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WO2005077971A1 - Peptide a croissance de fibroblastes inedit concu a partir d'un site a croissance de fibroblastes de proteine a facteur de croissance endothelial vasculaire (vegf) de venin de serpent et son utilisation - Google Patents

Peptide a croissance de fibroblastes inedit concu a partir d'un site a croissance de fibroblastes de proteine a facteur de croissance endothelial vasculaire (vegf) de venin de serpent et son utilisation Download PDF

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Publication number
WO2005077971A1
WO2005077971A1 PCT/JP2004/008109 JP2004008109W WO2005077971A1 WO 2005077971 A1 WO2005077971 A1 WO 2005077971A1 JP 2004008109 W JP2004008109 W JP 2004008109W WO 2005077971 A1 WO2005077971 A1 WO 2005077971A1
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WIPO (PCT)
Prior art keywords
heparin
peptide
amino acid
vegf
binding
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Application number
PCT/JP2004/008109
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English (en)
Japanese (ja)
Inventor
Takashi Morita
Yasuo Yamazaki
Original Assignee
Nec Soft, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nec Soft, Ltd. filed Critical Nec Soft, Ltd.
Priority to JP2005517889A priority Critical patent/JPWO2005077971A1/ja
Publication of WO2005077971A1 publication Critical patent/WO2005077971A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention solves the above-mentioned problems, and an object of the present invention is to provide a detailed description of VEGF-A.
  • a C-terminally truncated protein monomer was prepared from which the position was removed by plasmin digestion, and the heparin binding property was verified. It was confirmed that the heparin binding property was lost.
  • a potent homodimer of VEGF-derived C-terminally truncated proteins was produced in vitro.
  • VEGF-like protein derived from Vipera ammodytes ammodytes as a vascular endothelial growth factor VEGF-like protein derived from snake venom; vammin, a protein derived from Daboia russelli russelli For the VEGF-like protein; VR-1, the proteodalican-type peparin or heparan sulfate present on the cell surface is required to induce a physiological response in the cell following the binding to KDR. We found that it was necessary to bind to proteodalican at the same time.
  • the synthetic peptide fragment having heparin binding ability (affinity) designed based on the amino acid sequence derived from the heparin binding site in vammin and VR-1 is VEGFA or vammin. Inhibits vascular endothelial cell proliferation-inducing action in a concentration-dependent manner
  • VEGF-A exhibits KDR-mediated
  • composition Dissolving an effective amount of a peptide having the ability to bind carboxyl to the above-mentioned first aspect of the present invention in a pharmaceutically acceptable liquid carrier suitable for intravenous administration to the subject.
  • the composition can be
  • the composition can be obtained by dissolving the amount.
  • the present inventors have further modified the amino acid sequence on the basis of a peptide having heparin-binding ability that is strong in the first embodiment of the present invention, and A synthetic peptide fragment having binding ability was created.
  • the heparin binding ability (affinity) of the peptide having heparin binding ability according to the first aspect of the present invention is controlled by R-PR—X—KQG (X is R or W) by modifying the above-mentioned first amino acid sequence portion having a common function, and RX-X-X-KQG (X is P or R , X is
  • X has a modified first amino acid sequence portion of ⁇ , ⁇ or R), and has a heparin binding ability.
  • VEGF-A vascular endothelium by VEGF-A.
  • heparin binding site such as area, heparin binding site to have a three-dimensional structure despite the absence, it shows the binding of the heparin to the same ingredients, also accompanied Rere exerted binding to KDR vammin
  • the binding to heparin present on the surface of the target cell in which the KDR is expressed is also an essential process in the expression of various physiological activities.
  • VR_1 also exhibits binding properties to heparin, and the subject expressing the KDR is also involved in the expression of various physiological activities exerted upon the binding of VR-1 to the KDR. It has been clarified that binding to heparin present on the cell surface is also an essential process.
  • a and A are each selected from a peptide chain having 0 to 13 amino acids, and the A and A
  • the role of the -X-part is to compare the second partial amino acid sequence to the first partial amino acid sequence portion.
  • a method of adding or modifying an extra amino acid at the N-terminus and C-terminus is effective.
  • various N-terminal amino groups can be modified with various acyl groups, or the C-terminal carboxy group can be amidated.
  • the peptide having heparin-binding ability according to the first aspect of the present invention can be produced by using a chemical synthesis technique, for example, using a solid phase synthesis method, When extending the peptide chain, amidation of the C-terminal immobilized on the resin is also suitable for synthesis.
  • the linker is arranged as follows:
  • the linker One sequence One X-X-X-X-X part of the amino acid sequence is _E_P_D_G_P—
  • a and A are each selected from a peptide chain having 0 to 13 amino acids, and A and A
  • Nl CI The total number of amino acids in Nl CI is 13 or less.
  • a peptide having an amino acid sequence of 720 amino acid residues and having a heparin binding ability For example, the following synthetic peptide peptides 7 and 8 are exemplified. As described above, the portion A may be in a form in which no amino acid is present. Generally, N end
  • _K-P_R_R was converted from K-E-K_P_R_R to K-D-K-P-R-R in correspondence with _K-P_R_R,
  • linker sequence for example, from 5 amino acid residues to a linker system IJ: 1 X -X -X -X
  • the role of the -X-part is to compare the second partial amino acid sequence to the first partial amino acid sequence portion.
  • the purpose of the present invention is to link the column portions and to add the contribution of a weak interaction between the second partial amino acid sequence portion and heparin to the heparin binding property mainly composed of the first partial amino acid sequence portion. Things. Therefore, due to the action of proteases and peptidases existing in the body of the administration subject, cleavage of such a linker sequence: one X-X-X-X-X is not possible.
  • a method of adding or modifying an extra amino acid at the N-terminus and C-terminus is effective.
  • various N-terminal amino groups can be modified with various acyl groups, or the C-terminal carboxy group can be amidated.
  • the peptide having heparin-binding ability according to the second embodiment of the present invention can also be produced by using a chemical synthesis technique. When extending the peptide chain, C-terminal immobilized on the resin The terminal amidation is also synthetically suitable.
  • X-parts may contain artificial amino acids instead of natural amino acids
  • the peptide chain portion other than the modified first partial amino acid sequence is the same as the above-described first embodiment of the present invention. It is also possible to adopt an embodiment in which various mutations, modifications, and alterations described in the description of the peptide having the ability to bind to heparin and the like can be used in the same manner.
  • VEGF-A Blood caused by VEGF-A, which causes various diseases such as retinopathy of prematurity, retinopathy of prematurity, and psoriasis
  • the peptide having heparin binding ability according to the present invention is suitably administered directly into the bloodstream and administered to the surface of vascular endothelial cells at the site of action. It is preferable to prepare a pharmaceutical composition in a dosage form suitable for intravenous administration.
  • the dosage form is a dosage form used for intravenous administration of peptide preparations having various physiological activities, for example, dosage forms such as intravenous injections and infusions. It is determined appropriately according to the application.
  • the desired physiological activity is exhibited in the estimated total blood volume.
  • the administered dose so that the blood concentration is as follows.
  • the peptide having heparin-binding ability according to the present invention is used in the form of an intravenous injection, it is usually possible to administer the peptide in a plurality of divided doses. It is desirable to set the dose in the range of 100 mg / kg body weight, preferably in the range of 3-50 mg / kg body weight.
  • the average blood concentration is in the range of 0.1 ⁇ M ⁇ ⁇ ⁇ .
  • the total dose is set in the range of 1 / iM-3 / iM.
  • a therapeutic or prophylactic agent for the purpose of suppressing the promotion of angiogenesis caused by VEGF-A for diabetic retinopathy and retinopathy of prematurity in which the organ site to be applied is specified.
  • each peptide was prepared by a solid phase synthesis method using the F_moc method, using a peptide synthesizer (Applied Biosystems, model 431A). According to a conventional method, the synthetic peptide was deprotected and separated and eluted from the base resin by the F-moc tarry vedge method, and the recovered crude peptide was lyophilized.
  • the crude peptide was purified using AKTAexplorer 10S (Amersham Biosciences) and an HPLC system (JASCO). The detection of the peptide in the column elution fraction was performed by measuring the absorbance at 240 nm.
  • the peptide fraction showing the binding property to heparin was pooled and collected, and then Cosmosil 5 ⁇ 18 ⁇ _300 (2 ⁇ X 25 cm (L)) was applied, and a linear gradient of acetonitrile 0 ⁇ / ⁇ 30% was obtained. And the peptide fraction having the desired number of amino acids was isolated. The purified peptide was freeze-dried, the amino acid sequence was confirmed by an amino acid sequencer, and the peptide concentration was quantified by amino acid analysis.
  • the amino acid sequence of the purified peptide was confirmed using Protein 'Sequencer (Applied Biosystems models 473A, 477, Shimadzu model PPSQ-21A).
  • the peptide with heparin-binding ability described above is used to increase vascular endothelial cells by VEGF-A.
  • a cell suspension of P. aortic endothelial cells was seeded at a density of 5,000 cells / P in a 96 P cell culture plate. 0.1 0.1 after cell attachment in the well. The medium was replaced with a medium supplemented with / 0 ⁇ fetal serum and cultured for a total of 18 hours. At that time, the medium was supplemented with a final concentration of 1 nM of the vascular endothelial growth factor protein VEGF-A or vammin, and
  • the peptide 1 was added thereto at a predetermined final concentration. After continuing the culture for 6 days, the number of cells in each well was determined using Tetra Color One (Seikagaku Corporation). The viable cell number density was evaluated by the WST-8 method.
  • peptide 1 was added at a final concentration of 100 ⁇ M (dark gray column: right of center), 30 ⁇ ⁇ (light gray, gray column: middle), 0 ⁇ (no addition: positive control; Black column: center left) added gel,
  • peptide 1 having heparin-binding ability binds to heparin present on the surface of BAEC cells, and VEGF-A and vammin exert the effect of promoting the growth of vascular endothelial cells.
  • VEGF-A and vammin show the growth-promoting action of vascular endothelial cells as a result of competitively inhibiting the binding to heparin out of the binding to KDR and the binding to heparin required in
  • the peptide with heparin binding ability described above suppresses the blood pressure lowering effect of VEGF-A.
  • a polyethylene tube filled with 4 was introduced into the carotid artery and a pressure transducer (model P10EZ, Becton Dickinson) to monitor carotid artery pressure.
  • the carotid pressure measured by a pressure transducer was recorded by a recorder connected to an amplifier (model AP-621 Nihon Kohden).
  • a in FIG. 4 shows the top: when only vammin (dose 0.1 ⁇ g / g) was administered,
  • FIG. 4 shows the top: When only VEGF-A (dose 0.1 x gZg) was administered,
  • VEGF-A dose 0.1 ⁇ gZg after pre-administration of peptide 1 (dose 3 x g / g)
  • VEGF-A dose 0.1 / ig / g
  • peptide 1 dose 30 ig / g
  • the blood pressure lowering effect of vammin is based on the potent nitric oxide (NO) -dependent blood pressure lowering activity induced by the binding of VEGF protein to KDR.
  • VEGF-A and vammin lower blood pressure by binding to peptide 1 having heparin present on the surface of KDR-expressing cells.
  • VEGF-A and vammin lower blood pressure.
  • VEGF-A is formed only by a portion of R-P-R_X_K_Q_G (X is any one of R, W, H and K).
  • VEGF-A caused a decrease in blood pressure of peptide 2 corresponding to the N-terminal region of peptide 1 and peptide 3 corresponding to the C-terminal region.
  • VEGF-A dose 0.1 ⁇ gZg after pre-administration of peptide 1 (dose 30 g / g)
  • VEGF-A dose 0.1 ⁇ gZg
  • peptide 3 dose 30 ⁇ g / g
  • peptide 1 and peptide 2 which are administered beforehand, have the effect of suppressing the blood pressure lowering effect. Therefore, peptide 1 and peptide 2, which have heparin binding ability, bind to heparin present on the surface of cells expressing KDR, so that VEGF-A
  • peptide 3 does not show heparin-binding ability, and therefore, the inhibitory effect was observed, and it was judged to be poor.
  • Table 3 summarizes the measurement results of the eluted NaCl concentration at the peak maximum of the elution peak for the three peptides.
  • F-A and the test peptide were not added together, but in the 1% serum-supplemented medium.
  • the inhibitory effect of each of the co-added peptides on the promotion of cell proliferation was evaluated by the number of surviving cells after 3 days of culture.
  • the serum added to the medium originally contained a small amount of VEGF, and under the conditions that completely inhibited the growth promoting effect of vascular endothelial cells by VEGF-A,
  • the growth promotion rate shows a negative value.
  • the test compound peptide
  • the "negative growth promotion rate” shown in this figure does not mean "cytotoxicity”. It is confirmed by measuring the number of surviving cells when cultured in a medium containing a low concentration of serum containing 0.1% or less.
  • the difference is due to a difference in binding ability to heparin on the surface of vascular endothelial cells.
  • the inhibitory activity of peptide 9 was compared to the inhibitory activity of peptide 1 in the evaluation system for inhibitory activity.
  • Fig. 9 shows VEGF-A, which is shown by each of peptide 1 and peptide 9 (TFPI 254 265 ).
  • VEGF-A final concentration InM
  • peptide 9 (TFPI 254 " 265 ) showed only a slight inhibitory effect.
  • peptide 1 since peptide 1 has specific binding ability to heparin on the surface of vascular endothelial cells, peptide 1 binds to KDR on the surface of vascular endothelial cells and As a result of competitive inhibition of heparin binding, VEGF-A shows that vascular endothelial cells
  • FIG. 10 shows the strength of each peptide of peptide 1, peptide 7, and peptide 8.
  • VEGF-A final concentration InM
  • the growth promotion rate shows a negative value
  • the serum added to the medium originally contained a small amount of VEGF
  • the peptide having heparin-binding ability described above is used for the activation of vascular endothelial cells by VEGF-A.
  • a cell suspension of human umbilical vein endothelial cells was seeded at a density of 5,000 cells / well on a collagen-coated 96-well cell culture plate. After seeding, incubate for 6 hours, allow cells in the wells to adhere, replace the medium with 1% human serum, and overnight ( (18 hours in total). At that time, VEGF-A or bFGF was added to the medium at the final concentration.
  • test peptide was added at a final concentration of 1 nM, as well as the test peptide. After continuing the culture for 3 days, the number of cells in each well was evaluated for the viable cell number density by the WST-8 method using Tetra Color One (Seikagaku Corporation).
  • the color absorption coefficient A was used as an index of the number of viable cells.
  • the number of surviving cells when cultured in a supplemented medium was determined using the negative control: 0% growth promotion, 1% blood growth without VEGF-A or bFGF, without the addition of the test peptide.
  • the number of surviving cells when cultured in a fresh medium was defined as a positive control: proliferation promotion 100%, and the proliferation promotion rate was calculated based on the evaluated number of surviving cells.
  • FIG. 11 shows that VEGF-A or bFGF ligated peptide 1 was added to the medium.
  • Peptide 1 was added at a concentration that inhibited the growth of vascular endothelial cells by VEGF-A stimulation.
  • peptide 1 has specific binding ability to proteoglycan-type heparin chains present on the surface of vascular endothelial cells, and in particular, VEGF-A
  • heparin on the surface of vascular endothelial cells is not directly involved in the mechanism of bFGF-stimulated vascular endothelial cell proliferation.
  • the novel heparin-binding peptide according to the present invention is designed based on the amino acid sequence of the heparin-binding site in snake venom-derived vascular endothelial growth factor VEGF-like protein; vammin and VR-1. It is a peptide compound consisting of 7-20 amino acid residues.
  • VEGF-A and heparin on the cell surface are associated with the binding of VEGF-A to KDR.

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Abstract

: Il est prEvu un peptide A croissance de fibroblastes inEdit capable d'inhiber la liaison de VEGF-A165 au protEoglycane de sulfate d'hEparine ou d'hEparane et supprimant ainsi diffErentes rEactions physiologiques causEes par interaction entre KDR et VEGF-A165. A savoir, un peptide A croissance de fibroblastes conÇu en se basant du site A croissance de fibroblastes de vammin de protEine VEGF de venin de serpent, contient au moins une premiEre sEquence d'acides aminEs partielle R-P-R-X-K-Q-G (oU X reprEsente R, W, H ou K) provenant du site A croissance de fibroblastes dEcrit ci-dessus et a entre 7 et 20 rEsidus d'acide aminE.
PCT/JP2004/008109 2004-02-12 2004-06-10 Peptide a croissance de fibroblastes inedit concu a partir d'un site a croissance de fibroblastes de proteine a facteur de croissance endothelial vasculaire (vegf) de venin de serpent et son utilisation WO2005077971A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005517889A JPWO2005077971A1 (ja) 2004-02-12 2004-06-10 ヘビ毒由来の血管内皮増殖因子（ｖｅｇｆ）様タンパク質のヘパリン結合部位より設計された新規なヘパリン結合能を有するペプチドとその用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JPPCT/JP2004/001494 2004-02-12
PCT/JP2004/001494 WO2005077970A1 (fr) 2004-02-12 2004-02-12 Nouveau peptide se liant à l'héparine conçu à partir d'un site de liaison à l'héparine d'une protéine ressemblant à un facteur de croissance vasculaire endothélial (vegf) provenant du venin d'un serpent et utilisation de celui-ci

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PCT/JP2004/001494 WO2005077970A1 (fr) 2004-02-12 2004-02-12 Nouveau peptide se liant à l'héparine conçu à partir d'un site de liaison à l'héparine d'une protéine ressemblant à un facteur de croissance vasculaire endothélial (vegf) provenant du venin d'un serpent et utilisation de celui-ci
PCT/JP2004/008109 WO2005077971A1 (fr) 2004-02-12 2004-06-10 Peptide a croissance de fibroblastes inedit concu a partir d'un site a croissance de fibroblastes de proteine a facteur de croissance endothelial vasculaire (vegf) de venin de serpent et son utilisation

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PCT/JP2004/001494 WO2005077970A1 (fr) 2004-02-12 2004-02-12 Nouveau peptide se liant à l'héparine conçu à partir d'un site de liaison à l'héparine d'une protéine ressemblant à un facteur de croissance vasculaire endothélial (vegf) provenant du venin d'un serpent et utilisation de celui-ci

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Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072829A2 (fr) * 2000-03-31 2001-10-04 Institut Pasteur Peptides inhibant l'angiogenese induite par le vegf (facteur de croissance endotheliale), polynucleotides codant pour ces peptides et leurs procedes d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KEYT B A, ET AL: "The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency", J. BIOL. CHEM., vol. 271, no. 13, 1996, pages 7788 - 7795, XP000993198 *
KOMORI Y, ET AL: "Vascular endothelial growth factor VEGF-like heparin-binding protein from the venom of vipera aspis aspis (Aspic Viper)", BIOCHEMISTRY, vol. 38, no. 36, 1999, pages 11796 - 11809, XP002196145 *

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