the polypeptide capable of crossing the blood-cerebrospinal fluid barrier by the phage display technology comprises the following steps: a) Administering the phage randomly displayed peptide library intravenously, followed by recovery of phage from cerebrospinal fluid; the recovered phages are amplified and the steps of a) are repeated until a consensus peptide sequence is obtained that crosses the blood-cerebrospinal fluid barrier.
The phage display technology screens the application of the polypeptide capable of crossing the blood-cerebrospinal fluid barrier in a targeting preparation; the target preparation is, for example, drug-loaded nanoparticles, liposomes, vesicles or micelles. Polypeptide modification is carried out on the surfaces of the nanoparticles, the liposomes, the vesicles or the micelles, so that the targeting preparation of the peptide is obtained. Performing polypeptide modification on the surface of the preparation by using methods such as electrostatic adsorption, affinity connection or covalent connection.
A phage display peptide library is adopted to screen out peptides capable of crossing a blood-cerebrospinal fluid barrier through biological panning, which comprises the following steps: the in vivo screening method is adopted, phage random display peptide library is given to the phage intravenously, after a certain time, phage is recovered from cerebrospinal fluid, and phage monoclone capable of crossing the blood-cerebrospinal fluid barrier is finally obtained through 3-5 rounds of collection, amplification and enrichment; the amino acid sequence of the peptide can be obtained after sequencing. Phage in vivo screening methods, as well as methods for sequencing phage monoclonals, are well known to those skilled in the art.
The phage random displayed peptide library can be a commercially available phage random displayed peptide library, such as a phage displayed cyclic heptapeptide library, a phage displayed dodecapeptide library, or other suitable phage displayed random peptide library. The phage random display peptide library can be administered intravenously to an appropriate animal, e.g., rat, mouse, rabbit, etc. Phage recovery from cerebrospinal fluid can be amplified by drawing an appropriate volume of cerebrospinal fluid, co-incubation of phage in logarithmic growth phase with host E.coli, and subsequent recovery of phage. Methods of cerebrospinal fluid aspiration are well known to those skilled in the art.
In vitro and in vivo experiments show that the polypeptide screened by the phage display technology has the characteristics of crossing a blood-cerebrospinal fluid barrier and being enriched in cerebrospinal fluid. The polypeptide is used for modifying drug-loaded nanoparticles, liposomes, vesicles or micelles so as to construct a targeted drug carrier system, and the drug delivery system can improve the delivery of drugs in the precise selective brain, so that a better treatment effect is achieved, and the systemic toxicity caused by the drugs is reduced.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Sequence listing
<110> LiJingwein
<120> screening of polypeptides capable of crossing blood-cerebrospinal fluid barrier by phage display technology
<141> 2021-02-23
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Claims (3)
1. The screening of polypeptide capable of crossing blood-cerebrospinal fluid barrier by means of phage display technology features that the amino acid sequence of the polypeptide is shown in SEQ ID No. 2 and is CMWTHHHYQC.
2. The use of the polypeptide of claim 1 in the preparation of a brain-targeted drug delivery.
3. The use of claim 2, wherein the brain-targeted delivery of the drug is achieved by a drug-loaded nanoparticle, liposome, vesicle or micelle modified by a short peptide of the amino acid sequence of SEQ ID NO. 2.
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| US8053569B2 (en) * | 2005-10-07 | 2011-11-08 | Armagen Technologies, Inc. | Nucleic acids encoding and methods of producing fusion proteins |
| CN102174080B (en) * | 2010-09-19 | 2014-07-09 | 复旦大学 | Polypeptide with brain targeted medicine delivery characteristic and preparation method thereof |
| US10112987B2 (en) * | 2012-01-09 | 2018-10-30 | Icb International, Inc. | Blood-brain barrier permeable peptide compositions comprising a vab domain of a camelid single domain heavy chain antibody against an amyloid-beta peptide |
| EP2671597A1 (en) * | 2012-06-07 | 2013-12-11 | Cepep III AB | Chimeric constructs between glioma-homing peptide and cell-penetrating peptides, gHoPe2 |
| CN104371006B (en) * | 2014-08-15 | 2017-05-24 | 李婧炜 | Peptide capable of passing across blood-cerebrospinal fluid barrier |
| CN108752426A (en) * | 2018-06-07 | 2018-11-06 | 南方医科大学 | Cell-penetrating peptides with neutral charge and the purposes as intracellular transport carrier |
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