AMYLOID β-PROTEIN-SPECIFIC PRODUCTION-INHIBITING POLYPEPTIDE
|Posted date||Nov 29, 2013|
|International application number||2013JP050663|
|International publication number||WO 2013108780|
|Date of international filing||Jan 16, 2013|
|Date of international publication||Jul 25, 2013|
|Title||AMYLOID β-PROTEIN-SPECIFIC PRODUCTION-INHIBITING POLYPEPTIDE|
|Abstract||The main purpose of the invention is to develop a compound that specifically inhibits the production of Aβ-protein and serves as an active ingredient of a drug to treat and/or prevent Alzheimer's disease. Provided to achieve this goal are a polypeptide that binds to the N-terminal region of βCTF, the polypeptide having an amino acid sequence shown by any one of SEQ ID NO: 1, 13, 14, and 22; and a γ-secretase activity inhibitor, β-secretase activity inhibitor, Aβ-protein production-inhibiting agent, and an agent for treating and/or preventing Alzheimer's disease, the inhibitors and agents containing this polypeptide.|
|Outline of related art and contending technology||
Amyloid β protein (hereinafter, sometimes referred to herein A β protein.) Is, as one of the etiology of Alzheimer's disease is believed to be the 1 protein. Specifically, this A β protein is accumulated in the brain, of Alzheimer's disease has been recognized as one of the 1. Such A β protein, the brain due to build up the molecular structure of the rigid fibrous form, in the brain and nerve cells can be lethal to, a neurological function is damaged as a result of developing Alzheimer's disease are considered.
A β protein, cell transmembrane protein amyloid precursor protein (hereinafter, sometimes referred to as APP herein.) Is cleaved by β secretase cell transmembrane protein β CTF is, by cutting the γ secretase further free from the cell membrane, and store the brain thought.
A β γ secretase protein is cleaved by β CTF, known AICD and divided into, is cleaved by β secretase APP by, releasing sAPP β is also known (Fig. 1).
If based on mature APP, 653-694 A β protein corresponds to amino acid residue, β CTF is 653-751 corresponding to amino acid residue. In addition, sAPP β corresponds to the amino acid residue is 18-652, 701-751 AICD is corresponding to the amino acid residue.
From the above, inhibitors of γ secretase protein Alzheimer's disease, inhibit the buildup of protein A β effect has been considered as.
However, each transmembrane protein Pen-2, presenilin, secretase, Aph-1 and γ secretase is known as a complex comprising, belong to the aspartic acid protease, as well as the above-described APP APLP1, APLP2, Notch, Jagged 2, Delta 1, E-cadherin, N-cadherin, CD44, ErbB4, Nectin 1, LRP1 such as a transmembrane protein, and the like receptor substrate for protease.
Therefore, the effect of limiting the production of a protein A β in order to obtain, L-685,458, DAPT, γ secretase LY-411,575 such as the use of an inhibitor, a protein other than β CTF for γ-secretase described above as the enzymatic activity of the protease but also restrains the, agent such as it is used as the inhibitor, there is a possibility that side effects such as are feared.
For example, an inhibitor of γ secretase LY-411,575 is one of 1, atrophy of the spleen and thymus to mature B cells to reduce the number of cells have been reported and the like, such an inhibitor when it is a pharmaceutical composition, such as a side effect of immune suggested a possibility to cause a (non-patent document 1). Further, γ secretase enzyme activity itself is lowered, abnormalities in the skin, squamous cell carcinomas, and the like can also cause enlargement of the spleen have been reported (non-patent document 2).
In addition, the production of a protein in the mechanism of functionalities A β, β secretase inhibiting the enzymatic activity of a compound is considered to be effective, β secretase knockout mice, a decrease in the number and report such as birth, is not preferable as an agent for Alzheimer's disease.
Then, non-steroidal anti-inflammatory drugs (hereinafter, sometimes referred to as NSAIDs herein.) The production of a protein A β is effective as an inhibitor such as findings exist, some of the familial Alzheimer's disease (for example, in the case of a mutation in a presenilin.) Is, known to be ineffective (non-patent document 3). Further mild cognitive impairment and Alzheimer's disease γ secretase is isolated from patients that activity is modified, to reduce the effect of the γ secretase model dju aerator A β 42 found to be lower (non-patent document 4).
In addition, the extracellular region of the β CTF FLAG tag to N-terminus when expressed, in the presence of anti-FLAG antibody, not degradation of the γ-secretase (non-patent document 5).
|Scope of claims||
(In Japanese)請求の範囲 [請求項1]
|IPC(International Patent Classification)||
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN 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 PA 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 RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ 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
Contact Information for " AMYLOID β-PROTEIN-SPECIFIC PRODUCTION-INHIBITING POLYPEPTIDE "
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