WO2022156531A1 - Peptide de liaison à la dynéine capable de traverser une barrière biologique, et son utilisation - Google Patents

Peptide de liaison à la dynéine capable de traverser une barrière biologique, et son utilisation Download PDF

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Publication number
WO2022156531A1
WO2022156531A1 PCT/CN2022/070230 CN2022070230W WO2022156531A1 WO 2022156531 A1 WO2022156531 A1 WO 2022156531A1 CN 2022070230 W CN2022070230 W CN 2022070230W WO 2022156531 A1 WO2022156531 A1 WO 2022156531A1
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Prior art keywords
polypeptide
transporter
derivative
seq
drug
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PCT/CN2022/070230
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English (en)
Chinese (zh)
Inventor
郑爱萍
刘楠
王增明
张慧
高静
高翔
杜祎萌
吕佳琦
Original Assignee
中国人民解放军军事科学院军事医学研究院
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Priority claimed from CN202110069415.4A external-priority patent/CN114805595B/zh
Priority claimed from CN202110068300.3A external-priority patent/CN114805594B/zh
Application filed by 中国人民解放军军事科学院军事医学研究院 filed Critical 中国人民解放军军事科学院军事医学研究院
Publication of WO2022156531A1 publication Critical patent/WO2022156531A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • 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
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the invention relates to the field of biotechnology, in particular to a dynein-binding peptide capable of penetrating biological barriers and applications thereof.
  • drugs including various macromolecules (proteins, enzymes, antibodies, DNA), as well as drug nanocarriers, require intracellular delivery to achieve intracellular delivery in the cytoplasm or nucleus or other specific organelles such as lysosomes, mitochondria or endoplasm Internet) to play its therapeutic role.
  • Intracellular transport of different bioactive molecules is usually one of the key issues in drug delivery. For example, intracellular delivery in tumor therapy can overcome important obstacles such as multidrug resistance caused by P-glycoprotein in anticancer chemotherapy. .
  • non-invasive methods such as the use of pH-sensitive carriers, including pH-sensitive liposomes, to destabilize the membranes of phagocytic vesicles at low pH inside the endosome, release the entrapped drug into the cytoplasm, and Cell penetrating molecules (eg, penetrating peptides) are employed.
  • pH-sensitive carriers including pH-sensitive liposomes
  • Cell penetrating molecules eg, penetrating peptides
  • lysosome-targeted drug nanocarriers could significantly improve the delivery of therapeutic enzymes and chaperones into defective lysosomes for the treatment of lysosomal storage disorders, while the specific delivery of certain drugs to mitochondria may Helps treat a variety of diseases, including neurodegenerative and neuromuscular diseases, obesity, diabetes, ischemia-reperfusion injury, and cancer.
  • the delivery of all intracellular drug carriers cannot be achieved by targeting organelles in this way, such as nuclear delivery or macromolecular drugs or carriers that require wide intracellular distribution.
  • Nanocarrier delivery cannot achieve rapid intracellular transport, and macromolecular drugs with intracellular targets still have the problem of delivery.
  • Some studies use methods to reduce the stability of phagocytic vesicles to rupture phagosomes, but if the carrier Loaded with macromolecular drugs, the intracellular diffusion of the delivered drugs is still problematic.
  • the interior of all living cells is filled with macromolecules, which differs greatly in the thermodynamics and kinetics of biological reactions in vivo and in vitro, and studies have shown that the "excluded volume effect" in the cytoplasm is not sufficient to explain the macromolecular diffusion observed in vivo
  • the large reduction of , and the hydrodynamic interaction greatly reduce the diffusivity of monodisperse colloids, especially in dense systems.
  • the cytoplasm is crowded, with macromolecular concentrations up to about 300 g/L and volume occupancy reaching 30%, an environment that is quite different from the dilute, idealized conditions commonly used in biophysical research, such as in the nucleus, where all the deoxyribose Nucleic acid fragments are nearly all immobile, the highly restricted diffusion of DNA fragments in the nucleoplasm is due to extensive binding to immobile barriers, and the reduced lateral mobility of DNA >250 bp in the cytoplasm is due to molecular crowding. Based on this macromolecular crowding state, it is difficult for nano-drug carriers and linear macromolecules like DNA to rely on simple diffusion to achieve intracellular transport. So how to develop a way to actively transport carriers or drugs to achieve Methods for efficient intracellular transport are important.
  • This new intracellular/intercellular delivery method is derived from the understanding of the mechanism of virus infecting cells into and out of cells. Virus-sized particles cannot rely on simple diffusion to achieve rapid infection in cells. Through in-depth research in related fields, it was found that virus infection The process of entering and exiting cells relies on the dynein and kinesin in the cell.
  • the dynein can transport the virus from the side of the cell membrane to the center of the microtubule organization (in the direction of the nucleus), while the kinesin is used to transport the virus from the nucleus. Lateral transport to the cell membrane side.
  • Dynein is highly conserved in different organisms, and it is a potential method for drug/vehicle delivery, on the one hand, because of its transport from positive to negative (nuclear direction) along microtubules, which can achieve extensive coverage to the nucleus and the area covered by microtubules.
  • its more important feature as a drug/carrier transport engine is the diversity of its movement directions. Relevant studies have shown that the position of dynein at the intersection of microtubules not only passes through the intersection, but also has a certain proportion of steering, The possibility of reverse, stagnation, dissociation, etc., this feature makes it possible for the drug/carrier to be widely transported in cells and even transcellular as a drug delivery carrier.
  • the quasi-transport efficiency of dynein is very high, the movement speed of dynein in eukaryotic cells can reach 1-3 ⁇ m/s, and the traction force can reach pN level.
  • dynein for drug delivery.
  • One way is to construct a transcriptional expression system to prepare a partial subunit of dynein, and to combine the subunit with the target cargo to achieve delivery.
  • another way is to use dynein-binding peptides to make related attempts, and more functions can be achieved by further modification of multi-dynein-binding peptides.
  • it has been modified to the surface of gold nanoparticles, fluorescently labeled polystyrene particles, and PLGA nanoparticles.
  • the present invention uses the cell’s own dynein to achieve: 1.
  • the macromolecular drug/nanocarrier is rapidly transported in the cell to achieve the intracellular drug effect of the target; 2.
  • the problem of the drug/carrier passing through the biological barrier 3 drug core delivery.
  • the present invention claims a polypeptide.
  • polypeptide claimed in the present invention is polypeptide A or polypeptide B.
  • the polypeptide A is composed of a core region A (having dynein binding ability) and a penetrating peptide from the N-terminus to the C-terminus in turn; the amino acid sequence of the core region A is SEQ ID No.1, SEQ ID No.2, SEQ ID No.2, and SEQ ID No. 2. ID No.3 or SEQ ID No.4.
  • the polypeptide B is composed of a core region B (having dynein binding ability) and a membrane-penetrating peptide from the N-terminus to the C-terminus in turn; the amino acid sequence of the core region B is SEQ ID No.5, SEQ ID No.6, SEQ ID No. ID No. 7 or SEQ ID No. 8.
  • the penetrating peptide can be composed of 6-9 consecutive arginine residues (R).
  • the penetrating peptide is specifically composed of 8 consecutive arginine residues (R).
  • the present invention claims a polypeptide derivative.
  • polypeptide derivative claimed in the present invention is polypeptide derivative A or polypeptide derivative B.
  • the polypeptide derivative A is obtained by connecting a linker to the N-terminus of the polypeptide A in the first aspect above, and the linker can be used to connect a carrier or a drug or a fluorescent group.
  • the polypeptide derivative B is obtained by linking the N-terminus of the polypeptide B described in the first aspect above with a linker, and the linker can be used to link a carrier or a drug or a fluorescent group.
  • linker can be one or several glycine residues (G), cysteine residues (C) and/or lysine residues (K) and the like.
  • the linker is specifically GK, that is, it consists of a glycine residue (G) and a lysine residue (K).
  • the present invention claims a transporter.
  • the transporter claimed in the present invention is either transporter A or transporter B.
  • the transporter A is obtained by linking the polypeptide derivative A described in the second aspect above with a carrier or a drug or a fluorescent group by means of the linker.
  • the transporter B is obtained by linking the polypeptide derivative B described in the second aspect above with a carrier or a drug or a fluorescent group by means of the linker.
  • the carrier refers to a carrier for transporting drugs, such as nanoparticles, micelles, liposomes, vesicles, and the like.
  • the linker (GK) is specifically linked to carboxytetramethylrhodamine (TAMRA).
  • TAMRA carboxytetramethylrhodamine
  • the glycine residue (G) is a residue for reducing steric hindrance when the carrier is connected, and the lysine residue (K) is connected to TAMRA.
  • the present invention claims the use of the polypeptide described in the first aspect above or a derivative of the polypeptide described in the second aspect above in the preparation of the transporter described in the third aspect above.
  • the present invention claims the use of the polypeptide A described in the first aspect above or the polypeptide derivative A described in the second aspect above in the preparation of a drug transporter with biological barrier permeability and/or perinuclear aggregation properties.
  • the present invention claims the use of the polypeptide B described in the first aspect above or the polypeptide derivative B described in the second aspect above in the preparation of a drug transporter with biological barrier permeability and/or intranuclear aggregation properties.
  • the present invention claims the use of the polypeptide of the first aspect above or the polypeptide derivative of the second aspect above in the preparation of a formulation capable of improving the intracellular transport capacity of macromolecules and/or nanocarriers.
  • the present invention claims the use of the polypeptide according to the first aspect or the derivative of the polypeptide according to the second aspect in the preparation of a preparation capable of improving the effect strength of a drug acting in cells.
  • the present invention claims that the polypeptide described in the first aspect or the polypeptide derivative described in the second aspect can be prepared to reduce or improve the multidrug resistance (tumor multidrug resistance) caused by efflux factors such as P glycoprotein. drug resistance).
  • the present invention claims a method of preparing a drug transporter with biological barrier permeability and/or perinuclear aggregation properties.
  • the method for preparing a drug transporter with biological barrier permeability and/or perinuclear aggregation properties as claimed in the present invention may include the following steps: using the polypeptide A described in the first aspect above or the polypeptide derivative A described in the second aspect above. Prepare.
  • the present invention claims a method of preparing a drug transporter with biological barrier permeability and/or intranuclear aggregation properties.
  • the method for preparing a drug transporter with biological barrier permeability and/or nuclear aggregation properties as claimed in the present invention may include the following steps: using the polypeptide B described in the first aspect above or the polypeptide derivative B described in the second aspect above. Prepare.
  • the present invention claims a method of preparing a formulation capable of improving the intracellular transport capacity of macromolecules and/or nanocarriers.
  • the method for preparing a preparation capable of improving the intracellular transport capacity of a macromolecule and/or a nanocarrier as claimed in the present invention may comprise the steps of: preparing using the polypeptide described in the first aspect above or a derivative of the polypeptide described in the second aspect above.
  • the present invention claims a method of preparing a formulation capable of reducing or improving multidrug resistance.
  • the method for preparing a preparation capable of reducing or improving multidrug resistance as claimed in the present invention may comprise the steps of: preparing using the polypeptide described in the first aspect above or the derivative of the polypeptide described in the second aspect above.
  • the biological barrier is specifically the blood-brain barrier.
  • Figure 1 shows the intracellular fluorescence behavior of each polypeptide.
  • Figure 2 shows the intracellular fluorescence behavior of control polypeptides.
  • Figure 3 shows the intracellular specific behavior of polypeptide No. 1 and No. 5.
  • A is the perinuclear aggregation of No. 1 polypeptide;
  • B is the intranuclear aggregation of No. 5 polypeptide.
  • the following examples facilitate a better understanding of the present invention, but do not limit the present invention.
  • the experimental methods in the following examples are conventional methods unless otherwise specified.
  • the test materials used in the following examples were purchased from conventional biochemical reagent stores unless otherwise specified.
  • the quantitative tests in the following examples are all set to repeat the experiments three times, and the results are averaged.
  • the present invention designs a series of polypeptides with dynein binding ability with reference to the core sequence of virus binding to dynein.
  • the basic structure of polypeptide design is: GK/C + core sequence + penetrating peptide, and a polypeptide sequence with a purity of 95% is prepared by solid-phase synthesis method (general method).
  • R n is the penetrating peptide (it can also be other penetrating peptide CPPs).
  • the linker used to connect the N-terminus of the core polypeptide of the present invention to a drug or a carrier or a fluorescent group is specifically GK; wherein, the glycine residue (G) is a residue used to reduce steric hindrance when the carrier is connected, and is connected to TAMRA is the lysine residue (K).
  • the polypeptide of the present invention can be delivered to the drug carrier in two ways. One is to connect the polypeptide with the drug to be delivered by a synthetic method, so as to realize the intracellular delivery of the drug or to pass through the biological barrier; Polypeptides are linked to drug delivery carriers (such as nanoparticles, micelles, liposomes, etc.) to achieve intracellular delivery of drug carriers and penetration of biological barriers.
  • drug delivery carriers such as nanoparticles, micelles, liposomes, etc.
  • Example 2 Identification of the intracellular transport ability, cell proliferation toxicity and biological barrier permeability of the polypeptide of the present invention
  • GK at the N-terminus of the polypeptide in Example 1 is linked with carboxytetramethylrhodamine (TAMRA) to observe the intracellular behavior, which mainly involves intracellular transport ability, cell proliferation toxicity and biological barrier permeability.
  • TAMRA carboxytetramethylrhodamine
  • the "extracellular administration" polypeptide in Table 1 of Example 1 is used, and R n is specifically 8 Rs.
  • control polypeptide was set in each experiment, specifically replacing the core sequence in the polypeptide of Example 1 with "SLVSSDESVLHGSHESGEHV".
  • the control peptide was reported in the reference.
  • the specific synthesis method adopts the Fmoc cycle method, and according to the designed sequence, amino acids are added one by one according to deprotection (removal of amino protecting group), activation of cross-linking (peptide bond synthesis), elution and deprotection.
  • bEnd.3 cells mouse brain microvascular endothelial cells
  • TEER (transmembrane resistance of culture chamber-transmembrane resistance of blank chamber) ⁇ cell bottom area cm 2 ;
  • Example 2 In terms of cell proliferation and toxicity, the CCK-8 method was used to test bEnd.3 cells, and it was shown that each polypeptide in Example 1 and the control polypeptide were in contrast to the negative control (Ctrl, that is, without any growth-influencing substances added) when the concentration reached 100 ⁇ M. cell group), there was no significant difference (Table 2), no cell proliferation toxicity was shown, and the level of safety was good.
  • Example 1 In the research on the permeability of the barrier, through the transwell experiment, bEnd.3 cells were used to construct the blood-brain barrier model. In most cases, each polypeptide in Example 1 showed an apparent permeability coefficient greater than 10 -6 cm/s (Table 3 ), indicating that it can penetrate the biological barrier well.
  • the present invention designs a series of polypeptides with dynein binding ability with reference to the core sequence of virus-dynein binding.
  • polypeptide A can achieve pericellular delivery
  • polypeptide B can achieve cellular Delivered within the core, both polypeptides are biologically barrier permeable.
  • the present invention finds that it can improve the intracellular transport ability of macromolecular drugs (such as polypeptides, DNA, RNA, etc.) and/or nanocarriers, and improve the effect strength of intracellular drugs by comparing with control polypeptides. , can reduce or improve multidrug resistance (tumor multidrug resistance).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne un peptide de liaison à la dynéine capable de traverser une barrière biologique, et son utilisation. Le polypeptide selon la présente invention est un polypeptide A ou un polypeptide B, le polypeptide A étant composé de manière séquentielle d'une région noyau A et d'un peptide de pénétration cellulaire de l'extrémité N-terminale à l'extrémité C-terminale, et la séquence d'acides aminés de la région noyau A est SEQ ID NO : 1, SEQ ID NO : 2, SEQ ID NO : 3 ou SEQ ID NO : 4 ; et le polypeptide B est composé de manière séquentielle d'une région noyau B et d'un peptide de pénétration cellulaire de l'extrémité N-terminale à l'extrémité C-terminale, et la séquence d'acides aminés de la région noyau B est SEQ ID NO : 5, SEQ ID NO : 6, SEQ ID NO : 7 ou SEQ ID NO : 8. Selon la présente invention, le polypeptide A peut réaliser une administration intracellulaire périnucléaire, le polypeptide B peut réaliser une administration intranucléaire intracellulaire, et les deux polypeptides ont tous les deux une perméabilité de barrière biologique.
PCT/CN2022/070230 2021-01-19 2022-01-05 Peptide de liaison à la dynéine capable de traverser une barrière biologique, et son utilisation WO2022156531A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110068300.3 2021-01-19
CN202110069415.4A CN114805595B (zh) 2021-01-19 2021-01-19 具有生物屏障透过性和核内聚集特性的动力蛋白结合肽及其应用
CN202110068300.3A CN114805594B (zh) 2021-01-19 2021-01-19 一种能够透过生物屏障且聚集核周的动力蛋白结合肽及其应用
CN202110069415.4 2021-01-19

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020887A1 (fr) * 1996-11-14 1998-05-22 Brigham And Women's Hospital, Inc. Peptides se liant aux polyphosphoinositides, pour l'administration intracellulaire de medicaments
US20040132970A1 (en) * 2002-06-06 2004-07-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dermaseptin-derived peptides and their use in delivery systems
CN101160403A (zh) * 2005-02-18 2008-04-09 安吉奥开米公司 转运化合物穿过血脑屏障的分子
CN101412747A (zh) * 2008-10-21 2009-04-22 中国药科大学 新型穿膜肽及其用途
AU2012204135A1 (en) * 2005-02-18 2012-08-02 Angiochem, Inc. Aprotinin polypeptides for transporting a compound across the blood-brain barrier
CN103626850A (zh) * 2013-04-03 2014-03-12 安徽省新星药物开发有限责任公司 具有细胞穿透功能的多肽及其在药物递送中的用途
CN105050612A (zh) * 2012-10-19 2015-11-11 维克特-霍鲁斯公司 用于药物递送的组合物和方法
US20180346531A1 (en) * 2015-09-15 2018-12-06 Regents Of The University Of California Compositions and methods for delivering biotherapeutics
WO2020017496A1 (fr) * 2018-07-17 2020-01-23 国立大学法人熊本大学 Peptide perméable à la barrière hémato-encéphalique
CN111182913A (zh) * 2017-10-02 2020-05-19 西奈医疗中心 用于通过多个生物屏障进行有效递送的方法和组合物
US20200206304A1 (en) * 2017-10-02 2020-07-02 Cedars-Sinai Medical Center Methods and compositions for efficient delivery through multiple bio barriers
WO2020206189A1 (fr) * 2019-04-04 2020-10-08 Regenxbio Inc. Virus adéno-associés recombinants et leurs utilisations

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998020887A1 (fr) * 1996-11-14 1998-05-22 Brigham And Women's Hospital, Inc. Peptides se liant aux polyphosphoinositides, pour l'administration intracellulaire de medicaments
US20040132970A1 (en) * 2002-06-06 2004-07-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dermaseptin-derived peptides and their use in delivery systems
CN101160403A (zh) * 2005-02-18 2008-04-09 安吉奥开米公司 转运化合物穿过血脑屏障的分子
AU2012204135A1 (en) * 2005-02-18 2012-08-02 Angiochem, Inc. Aprotinin polypeptides for transporting a compound across the blood-brain barrier
CN101412747A (zh) * 2008-10-21 2009-04-22 中国药科大学 新型穿膜肽及其用途
CN105050612A (zh) * 2012-10-19 2015-11-11 维克特-霍鲁斯公司 用于药物递送的组合物和方法
CN103626850A (zh) * 2013-04-03 2014-03-12 安徽省新星药物开发有限责任公司 具有细胞穿透功能的多肽及其在药物递送中的用途
US20180346531A1 (en) * 2015-09-15 2018-12-06 Regents Of The University Of California Compositions and methods for delivering biotherapeutics
CN111182913A (zh) * 2017-10-02 2020-05-19 西奈医疗中心 用于通过多个生物屏障进行有效递送的方法和组合物
US20200206304A1 (en) * 2017-10-02 2020-07-02 Cedars-Sinai Medical Center Methods and compositions for efficient delivery through multiple bio barriers
WO2020017496A1 (fr) * 2018-07-17 2020-01-23 国立大学法人熊本大学 Peptide perméable à la barrière hémato-encéphalique
WO2020206189A1 (fr) * 2019-04-04 2020-10-08 Regenxbio Inc. Virus adéno-associés recombinants et leurs utilisations

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