Top > Search of International Patents > PHOSPHORYLATED PEPTIDE, HARD TISSUE AND/OR ECTOPIC CALCIFICATION INHIBITOR, ANTIBODY, AND HARD TISSUE AND/OR ECTOPIC CALCIFICATION PROMOTER

PHOSPHORYLATED PEPTIDE, HARD TISSUE AND/OR ECTOPIC CALCIFICATION INHIBITOR, ANTIBODY, AND HARD TISSUE AND/OR ECTOPIC CALCIFICATION PROMOTER

Foreign code F130007278
File No. F10180
Posted date Apr 5, 2013
Country WIPO
International application number 2012JP067351
International publication number WO 2013005839
Date of international filing Jul 6, 2012
Date of international publication Jan 10, 2013
Priority data
  • P2011-150487 (Jul 6, 2011) JP
Title PHOSPHORYLATED PEPTIDE, HARD TISSUE AND/OR ECTOPIC CALCIFICATION INHIBITOR, ANTIBODY, AND HARD TISSUE AND/OR ECTOPIC CALCIFICATION PROMOTER
Abstract Provided are a phosphorylated peptide having the effect of inhibiting hard tissue and/or ectopic calcification using the active sites for a calcification inhibiting effect of MEPE-derived ASARM peptide, a hard tissue and/or ectopic calcification inhibitor, antibody having a hard tissue and/or ectopic calcification-promoting effect, and a hard tissue and/or ectopic calcification promoter. The phosphorylated peptide is characterized in that the peptide has the entire or partial amino acid sequence of MEPE-derived ASARM peptide, at least two of the amino acid residues in the amino acid sequence are phosphorylated serine, and the peptide has a hard tissue and/or ectopic calcification-inhibiting effect. The antibody is characterized in recognizing phosphorylated serine, which is the active center of the phosphorylated peptide.
Outline of related art and contending technology BACKGROUND ART
Calcification of the biological tissue is, for example, bone diseases such as osteoporosis or Osteomalacia calcified hard tissue associated with, or, diabetes, chronic kidney disease is vascular calcification associated with aging or the like included in the ectopic calcification and the like. Such a hard tissue or vascular calcification associated with the prevention of disease, therapeutic agents include, mainly, calcimimetic, vitamin D formulation, estrogen, ipriflavone, calcitonin, a bisphosphonate, vitamin K2 formulation, and the like phosphate adsorbent or statin can be cited.
Is one of the family of proteins (small integrin-binding ligand N-linked glycoproteins) MEPE(Matrix Extracellular Phosphoglycoprotein) SIBLING, low phosphorus in the treatment of neoplastic osteomalacia and proteins found from patients, primarily of bone mineralization (see non-patent document 1) plays a role. For example, in patent document 1, MEPE (a partial peptide thereof, a salt or also including DNA encoding them) from the bone differentiation promoting having an activity, metabolic bone diseases and metabolic cartilage diseases that exhibit low toxicity and safe preventive, therapeutic agents for the use described. In addition, the patent document 2, the production of bone cells such as MEPE protein or its gene as an indicator, a method for evaluating the bone is described. Further, in Patent Document 3, the bone mineral and the like are used MEPE (bone density) is particularly effective in the treatment of the disease in the renal or phosphoric acid to regulate lipid metabolism unit such as described. On the other hand, the knock-out mouse MEPE, bone mass, when the number of osteoblasts because of the increased, a potent inhibitor of bone formation MEPE have been reported (see non-patent document 2).
In addition, MEPE is, cathepsin B is easily cut, and a peptide fragment containing ASARM(acidic serine aspartate rich motif) appears (hereinafter, ASARM peptide). ASARM peptide, the higher the binding affinity of the hydroxyapatite, apatite crystals in vitro in inhibiting the growth of osteoblasts or inhibition of the substrate by calcification and the (see non-patent document 3 and 4). Derived from MEPE ASARM peptide, casein kinase II phosphorylation sites are present. In a recent report, the above described active phosphorylation is presumed to be essential for (see non-patent document 2). In addition, also Patent Document 4, ASARM peptide as described above, bone, soft tissue calcification of the relationship between the teeth and the possibility of, as well as Asp-Glu-Ser-Ser Ser-Ser-Glu-Ser and the amino acid sequence of the associations described.
Protein SIBLING ASARM peptide motifs found in all but, all MEPE ASARM peptide derived from an action similar to that of whether or not the calcification is unknown. In addition, is thought to have endopeptidase activity MEPE PHEX(phosphate-regulating gene with homologies to endopeptidases on the X chromosome) are coupled, and by cathepsin B to suppress decomposition of the MEPE has been reported (see non-patent document 5). On the other hand, non-phosphorylated or phosphorylated ASARM PHEX to bind to the peptides, wherein the peptide phosphorylated ASARM are shown (see non-patent document 2).
Is PHEX, bone (osteoblasts and bone cells) expressed in the teeth (dentin osteoblast) membrane protein, acidosis-low phosphorus-linked X be the causative agent of rickets. A deficiency of that PHEX, its substrate (unidentified, phosphatonin and a provisional name) with a phosphor with an increase in circulating levels of natriuretic factor believed to bring the. In addition, the functional deficit PHEX, phosphatonin, FGF23(fibroblast growth factor 23) natriuretic factor promoting the expression of which is different from the phosphorus has been demonstrated. FGF23 Produced in the bone, kidney function indirectly via factor to suppress bone mineralization. In addition, the effect of such FGF23, such as for example Klotho is associated with the recently it was found that the (non-patent document 6 and non-patent document 7 reference). In addition, also act directly on the bone FGF23 has been suggested.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 MEPEに由来するASARMペプチドの全部または一部のアミノ酸配列を含有し、前記アミノ酸配列における少なくとも二つ以上のアミノ酸残基がリン酸化されたセリンであり、かつ硬組織石灰化および/または異所性石灰化を抑制する作用を有することを特徴とする、リン酸化ペプチド。

[請求項2]
 前記アミノ酸配列は、ヒトにおけるPHEX切断部位からN末端側の3アミノ酸残基を含むことを特徴とする、請求項1に記載のリン酸化ペプチド。

[請求項3]
 前記アミノ酸配列における少なくとも三つ以上のアミノ酸残基がリン酸化されたセリンであることを特徴とする、請求項1または2に記載のリン酸化ペプチド。

[請求項4]
 前記リン酸化ペプチドは、少なくとも12アミノ酸残基を有することを特徴とする、請求項1ないし3のいずれか1項に記載のリン酸化ペプチド。

[請求項5]
 前記ASARMペプチドは、以下(a)ないし(c)のいずれかに記載のアミノ酸配列で表されることを特徴とする、請求項1ないし4のいずれか1項に記載のリン酸化ペプチド。
 (a)配列番号1ないし3のいずれかに記載のアミノ酸配列。
 (b)配列番号1ないし3のいずれかに記載のアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列。
 (c)配列番号1ないし3のいずれかに記載のアミノ酸配列において、1または数個のアミノ酸が欠失、置換、付加もしくは挿入またはこれらの組み合わせにより配列に変異が生じているアミノ酸配列。

[請求項6]
 前記アミノ酸配列は、配列番号4に記載のアミノ酸配列を含有し、前記配列番号4に記載のアミノ酸配列のN末端側から数えて3番目と5番目のセリンがリン酸化されていることを特徴とする、請求項1ないし5のいずれか1項に記載のリン酸化ペプチド。

[請求項7]
 さらに、前記配列番号4に記載のアミノ酸配列のN末端側から数えて1番目のセリンがリン酸化されていることを特徴とする、請求項6に記載のリン酸化ペプチド。

[請求項8]
 前記リン酸化ペプチドは、配列番号5ないし9のいずれかに記載のアミノ酸配列で表されることを特徴とする、請求項1ないし7のいずれか1項に記載のリン酸化ペプチド。

[請求項9]
 請求項1ないし8のいずれか1項に記載のリン酸化ペプチドを有効成分として含むことを特徴とする、硬組織および/または異所性石灰化抑制剤。

[請求項10]
 配列番号9に記載のアミノ酸配列のN末端側の3アミノ酸残基の少なくとも1つ以上のアミノ酸残基、ならびに、C末端側から数えて2番目、4番目および6番目のセリンのリン酸化による活性中心を認識することを特徴とする、抗体。

[請求項11]
 請求項10に記載の抗体を有効成分とすることを特徴とする、硬組織および/または異所性石灰化促進剤。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • HIROSHIMA UNIVERSITY
  • Inventor
  • YOSHIKO Yuji
  • MINAMIZAKI Tomoko
  • YOSHIOKA Hirotaka
  • HIRATA Isao
  • KOUZAI Katsuyuki
  • MAEDA Norihiko
  • WATANABE Kazuaki
  • SEITO Tsutomu
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 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 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

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