JP2010090054A - Inhibitor of amyloid fiber formation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an inhibitor of amyloid fiber formation, containing a substance inhibiting the formation of the amyloid fiber of a TTR protein and having a high safety, as an active ingredient. <P>SOLUTION: The inhibitor of amyloid fiber formation contains a cyclodextrin derivative modified by at least one kind selected from the group consisting of a sugar which may be substituted, a peptide and polyethylene glycol, or its salt as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an amyloid fibril formation inhibitor comprising a cyclodextrin derivative or a salt thereof as an active ingredient, and a medicament for the prevention and / or treatment of amyloidosis comprising the amyloid fibril formation inhibitor.

  Amyloidosis refers to a group of diseases in which a protein having a β-sheet structure is polymerized to form insoluble fibrils called amyloid, which are deposited in the living body and cause tissue damage. Virchow, a German pathologist, has discovered that tissue samples of amyloidosis are stained purple with iodine. From this result, Virchow considered that the substance deposited in the tissue was a polysaccharide, named it “starch-like substance”, that is, “amyloid”, and proposed that the pathological condition caused by amyloid deposition was called amyloidosis . Subsequent studies have shown that the main component of amyloid is a protein that forms fibers by polymerizing like nylon, and that amyloid contains serum amyloid P component, glycosaminoglycan, and the like. At present, amyloid is defined as “a collection of unbranched fine fibers having a width of 8 to 15 nm that causes a birefringence that is dyed orange-red with Congo red staining and strongly shines green when observed under a polarizing microscope”.

  Amyloidosis includes various diseases such as familial amyloid polyneuropathy (FAP), Alzheimer's disease, Creutzfeldt-Jakob disease (mad cow disease), Huntington's disease and other inherited diseases. Among them, FAP is amyloidosis that causes amyloid deposition in systemic organs such as peripheral nerves, autonomic nerves, kidneys, skin, and mucous membranes, and infiltrates in an autosomal dominant manner, and is widely used in Japan, particularly in the Kyushu and Chubu regions. Case has been confirmed. Since the first report of Portuguese FAP cases in 1952, similar cases have been reported from around the world. Amyloid fibrils that cause FAP are mainly composed of mutated serum protein transthyretin (TTR).

  Normal TTR has a three-dimensional structure including a lot of β-sheet structures, and is produced by the liver, the choroid plexus, the retina, pancreatic α cells, etc., and more than 90% of them are said to be produced by the liver. Yes. Normal TTR forms a tetramer and plays a role as a transporter of vitamin A via thyroxine (T4), retinol binding protein (RBP) and the like. More than 100 types of mutants of normal TTR have been reported so far, and it has been clarified that the structural stability is low and the structural change from tetramer to monomer is likely to occur.

  Many FAPs in Japan are type I FAPs that use Val30Met type mutant TTR as a causative protein. The major characteristics of type I FAP are polyneuritis and autonomic neuropathy (alternative diarrhea and constipation, orthostatic hypotension, urination injury, etc.) with perceptual impairment that rises symmetrically from the lower limb end. Both are caused by nerve damage caused by amyloid. Later, amyloid deposits in the heart, kidney, and gastrointestinal tract become prominent, causing dysfunction of these organs. Generally, it is a disease with a poor prognosis that develops in the late 20s to 30s, becomes unwalkable in 10 years, and dies from infection, heart failure, renal failure, etc. in the course of 10 to 20 years. Is also one of the designated intractable diseases.

  A mutant TTR protein that can lead to type I FAP is said to have lower structural stability than normal TTR protein, and β-sheet structures in the molecule associate with each other to form insoluble amyloid fibrils and deposit in tissue. Therefore, it is considered that type I FAP can be prevented and / or treated by inhibiting amyloid fibril formation by the mutant TTR protein. As a method of suppressing amyloid fibril formation, a method of inhibiting the dissociation of tetrameric TTR molecule has been tried, but clinical therapeutic effect has not been recognized (Yoshiki Sekijima et.al., "Long- term effects of diflunisal on familial amyloid polyneuropathy, "2008, VIIth International symposium on Familial Amyloid Polyneuropathy). Furthermore, no highly safe substance that suppresses amyloid fibril formation that can be applied to the prevention and / or treatment of amyloidosis has been reported so far (Non-patent Document 1).

The contents of all documents described in this specification, including the following documents, are incorporated herein by reference.
Yukio Ando, (2005), Med Mol Morphol, 38: pp. 142-154

  Accordingly, a first object of the present invention is to provide a highly safe amyloid fibril formation inhibitor containing a substance that suppresses amyloid fibril formation of a TTR protein as an active ingredient. Furthermore, a second object of the present invention is to provide a medicament for the prevention and / or treatment of amyloidosis, particularly a medicament for the prevention and / or treatment of familial amyloidosis polyneuropathy (FAP), comprising the inhibitor. Furthermore, the present invention provides a medicament for preventing the onset of sensory impairment and autonomic neuropathy caused by amyloidosis, and a medicament for treatment that enables prevention of progression of the perceptual disorder and autonomic neuropathy. There is.

  As a result of various studies to solve the above problems, the present inventors have found that a cyclodextrin derivative can suppress amyloid fibril formation and have completed the present invention. Therefore, according to the present invention, an amyloid fibril formation inhibitor comprising as an active ingredient a cyclodextrin derivative modified with at least one selected from the group consisting of an optionally substituted sugar, a peptide, and polyethylene glycol, or a salt thereof. Is provided.

  In a preferred embodiment of the amyloid fibril formation inhibitor of the present invention, the cyclodextrin derivative is a β-cyclodextrin derivative.

［式中、Ｒはカルボキシル基、メトキシカルボニル基、ヒドロキシメチル基、ヒドロキシエチル基、メチル基、エチル基、ホルミル基、又はアセチル基である］
の化合物である。 In a preferred embodiment of the amyloid fibril formation inhibitor of the present invention, the cyclodextrin derivative is represented by the following formula 1.

[Wherein, R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group]
It is a compound of this.

  According to another aspect of the present invention, there is provided a medicament for preventing and / or treating amyloidosis comprising the amyloid fibril formation inhibitor of the present invention.

  The amyloid fibril formation inhibitor of the present invention can significantly suppress amyloid fibril formation. Therefore, the medicament containing the amyloid fibril formation inhibitor of the present invention is useful as a medicament for the prevention and / or treatment of amyloidosis, and particularly familial amyloidosis polyneuropathy (FAP), which has only a symptomatic treatment or a liver transplantation treatment method. Can be used as a highly effective medicine. Furthermore, the pharmaceutical of the present invention is effective for the highly safe cyclodextrin derivative in which the amyloid fibril formation inhibitor of the present invention is widely used as a pharmaceutical excipient for the purpose of solubilizing and stabilizing fat-soluble drugs and the like. Because it is contained as a component, it is a highly safe pharmaceutical for the human body. Therefore, the medicament of the present invention is a medicament that can be put to practical use at an early stage in the prevention and / or treatment of amyloidosis because of its effectiveness and safety.

  In the cyclodextrin derivative, which is an active ingredient of the amyloid fibril formation inhibitor of the present invention, a part or all of the glucose skeleton constituting the cyclodextrin is modified.

  Cyclodextrin is a cyclic oligosaccharide in which several molecules of D-glucose are bonded by α (1 → 4) glucoside bonds, and has a characteristic that a hydrophobic molecule can be included in the pores in the molecule. Cyclodextrins are widely used in the pharmaceutical field from the viewpoint of their properties and safety, such as solubilization and stabilization of fat-soluble drugs and reduction of local irritation (Kaneto Uekama, (2004), YAKUGAKU ZASSHI, 124, ( 12), pp.909-935). Furthermore, cyclodextrin exhibits actions such as control of cholesterol and phospholipids and protein stabilization, and has various functions as well as a use as a mere pharmaceutical additive.

  The cyclodextrin that constitutes the cyclodextrin derivative is not particularly limited as long as it can include molecules. For example, α-cyclodextrin having 6 glucose skeletons and β- having 7 glucose skeletons Cyclodextrin and γ-cyclodextrin having 8 glucose skeletons are preferable. Among them, β-cyclodextrin is easily available, has a proven track record as a pharmaceutical excipient, and has a wide variety of inclusion targets. Is more preferable.

  The cyclodextrin derivative is not particularly limited as long as it can suppress amyloid fibril formation of TTR protein. For example, cyclodextrin modified with one or more selected from the group consisting of sugar, peptide, and polyethylene glycol A derivative is preferable, and a cyclodextrin derivative modified with a sugar is more preferable. The number of modifying groups in the cyclodextrin derivative is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and still more preferably 1 type.

  Examples of sugars used for modification of cyclodextrin derivatives include monosaccharides such as glucose, mannose, galactose, fructose, ribose, xylose, and arabinose; maltose, trehalose, cozybiose, nigerose, isomaltose, sophorose, laminaribio , Cellobiose, gentiobiose, lactose, sucrose, palatinose, melibiose, lutinose, primebellose, tulanose and other disaccharides; maltotriose, isomaltotriose, panose, cellotriose, manninotriose, solatriose, melistose, planteose, gentianose Not only trisaccharides such as umbelliferose, lactosucrose, and raffinose, but also xylooligosaccharides with higher polymerization degree, galactooli Sugar, maltooligosaccharides, and oligosaccharides such as isomaltooligosaccharides are preferred.

  The peptide that modifies cyclodextrin preferably has, for example, 1 to 10 amino acids, more preferably 2 to 8 amino acids, and still more preferably 2 to 6 amino acids. . Although the kind of amino acid which comprises a peptide can be set suitably, the thing containing many amino acids which have a hydrophobic side chain is preferable.

  The polyethylene glycol that modifies cyclodextrin preferably has a molecular weight of 200 to 50000, more preferably 1000 to 50000, and still more preferably 10,000 to 30000.

  In the sugar for modifying cyclodextrin, part or all of the hydroxyl group may be substituted with a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, an acetyl group, etc. . As such an optionally substituted sugar, 6-O-α-maltose and 6-O-α- (4-O-α-D-gluconyl) -D-glucose are most preferably used.

［式中、Ｒはカルボキシル基、メトキシカルボニル基、ヒドロキシメチル基、ヒドロキシエチル基、メチル基、エチル基、ホルミル基、又はアセチル基である］
の化合物である。 A preferred embodiment of the cyclodextrin derivative is represented by the following formula 1

[Wherein, R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group]
It is a compound of this.

As a method for synthesizing the compound of the above formula 1, a method known so far can be used without limitation. For example, Ishiguro et al. (Toshihiro Ishiguro et. Al., (2001), Carbohydrate Research, 331, pp. 423-430). As an example, synthesis of dimethylacetyl-β-cyclodextrin (2,6-di-O-methyl-3-O-acetyl-b-cyclodextrin) is shown below (FIG. 6).
After the dried dimethyl-β-cyclodextrin (2,6-di-O-methyl-b-cyclodextrin) was dissolved in anhydrous pyridine, acetic anhydride was added over 2 to 3 hours under anhydrous conditions at room temperature. Warm to ℃ and stir for about 12 hours. After the completion of the reaction is confirmed by thin layer chromatography (TLC; methanol: chloroform = 15: 2), ice water is added to the reaction solution to stop the reaction, followed by extraction with chloroform. Thereafter, it is washed twice with 2 mM aqueous sodium hydrogen carbonate solution and then with water. The obtained reaction product is dried over anhydrous magnesium sulfate, and then separated and / or purified by silica gel chromatography (Kieselgel 60; 0.063 to 0.2 mm [70 to 230 mesh]). Using a moving bed in which the ratio of chloroform to methanol was gradually increased (chloroform: methanol = 15: 2), dimethylacetyl-β-cyclodextrin having a low degree of acetyl group substitution was eluted in this order, and then recrystallized with water. To do. Dimethylacetyl-β-cyclodextrin is confirmed by TLC (methanol: chloroform = 15: 2) using a dimethylacetyl-β-cyclodextrin preparation whose degree of substitution has been examined by NMR.

  When the amyloid fibril formation inhibitor of the present invention contains the compound of the above formula 1 as an active ingredient, for example, the concentration of the compound of the above formula 1 in which R is a carboxyl group or a hydroxymethyl group is 0.2 mg / mL TTR 10 mM or more is preferable with respect to the protein, 40 mM or more is more preferable, and 100 mM or more is more preferable.

As the cyclodextrin derivatives, including those described above, for example, the compounds described in Table 1 have been known so far.

  The compounds in Table 1 are described in Ueka et al. Literature (Kaneto Uekama, Fumitoshi Hirayama, and Tetsumi Irie, (1998), Chem. Rev., 98, pp. 2045-2076), and the production method thereof is described in the literature. Is described in the literature cited.

  Common methods for modifying cyclodextrins include methylation, hydroxyalkylation such as hydroxyethyl and hydroxypropyl, glucosylation, maltosylation, alkylation, acylation, acetylation, sulfation, sulfobutylation, carboxymethylation Modification methods such as carboxyethylation, amination, carboxylation, tosylation, and dimethylacetylation, and a combination of these methods are known. Modification of these cyclodextrins can be carried out with reference to, for example, the following literature: cyclodextrin-basics and applications-supervised by Fujio Toda, industrial books.

  The amyloid fibril formation inhibitor of the present invention may be a cyclodextrin derivative or a salt thereof. The ratio of the cyclodextrin derivative or a salt thereof contained in the amyloid fibril formation inhibitor of the present invention is not particularly limited as long as it is an amount capable of suppressing amyloid fibril formation of TTR protein. For example, 80% to 100% Is preferred.

  The amyloid fibril formation inhibitor of the present invention can be used in either a solid or liquid form as long as it contains an effective amount of a cyclodextrin derivative or a salt thereof, and a pharmaceutically acceptable carrier or additive is added thereto. It can also be blended and prepared as a solid or liquid pharmaceutical composition.

  The amyloid fibril formation inhibitor of the present invention can be used for the purpose of suppressing amyloid fibril formation, and can be included, for example, in a medicament for the prevention and / or treatment of amyloidosis. Therefore, another aspect of the present invention is a medicament for preventing and / or treating amyloidosis, which comprises the amyloid fibril formation inhibitor of the present invention.

  Examples of amyloidosis to which the medicament of the present invention is applied include, for example, familial amyloidosis polyneuropathy (FAP), neurodegenerative diseases such as Alzheimer's disease, bovine spongiform encephalopathy (BSE), Examples include Creutzfeldt-Jakob disease (CJD), laughing death syndrome, scrapie, and deformed Creutzfeldt-Jakob disease in humans. Of these, familial amyloidosis polyneuropathy is a particularly suitable subject of the medicament of the present invention.

Without being bound to any particular theory, the mechanism of action of the medicament of the present invention is presumed as follows.
Amyloid fibrils by transthyretin (TTR), which is a serum protein, are formed through the following three stages. First, transthyretin present in serum as a tetrameric protein is decomposed into monomers by some action. Next, most of the monomer is decomposed and part is excreted out of the body as urine via a biological metabolic pathway, but part of the monomer is recombined to form a β-sheet structure. Eventually, this β-sheet structure is linearly polymerized to produce insolubilized fibrous amyloid fibers. Mutant transthyretin has the property that tetrameric proteins are easily dissociated into monomers, resulting in an increase in the production of amyloid fibrils. As a result of intensive studies on the β-sheet structuring and / or stabilization of transthyretin, the present inventors have used amyloid fibrils by using the cyclodextrin derivative of the present invention, which is an improved cyclodextrin capable of including a hydrophobic molecule. It has been found that formation can be suppressed. This is because hydrophobic amino acids (for example, tryptophan etc.) may be involved in β-sheet formation and / or stabilization of transthyretin, and the cyclodextrin derivative of the present invention is a hydrophobic amino acid of transthyretin. Is expected to inhibit protein polymerization by inhibiting β-sheet formation of transthyretin monomer in the process of amyloid fibril formation, resulting in suppression of amyloid fibril formation. Is done. Therefore, the amyloid fibril formation inhibitor of the present invention can suppress the amyloid fibril formation reaction from mutant transthyretin, and the medicament containing the amyloid fibril formation inhibitor of the present invention prevents and / or prevents amyloidosis. Can be treated.

  For example, among patients who develop FAP, patients with mild symptoms can prevent the progression and worsening of symptoms by administering the medicament of the present invention. There are cases in which a therapeutic effect can be expected even for patients with severe symptoms. In addition, an individual having a mutant transthyretin is a potential patient who has a high possibility of developing FAP with aging, but the administration of the medicament of the present invention can prevent the onset of FAP.

  As the medicament of the present invention, the amyloid fibril formation inhibitor of the present invention may be used as it is. However, the amyloid fibril formation inhibitor of the present invention which is usually an active ingredient or a mixture containing the same and one or more preparations It is desirable to prepare and use a form of a pharmaceutical composition containing a pharmaceutical additive.

  In the prevention and treatment of FAP, it is desirable to use not only the amyloid fibril formation inhibitor of the present invention but also a nonsteroidal anti-inflammatory drug that stabilizes the transthyretin tetramer, such as diflunisal.

  Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. Examples of the pharmaceutical composition suitable for parenteral administration include Injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, transdermal absorbents, transmucosal absorbents, and the like. Examples of pharmaceutical additives used in the production of the above pharmaceutical composition include excipients such as lactose and oligosaccharides, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, and diluents. , Bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, etc., and these can be used by those skilled in the art depending on the form of the pharmaceutical composition. Can be selected as appropriate, and two or more of them may be used in combination.

  An example of a preferred form of the medicament of the present invention is an injection. Injectables are usually substantially free of non-aqueous solvents (or water-soluble organic solvents) and can be dissolved or diluted with a solvent whose medium is substantially water. Furthermore, lyophilized preparations (lyophilized injections) can also be mentioned as a preferred form of the pharmaceutical product of the present invention. Even such lyophilized preparations can be dissolved in at least one liquid or solvent selected from water for injection (distilled water for injection), infusion containing electrolyte solution (such as physiological saline), nutrient infusion, and the like. An injection solution can be easily prepared, and a glass container and a plastic container can be used as the container. The amyloid formation inhibitor of the present invention can be contained in an amount of 0.01 parts by weight or more, preferably 0.1 to 10 parts by weight with respect to 100 parts by weight of the contents of the injection.

  The dosage and number of administrations of the medicament of the present invention are not particularly limited, and can be appropriately selected according to conditions such as the age, weight, and sex of the patient, the type and severity of the disease, the purpose of prevention or treatment, etc. It is. Usually, in the case of parenteral administration, the active ingredient amount is preferably 1 mg to 30 g per day, more preferably 10 mg to 10 g, and more preferably 100 mg to 5 g, but the dose is divided into several times a day. May be.

  The amyloid fibril formation inhibitor of the present invention or the medicament of the present invention can be used not only as a pharmaceutical as described above, but also as a quasi-drug, cosmetic, functional food, nutritional supplement, food and drink, etc. . When used as a quasi-drug or cosmetic, it can be used together with various adjuvants commonly used in the technical field such as quasi-drug or cosmetic, if necessary. Or, when used as a functional food, nutritional supplement, or food and drink, it is usually used in foods such as sweeteners, spices, seasonings, preservatives, preservatives, bactericides, and antioxidants as necessary. You may use with the additive used. Further, it may be used in a desired shape such as solution, suspension, syrup, granule, cream, paste, jelly, etc., or as necessary. The ratio contained in these is not specifically limited, It can select suitably according to a use purpose, a usage form, and a usage-amount.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples.

(1) Experimental Material Transthyretin (TTR) used in this example was purified from serum obtained from healthy volunteers. The purity test was performed using non-heated (non-reduced) SDS-PAGE. Cyclodextrin (CyD) derivatives 6-O-a- (4-O-a-Dglucuronyl) -D-glucosyl-b-CyD (GUG-b-CyD) and 6-O-a-maltosyl-b -CyD (G ₂ -b-CyD) are Ishiguro et al (Toshihiro Ishiguro et. al., (2001), Carbohydrate Research, 331, pp.423-430) were synthesized according. As comparative controls, Hydropropylated-b-CyD (HP-b-CyD) and Sulfobutyl ether-b-CyD (SBE-b-CyD) were also synthesized according to the above documents.

(2) Method for forming amyloid fibrils TTR was prepared with 20 mM acetate buffer (pH 3.0-6.5) containing 100 mM sodium chloride to a concentration of 0.2 mg / mL, and incubated at 37 ° C. with light shielding. Amyloid fibrils were formed.

(3) Method for measuring amyloid fibrils The prepared amyloid fibrils were detected using thioflavin T, which is a fluorescent probe that selectively binds to the polymerized b-sheet. 10 mL of the incubated sample was added to 1 mL of 10 mM thioflavin T solution dissolved in 50 mM glycine solution (pH 9.5) and mixed to prepare a measurement sample. Using a Hitachi fluorescence spectrophotometer F-4500, the fluorescence intensity of 489 nm excited by 442 nm excitation light at 25 ° C. was measured. The slit width was measured at 5 nm on both the excitation side and the fluorescence side.

(4) Result of inhibition of amyloid fibril formation by GUG-b-CyD Using the above method, wild type TTR derived from human serum is treated with amyloid in the presence or absence of 10 mM, 20 mM or 30 mM GUG-b-CyD. And quantitative analysis of amyloid fibril formation of TTR was performed (FIG. 1). As a result of analysis, in the presence of GUG-b-CyD, the ability of TTR to form amyloid fibrils was significantly reduced in a dose-dependent manner. Furthermore, the initial administration (Day 0) of 40 mM GUG-β-CyD was performed, and the maintenance effect of GUG-β-CyD on the suppression of amyloid fibril formation was evaluated by sampling over time and measuring amyloid fibrils (Fig. 7). As FIG. 7 shows, the initial administration of GUG-β-CyD was able to suppress amyloid fibril formation over time.

(5) Inhibition result of amyloid fibril formation by G ₂ -b-CyD Using the above method, wild type TTR derived from human serum is subjected to coexistence or non-coexistence of 1 mM, 10 mM or 100 mM G ₂ -b-CyD. And quantified analysis of TTR amyloid fibril formation (FIG. 2). As a result of the analysis, when G ₂ -b-CyD was allowed to coexist, the amyloid fibril formation ability of TTR was reduced in a dose-dependent manner, although at a relatively high concentration.

Comparative example

(1) Evaluation of the effects of branched sugar chains in cyclodextrin derivatives 1
Using the above method, human serum-derived wild-type TTR is amyloidized in the presence or absence of 40 mM each of HP-b-CyD, GUG-b-CyD, G ₂ -b-CyD, Quantitative analysis of TTR amyloid fibril formation was performed (FIG. 3). As a result of the analysis, the inhibitory effect of cyclodextrin derivatives on amyloid fibrils greatly changed due to the difference in branched sugar chains between various branched b-CyDs, and GUG-b-CyD showed the strongest amyloid formation inhibitory effect.

(2) Effect assessment of branched sugar chains in cyclodextrin derivatives 2
Using the above method, wild type TTR derived from human serum is amyloidated in the presence or absence of 40 mM SBE-b-CyD and GUG-b-CyD, and quantification of amyloid fibril formation of TTR Analysis was performed (FIG. 4). As a result of the analysis, the inhibitory effect of cyclodextrin derivatives on amyloid fibrils was greatly changed by the difference in branched sugar chains between various branched b-CyDs, and was enhanced on the contrary in SBE-b-CyD.

(3) Comparison with cyclodextrin Using the above-mentioned method, wild-type TTR derived from human serum is amyloidated in the presence or absence of 20 mM GUG-b-CyD and β-CyD, respectively. Quantitative analysis of amyloid fibril formation was performed (FIG. 5). As a result, when GUG-b-CyD was allowed to coexist, an inhibitory effect on amyloid fibril formation was observed, but even when β-CyD was allowed to coexist, no inhibitory effect was obtained. From these results, it was suggested that β-CyD can inhibit amyloid fibril formation only after being modified.

  Diseases that cause organ damage due to amyloid fibril deposition include FAP, Alzheimer's disease, Creutzfeldt-Jakob disease (mad cow disease), Huntington's disease, and other inherited diseases. Since the deposition of amyloid fibrils is due to the formation of insoluble fibrous aggregates of proteins, cyclodextrin derivatives can also be applied in the treatment of these various amyloidosis diseases.

FIG. 1 shows the results of suppression of amyloid fibril formation by 10 mM, 20 mM and 30 mM GUG-b-CyD. FIG. 2 shows the results of suppression of amyloid fibril formation by 1 mM, 10 mM, and 100 mM G ₂ -b-CyD. FIG. 3 shows the results of comparison of suppression of amyloid fibril formation in the presence or absence of HP-b-CyD, GUG-b-CyD, and G ₂ -b-CyD. FIG. 4 shows the suppression results of amyloid fibril formation in the presence or absence of SBE-b-CyD and GUG-b-CyD. FIG. 5 shows the results of suppression of amyloid fibril formation in the presence or absence of GUG-b-CyD and β-CyD. FIG. 6 shows an outline of the synthesis route of dimethylacetyl-β-cyclodextrin. FIG. 7 shows the sustained effect of GUG-β-CyD in inhibiting amyloid fibril formation.

Claims (4)

  An amyloid fibril formation inhibitor comprising, as an active ingredient, a cyclodextrin derivative modified with at least one selected from the group consisting of an optionally substituted sugar, peptide, and polyethylene glycol, or a salt thereof.   The amyloid fibril formation inhibitor according to claim 1, wherein the cyclodextrin derivative is a β-cyclodextrin derivative. The cyclodextrin derivative is represented by the following formula 1

[Wherein, R is a carboxyl group, a methoxycarbonyl group, a hydroxymethyl group, a hydroxyethyl group, a methyl group, an ethyl group, a formyl group, or an acetyl group]
The amyloid fibril formation inhibitor of Claim 1 or 2 which is a compound of these.   The pharmaceutical for the prevention and / or treatment of amyloidosis containing the amyloid fibril formation inhibitor of any one of Claims 1-3.

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