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METHOD FOR SCREENING BINDING INHIBITOR OF RAGE AND AGE commons

Foreign code F120006980
File No. S2010-1251-C0
Posted date Oct 29, 2012
Country WIPO
International application number 2011JP071669
International publication number WO 2012039469
Date of international filing Sep 22, 2011
Date of international publication Mar 29, 2012
Priority data
  • P2010-214019 (Sep 24, 2010) JP
Title METHOD FOR SCREENING BINDING INHIBITOR OF RAGE AND AGE commons
Abstract Provided is a method for screening a binding inhibitor of RAGE and AGE focused on the new activity of β-amyloid peptide. Provided is a method for screening a binding inhibitor of RAGE and AGE by sorting candidate compounds inhibiting the activity affecting the binding affinity of RAGE and AGE of β-amyloid peptide through finding, for the first time, that the β-amyloid peptide makes the binding of RAGE and AGE change to high binding affinity. The binding inhibitor obtained by this screening method can be used as a therapeutic agent for any diseases or symptoms caused by the binding of RAGE and AGE in which β-amyloid peptide involves. Especially, the binding inhibitor is capable of contributing to the development of the therapeutic drug for Alzheimer's disease focused on the new mechanism.
Outline of related art and contending technology BACKGROUND ART
(Alzheimer's disease) is Alzheimer's disease, progressive neurological disorder of cognitive function and adversely affected, falling off of the cerebral nerve cells of the considered for developing. For the genesis of Alzheimer's disease, β - amyloid peptide is the most promising current theory. This theory is, a so-called senile plaques in Alzheimer's disease brain structure of the modified protein deposition has been found that a large number of, as the important constituents of neuritic plaques, β - amyloid peptide has been identified, the analysis of familial Alzheimer's disease have been found in the amyloid precursor protein (Amyloid Precursor Protein: APP) and presenilin 1/2(Presenillin 1/2) variants, increased production of β - amyloid peptides can act to be known, β - amyloid β oligomer or a further polymer sheet structure has a neurotoxic effects are based on the findings.
From the knowledge as described above, suppress production of β - amyloid in the brain, promote metabolism, anti-β - amyloid peptide antibody, amyloid β - oligomerization, polymerization inhibitor is continued to be developed. For example, Alzheimer's disease β - amyloid peptide inhibiting the formation of the therapeutic compound is disclosed (new ginsenosides compound) (Patent Document 1: Japanese Patent Application JP-2008-506686). Β - amyloid protein in Alzheimer's disease and other disorders of the fibril formation of low molecular weight peptides for the treatment of is disclosed (Patent Document 2: Japanese Patent Application JP-2007-535494). To suppress the flocculation of the amyloid protein and the material for the action, lipocalin-type prostaglandin D synthase (L-PGDS) is focused on the disclosure of which is for the agent (Patent Document 3: Japanese Patent Application Laid-open 2007-284351). Β - amyloid peptide and Alzheimer's disease using the method of screening a therapeutic or prophylactic agent is disclosed (Patent Document 4: Japanese Patent Application Laid-open 2006-265189). In addition, as a screening method for the therapeutic agent of Alzheimer's disease, amyloid-β - (1-40) activity as an index for the transport of those is also disclosed (Patent Document 5: Patent Publication 4270976). Otherwise, the β - amyloid peptide, β-secretase or γ secretase amyloid precursor protein and that is generated by the action of the β secretase (BACE) focused on the γ secretase inhibitors or inhibitors, β - amyloid peptide antibody is an anti - β - amyloid peptide itself has been developed (see Fig. 1). However, such an effort has been made in spite of the inventors, is a promising potential new not available in the market.
Β - amyloid peptide is, its own as a oligomer or polymer fibers to form a halide, and is operative for a certain type of receptor structure, the neurotoxin is believed to be exhibited. Is mentioned as one of the receptor, is RAGE(Receptor for advanced glycation endproducts). This receptor, a receptor for AGE(advanced glycation endproducts) as the name implies has been identified as, RAGE ligand β - amyloid peptide in vivo may be considered to be one of the (non-patent document 1-3). AGE is, a reducing sugar and a protein non-enzymatic saccharization reaction (also referred to as the Maillard reaction) is generated in the late stages of the structure (see Fig. 2) is a general term. AGE and RAGE is, as well as the vascular complications of diabetes, arteriosclerosis, tumor growth, metastasis, inflammatory response is also involved in Alzheimer's disease has been bright et al. In addition, the test tube by AGE and RAGE-binding experiments for the assay method (measurement method) has been reported (Non-Patent Document 4). However, in relation to amyloid β - RAGE, involved in Alzheimer's disease may be determined based on how the, has been solved sufficiently less.
Scope of claims (In Japanese)請求の範囲 [請求項1]
RAGE(Receptor for advanced glycation endproducts)、AGE(advanced glycation endproducts)及びβ‐アミロイドペプチドを含む検査系において、RAGEとAGEの結合を抑制しうる候補物質を選別することによるRAGEとAGEの結合抑制剤のスクリーニング方法。

[請求項2]
以下の工程を含む、請求項1に記載のRAGEとAGEの結合抑制剤のスクリーニング方法:
1)AGE化蛋白質を固定した固相を準備する工程;
2)候補物質を含む溶液を固相に加える工程;
3)β‐アミロイドペプチドを含む溶液を固相に加える工程;
4)可溶化したRAGEを含む溶液を固相に加える工程;
5)上記4)の工程の後、固相に固定したAGE化蛋白質に結合したsRAGEの量を測定してRAGEとAGEの結合親和性を測定し、RAGEとAGEの結合を抑制しうる候補物質を選別する工程。

[請求項3]
候補物質とβ‐アミロイドペプチドを反応させた後、RAGEとAGEの結合親和性を測定することを特徴とする、請求項1又は2に記載のRAGEとAGEの結合抑制剤のスクリーニング方法。

[請求項4]
β‐アミロイドペプチドが、以下の配列番号1に示すアミノ酸配列、又は配列番号1に示すアミノ酸配列のうちC末端側のアミノ酸が1~2個欠失又は付加されたアミノ酸配列からなるポリペプチドである、請求項1~3のいずれか1に記載のRAGEとAGEの結合抑制剤のスクリーニング方法:
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA(配列番号1)

[請求項5]
AGEのサブタイプが、AGE2、AGE3、AGE4及びAGE5より選択されるいずれか1種又は2種以上である、請求項1~4のいずれか1に記載のRAGEとAGEの結合抑制剤のスクリーニング方法。

[請求項6]
RAGEとAGEの結合抑制剤が、アルツハイマー病治療薬、糖尿病合併症治療薬、動脈硬化治療薬のいずれかである、請求項1~5のいずれか1に記載のRAGEとAGEの結合抑制剤のスクリーニング方法。

[請求項7]
固相、AGE化蛋白質、β‐アミロイドペプチド、及び可溶化RAGEを構成として含む、RAGEとAGEの結合抑制剤のスクリーニング用キット。

[請求項8]
請求項1~6のいずれか1に記載のRAGEとAGEの結合抑制剤のスクリーニング方法により選別されるRAGEとAGEの結合抑制剤。

[請求項9]
選別されるRAGEとAGEの結合抑制剤が、以下の式(I)~(III)のいずれかで示す化合物である、請求項8に記載のRAGEとAGEの結合抑制剤。
[化1]

[化2]

[化3]

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY
  • Inventor
  • NISHIBORI, Masahiro
  • MORI, Shuji
  • TAKAHASHI, Hideo
  • WAKE, Hidenori
  • LIU, Keyue
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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