WO2001057078A1 - Procede de production de noyaux de polymerisation de fibres d'amyloide par dialyse, methode de criblage de remedes pour amyloide de dialyse et remedes pour amyloide de dialyse - Google Patents

Procede de production de noyaux de polymerisation de fibres d'amyloide par dialyse, methode de criblage de remedes pour amyloide de dialyse et remedes pour amyloide de dialyse Download PDF

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Publication number
WO2001057078A1
WO2001057078A1 PCT/JP2000/009145 JP0009145W WO0157078A1 WO 2001057078 A1 WO2001057078 A1 WO 2001057078A1 JP 0009145 W JP0009145 W JP 0009145W WO 0157078 A1 WO0157078 A1 WO 0157078A1
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Prior art keywords
amyloidosis
dialysis
fucoidan
amyloid
therapeutic agent
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PCT/JP2000/009145
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English (en)
Japanese (ja)
Inventor
Itaru Yamaguchi
Hiroshi Suda
Katsuyuki Ishii
Yoshiaki Tanaka
Hironobu Naiki
Fumitake Gejyo
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Zeria Pharmaceutical Co., Ltd.
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Application filed by Zeria Pharmaceutical Co., Ltd. filed Critical Zeria Pharmaceutical Co., Ltd.
Priority to AU2001222228A priority Critical patent/AU2001222228A1/en
Publication of WO2001057078A1 publication Critical patent/WO2001057078A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein

Definitions

  • the present invention relates to a method for producing a dialysis amyloid fibril polymerization nucleus, a method for screening a therapeutic agent for dialysis amyloidosis, and a therapeutic agent for dialysis amyloidosis.
  • Amyloidosis is a factor in Alzheimer's disease, nephropathy, rheumatism, inflammation, diabetes, and neurotoxic diseases, and suppresses the formation and deposition of fibrils caused by amyloidosis, thereby reducing the symptoms of the resulting diseases. Can be improved.
  • Dialysis amyloidosis; 3 2 _ be caused by microglobulin fibrosis and deposition are known.
  • Organ lesions in amyloid deposition include dialysis complications such as carpal tunnel syndrome, destructive spondyloarthropathy, and bone cysts. These lesions, as a screening method for creating a drug that inhibits dialysis amyloid one cis to improve symptoms) 3 2 - inhibition test of microglobulin fibrils extension reaction has been attempted.
  • microglobulin also needs to be purified from urine and blood. Therefore, it can be mass-produced, and 3 2 - microglobulin fibrils elongation reaction without using a human tissue that can be used for dialysis amyloid fibrils polymerization nucleus production Nozomu rare, yet 3 2 can be easily obtained - using a micro-Glo purine Realization of the fiber elongation reaction is desired.
  • Producing a large amount of dialysis amyloid fibril polymerization nuclei can contribute to screening for a therapeutic agent for dialysis amyloidosis. Disclosure of the invention
  • the present invention dialysis amyloidosis patients from dialysis amyloid fibrils polymerization nuclei and Rico Nbinanto i3 2 - reacting the micro Glo purine to form amyloid fibrils, the amyloid fibrils obtained fragmented by sonication, resulting
  • An object of the present invention is to provide a method for producing a dialyzed amyloid fibril polymer nucleus by repeatedly and successively repeating the same reaction and fragmentation as described above by using a part of the obtained fragment as a dialysate amyloid fibril polymer nucleus.
  • the present invention is a dialysis amyloid one cis inhibitory effect dialysis and drug screening amyloid fibrils polymerization nuclei and recombinant 3 2 - dialysis amyloid by reacting a microglobulin - a method of screening for cis therapeutic agents, polymerization nucleus
  • the present invention also provides a method for screening a therapeutic agent for dialysis amyloidosis, wherein the method comprises using the dialyzed amyloid fibril polymerization nucleus obtained by the above method.
  • the present invention provides a therapeutic agent for dialysis amyloidosis obtained by the above screening method.
  • the present invention comprises, as an active ingredient, glycosaminoglycan or a salt thereof, fucoidan, a diazo dye compound having a sulfate group, or a polymer compound in which glycosaminoglycan or fucoidan has a diazo dye compound having a sulfate group bonded thereto. It is intended to provide a therapeutic agent for dialysis amyloidosis.
  • the present invention relates to dialysis amyloidosis of a glycosaminodalican or a salt thereof, fucoidan, a diazo dye compound having a sulfate group, or a polymer compound in which a daricosaminoglycan or fucoidan has a diazo dye compound having a sulfate group bonded thereto. It provides a use for the manufacture of a therapeutic agent.
  • the present invention provides a method for treating glycosaminodalican or a salt thereof, fucoidan, a diazo dye compound having a sulfate group, or a polymer compound in which glycosaminodalican or fucoidan has a diazo dye compound having a sulfate group bonded thereto. It is intended to provide a method for treating dialysis amyloidosis, which comprises administering to a patient in need thereof.
  • a dialysis polymerization amyloid fiber nucleus (SO 2 ) derived from human tissue is reacted with recombinant i32-microglobulin to form amyloid fibril.
  • the obtained amyloid fiber is fragmented by ultrasonic treatment, and a part of the obtained fragment is used as the amyloid fibril polymerization nucleus, so that the reaction and fragmentation operations are repeated in the same manner as described above.
  • the dialyzed amyloid fibril polymerization nucleus (S 1) can be produced.
  • the subculture repetition manipulate X times (X is an integer of 1 or more.)
  • X is an integer of 1 or more.
  • Repeating amyloid fibrils polymerization nucleus obtained by (S x) is 3 2 - increased affinity to microglobulin, the extension reaction Initial speed increased. Therefore, an infinite number of successive repetitive operations (S ⁇ ) can be performed, thereby realizing mass production of polymerization nuclei.
  • the starting material is derived from human tissue Yes, it can be obtained by extraction from amyloid-deposited tissue from dialysis amyloidosis patients by the method of Pras et al. (J. Exp. Med., 130, 777-791, 1969).
  • Dialysis Amyloid fibrils polymerization nuclei and recombinant / 3 2 - sonication to fragment the amyloid fibrils formed by the reaction of micro Gros purine can be performed by ultrasonic fracture frame machine.
  • the amount of the fragment obtained by the sonication used for the polymerization nucleus (S x) in the successive extension reaction is preferably 2.5 to 100 g / mL, particularly preferably 10 g / mL.
  • the amount of the recombinant 32 2 -microglobulin used is preferably from 10 xg / mL to 10 mg / mL (1::! To 1: 1 000).
  • test agent is dissolved in acidic buffer, dialysis amyloid fibrils polymerization nuclei. 25 to 100 g / mL and Rico Nbinanto) 3 2 _ microglobulin 5-100 additives It is preferable to carry out an amyloid fiber elongation reaction.
  • ThT Measured by the fluorescence method (Amyloid: Int. J. Exp. Clin. Invest., 4, 223-232, 1997), and the increase in fluorescence intensity is used as an indicator of amyloid fibril elongation.
  • the reaction mixture was centrifuged, the protein content in the centrifuged supernatant (i3 2 - microglobulin amount) is measured and a decrease in the protein content as an indicator of amyloid fibril elongation.
  • the protein content in the centrifuged supernatant (3 2 - Mikuroguro
  • the decrease in the amount of protein in the centrifugal supernatant is suppressed by suppressing the formation of amyloid fibrils, so that a drug with a smaller decrease in the amount of protein in the centrifugal supernatant suppresses amyloidosis In other words, it is excellent as a therapeutic agent for dialysis amyloidosis.
  • the present invention includes the therapeutic agent for dialysis amyloidosis obtained by the above screening method.
  • a therapeutic agent for dialysis amyloidosis was searched for by the above screening method, it was found that daricosaminodalican or a salt thereof, which is a main component of cell connective tissue, had an excellent dialysis amyloidosis inhibitory action.
  • Glycosaminodalican is preferably chondroitin sulfate C, dermatan sulfate, heparan sulfate, heparin or hyaluronic acid, and the salts thereof are physiologically acceptable, such as sodium salt, potassium salt and calcium salt.
  • Fucoidan has an excellent inhibitory effect on dialysis amyloidosis.
  • Fucoidan includes Gagomefukoidan, Mozukufukoidan, Futomozkofukoidan, Nebarimovkoidan, Ishigefukoidan, and Yirolovkoidan.
  • a diazo dye compound having a sulfate group and a polymer compound having a diazo dye compound having a sulfate group bound to glycosaminoglycan or fucoidan were found.
  • Diazo dye compounds having a sulfate group include Congo red, Direct Red 75, Direct Red 80, Direct Red 81 and Direct Red 81.
  • the therapeutic agent for dialysis amyloidosis of the present invention is useful for treating dialysis amyloidosis patients. It is effective and its dosage varies depending on symptoms, administration method, administration period, etc., but it is usually 100-10000 mg / day for oral administration, preferably 900-1800 mg / day. Days, and is preferably administered in the range of 1 to 3 times a day. It can also be directly injected into the affected area or administered intravenously as a 1-100 g / mL solution for injection. These therapeutic agents are used at doses that do not cause toxicity or side effects when administered to the human body.
  • the active ingredient such as glycosaminoglycan or a salt thereof, fucoidan, etc.
  • a formulation for oral administration or a formulation for parenteral administration by mixing pharmaceutically acceptable and commonly used carriers and additives.
  • Preparations for oral administration include tablets, powders, granules and capsules, and preparations for parenteral administration include injections.
  • Example 1 Method for producing dialyzed amyloid fibril polymerization nucleus
  • Recombinant 3 2 - microglobulin (manufactured by Oriental Yeast Co., Ltd.) was desalted and dialyzed in refining water and lyophilized. Then, it was dissolved in a 5 OmM aqueous sodium chloride solution at a concentration of 300 to 500 iM, and stored at -80 ° C until use.
  • S 0 polymerized nucleus 1 0 g / mL, 25 M recombinant
  • the amyloid fibrils formed by this reaction were centrifuged at 15000 ⁇ m and 4 ° C for 2 hours to obtain a precipitate.
  • This sediment was washed lightly with 0.5 mL of a 0.05% aqueous sodium azide solution, suspended in 300 L of a 0.05% aqueous sodium azide solution, and then sonicated (Ultrasonic Disruptor, TOMY UD-1201). ) To obtain 100 crushed fragments. This was used as the S 1 polymerization nucleus.
  • a successive polymerization nucleus (S 2 to S x) (X represents an integer of 1 or more) is formed by repeating the following method. Was.
  • the reaction solution 50 Kuen acid buffer (p H 2. 5) and 100 polymerization nuclei in a mixture of chloride Natoriumu water solution (Sx) and Recombinant] 3 2 - microglobulin their respective final concentration 10 zg / mL And 25 were used.
  • the temperature was increased at the fastest speed to 37 ° C. 10 minutes after the start of the reaction, the reaction was stopped under ice cooling, and the fluorescence intensity was measured by the ThT method.
  • glycosaminodalican examples include chondroitin sulfate C sodium salt (derived from shark joint, manufactured by Sigma), dermatan sulfate sodium salt (derived from bu-intestinal mucosa, Sigma), heparan sulfate sodium salt (derived from bu-intestinal mucosa) , Sigma), heparin sodium salt (derived from mucosal mucosa, manufactured by Sigma), or sodium hyaluronate (derived from human umbilical cord, manufactured by Nacalai Tesque, Inc.).
  • glycosaminodalican was dissolved in purified water to a concentration of 1 mg / mL, and diluted to a concentration of 300 g / mL.
  • reaction solution was dispensed in 50 L aliquots into PCR tubes (for 0.5 mL) and heated to 37 ° C to initiate the amyloid fibril elongation reaction.
  • Amyloid fiber elongation was measured by the ThT method, and the increase in fluorescence intensity 2 hours or 4 hours after the start of the reaction was used as an index.
  • the measurement method of the T h T method was performed as follows.
  • Table 2 shows the suppression effect of glycosaminoglycan on the fluorescence intensity.
  • glycosaminoglycan strongly suppresses dialysis amyloid fibril elongation reaction and is useful as a therapeutic agent for dialysis amyloidosis.
  • Example 3 (Screening for dialysis amyloidosis using fucoidan. Inhibitory effect on the elongation reaction of sulfide fibers)
  • Fucoidan collected the following seaweed using the method of Furukawa et al. (Hijiyama University Junior College bulletin)
  • Gagome Korean bandit iella, a commercial product from Hokkaido
  • Nebarimo (Leathesia di f formis)
  • the purified fucoidan was dissolved in purified water to a concentration of lmg / ml.
  • the reaction solution was dispensed in 50 L portions into a PCR tube (for 0.5 mL) and heated to 37 ° C to initiate the amyloid fibril extension reaction.
  • Amyloid fiber elongation was measured by the ThT method, and the increase in fluorescence intensity 4 hours after the start of the reaction was used as an index.
  • Table 3 shows the effect of suppressing the fluorescence intensity of each fucoidan.
  • each fucoidan potently inhibits the dialysis amyloid fibril elongation reaction and is therefore useful as a therapeutic agent for dialysis amyloidosis.
  • Example 4 Screening for dialysis amyloidosis using Congo Red. Inhibitory effect of amyloid fibril elongation reaction
  • Congo Red (Sigma) was dissolved in purified water to a concentration of 1 OmM and diluted to a concentration of 300.
  • the reaction solution was dispensed in 50 L aliquots into PCR tubes (for 0.5 mL) and heated to 37 ° C to initiate the amyloid fibril elongation reaction.
  • Amyloid fiber elongation was measured by the amount of centrifugal supernatant protein, and the decrease in the amount of centrifugation supernatant protein before the start of the reaction and 4 hours after the reaction was used as an indicator of amyloid fiber elongation.
  • the control group was prepared by adding purified water instead of the above Congolese. Quantification of the protein in the centrifuged supernatant was performed as follows.
  • the reaction solution was centrifuged at 14500 rpm at 4 ° C for 20 minutes to precipitate amyloid fibrils, and the amount of protein in the supernatant was measured using a Micro BCA protein quantification kit (Pierce).
  • Congolese is useful as a therapeutic agent for dialysis amyloidosis because it strongly suppresses the elongation reaction of dialysis amyloid fibrils.
  • chondroitin sulfate C sodium salt dissolve in water for injection to make 100 mL, filter using a 0.2 m membrane filter, fill aseptically into a vial, and mix with the injection. did.
  • the dialysis amyloid fiber polymerization nucleus can be manufactured in large quantities. Therefore, it is industrially useful, and the obtained dialyzed amyloid fibril polymerization nucleus can be used as it is for screening for a therapeutic agent for dialysate amyloidosis.

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Abstract

L'invention concerne un procédé de production de noyaux de polymérisation de fibres d'amyloïde par dialyse, consistant à faire réagir lesdits noyaux avec de la β2-microglobuline recombinante pour provoquer une fragmentation de passage. Ladite invention concerne également une méthode de criblage de remèdes destinés à l'amyloïde de dialyse consistant à inhiber la réaction impliquant des fibres d'amyloïde au moyen des noyaux de polymérisation susmentionnés, et des remèdes élaborés pour l'amyloïde de dialyse tels que le glycosaminoglycane, le fucoïdane, des composés colorants diazoïques sulfatés, etc. qui sont obtenus au moyen de la méthode de criblage susmentionnée.
PCT/JP2000/009145 2000-02-01 2000-12-22 Procede de production de noyaux de polymerisation de fibres d'amyloide par dialyse, methode de criblage de remedes pour amyloide de dialyse et remedes pour amyloide de dialyse WO2001057078A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001222228A AU2001222228A1 (en) 2000-02-01 2000-12-22 Process for producing dialytic amyloid fiber polymerization nuclei, method of screening remedies for dialytic amyloidosis and remedies for dialytic amyloidosis

Applications Claiming Priority (2)

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JP2000023514A JP2005231998A (ja) 2000-02-01 2000-02-01 透析アミロイド線維重合核の製造方法及び透析アミロイド−シス治療剤のスクリーニング方法並びに透析アミロイドーシス治療剤
JP2000-23514 2000-02-01

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015184A1 (fr) * 1993-11-30 1995-06-08 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Substance pour detecter le depot d'amyloide
WO1996028187A1 (fr) * 1995-03-15 1996-09-19 Queen's University At Kingston Procedes de traitement de l'amylose
DE19907493A1 (de) * 1998-02-23 1999-08-26 Exonhit Therapeutics Sa Verfahren zum Erhalten von Zell- und Tiermodellen neurodegenerativer Erkrankungen und Mittel zur Durchführung dieser Verfahren

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015184A1 (fr) * 1993-11-30 1995-06-08 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Substance pour detecter le depot d'amyloide
WO1996028187A1 (fr) * 1995-03-15 1996-09-19 Queen's University At Kingston Procedes de traitement de l'amylose
DE19907493A1 (de) * 1998-02-23 1999-08-26 Exonhit Therapeutics Sa Verfahren zum Erhalten von Zell- und Tiermodellen neurodegenerativer Erkrankungen und Mittel zur Durchführung dieser Verfahren

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KLUNK W.E. ET AL.: "Crysamine-G, a lipophilic analogue of congo red, inhibits A beta-induced toxicity in PC12 cells", LIFE SCI., vol. 63, no. 20, 1998, pages 1807 - 1814, XP002937482 *
LEVEUGLE B. ET AL.: "Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide", J. NEUROCHEM., vol. 70, no. 2, 1998, pages 736 - 744, XP002937481 *
TAKEFUMI SHIMOJO ET AL.: "Amyloid seni kaisei kikou no hanno sokudoronteki kaiseki; Mouse rouka amyloidosis, Alzheimer's disease beta amyloidosis, oyobi touseki amyloidosis ni okeru ippansoku", TAISHAKEI SHIKKAN CHOUSA KENKYUHAN AMYLOIDOSIS BUNKAKAI, 1996 NENDO KENKYU HOUKOKU, March 1997 (1997-03-01), pages 54 - 57, XP002937480 *

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