JP4800932B2 - カルシウムイオンリーク抑制物 - Google Patents
カルシウムイオンリーク抑制物 Download PDFInfo
- Publication number
- JP4800932B2 JP4800932B2 JP2006511679A JP2006511679A JP4800932B2 JP 4800932 B2 JP4800932 B2 JP 4800932B2 JP 2006511679 A JP2006511679 A JP 2006511679A JP 2006511679 A JP2006511679 A JP 2006511679A JP 4800932 B2 JP4800932 B2 JP 4800932B2
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- Prior art keywords
- calcium ion
- polypeptide
- calcium
- present
- leak
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
(a)配列番号3〜9のいずれかで示されるアミノ酸配列からなるポリペプチド
(b)配列番号3〜9のいずれかで示されるアミノ酸配列において1若しくは複数個のアミノ酸が欠失、挿入、置換又は付加されたアミノ酸配列からなるポリペプチド
からなる群より選ばれ、標的細胞においてカルシウムイオンリーク抑制作用を有するポリペプチドを提供するものである。
(c)配列番号3〜9のいずれかで示されるアミノ酸配列からなるポリペプチドをコードするポリヌクレオチド
(d)上記(c)のポリヌクレオチドとストリンジェントな条件でハイブリダイズし得、且つ発現可能なポリヌクレオチド
(e)上記(c)のポリヌクレオチドと80%以上相同するDNA配列からなり、且つ発現可能なポリヌクレオチド
からなる群より選ばれ、その発現物が標的細胞においてカルシウムイオンリーク抑制作用を有するポリヌクレオチドを提供するものである。
(1)前記ポリペプチドをコードするポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞の小胞体にFK506を添加して、カルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での標的細胞の小胞体からのカルシウムイオンリークをカルシウムイオン・インディケーターにより計測し、小胞体からのカルシウムイオン流出の変化量をそれぞれ求める工程
(4)被験物質の非存在下に、非形質転換細胞の小胞体にFK506を添加して、カルシウムイオンリークを誘導させた小胞体からのカルシウムイオンリークをカルシウムイオン・インディケーターにより計測し、小胞体の外側におけるカルシウムイオンの値を基準値として、上記(3)で求められた各値と該基準値との差を求める工程
(5)被験物質の存在下における基準値との差が、被験物質の非存在下における基準値との差と比べて、小である場合に、該被験物質を候補物質として選択する工程
を含む、前記ポリペプチドによる標的細胞の小胞体におけるカルシウムイオンリーク抑制作用を増強する候補物質のスクリーニング方法を提供するものである。
(1)前記ポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞に小胞体にFK506を添加してカルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での標的細胞の小胞体におけるポリヌクレオチド発現量を、RT−PCR法を用いて、それぞれ求める工程
(4)被験物質の存在下における上記発現量を、被験物質の非存在下における同発現量と対比する工程
(5)被験物質の存在下における発現量が、非存在下における発現量に比して増加している場合に、該被験物質を候補物質として選択する工程
を含む、前記ポリヌクレオチドの発現物による標的細胞の小胞体におけるカルシウムイオンリーク抑制作用を増強する候補物質のスクリーニング方法を提供するものである。
(1)前記ポリペプチドをコードするポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞の小胞体にFK506を添加してカルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での標的細胞におけるポリペプチド産生量を、該ポリペプチドに対する抗体を用いて、それぞれ求める工程
(4)被験物質の存在下における産生量と、被験物質の非存在下における産生量とを対比する工程
(5)被験物質の存在下における産生量が、被験物質の非存在下における産生量に比して増加している場合に、該被験物質を候補物質として選択する工程
を含む、前記ポリペプチドによる標的細胞におけるカルシウムイオンリーク抑制作用を増強する候補物質をスクリーニングする方法を提供するものである。
本明細書におけるアミノ酸、ペプチド、塩基配列、核酸などの略号による表示は、IUPAC−IUBの規定〔IUPAC−IUB Communication on Biological Nomenclature, Eur. J. Biochem., 138: 9 (1984)〕、「塩基配列又はアミノ酸配列を含む明細書等の作成のためのガイドライン」(特許庁編)及び当該分野における慣用記号に従うものとする。
Ala Ser
Arg Lys
Asn Gln又はHis
Asp Glu
Cys Ser
Gln Asn
Glu Asp
Gly Pro
His Asn又はGln
Ile Leu又はVal
Leu Ile又はVal
Lys Arg、Asn又はGlu
Met Leu又はIle
Phe Met、Leu又はTyr
Ser Thr
Thr Ser
Trp Tyr
Tyr Trp又はPhe
Val Ile又はLeu
b) Cys及びPro以外のアミノ酸残基のCys 又はProへの置換、
c) 電気的陽性側鎖を有している残基、例えばLys、Arg、Hisの、電気的陰性残基、例えば、Glu又はAspへの置換、
d) 非常に大きな側鎖を有しているアミノ酸残基、例えばPheのGlyのような側鎖を有しないアミノ酸残基への置換。
本発明のポリペプチド(及び本発明スクリーニング方法に利用するポリペプチド;以下、単に「本発明ポリペプチド」という)は、下記の(a)又は(b)
(a)配列番号3〜9のいずれかで示されるアミノ酸配列からなるポリペプチド
(b)上記ポリペプチドの相同物、即ち、配列番号3〜9のいずれかで示されるアミノ酸配列において、1若しくは複数個のアミノ酸が欠失、挿入、置換又は付加されたアミノ酸配列からなるポリペプチド
であって、標的細胞においてカルシウムイオンリーク抑制作用を有するものである。
・Genebank (http://www.ncbi.nlm. nih.gov/web/Genebank/Index.htlm)
・the European Molecular Biology Laboratory Nucleic Acid Sequence Database (EMBL) (http://www.ebi.ac.uk/ebi docs/embl db.html)
また、本発明のポリヌクレオチドは、下記の(c)、(d)又は(e)
(c)配列番号3〜9のいずれかで示されるアミノ酸配列からなるポリペプチドをコードするポリヌクレオチド
(d)上記(c)のポリヌクレオチドとストリンジェントな条件でハイブリダイズし得、且つ発現可能なポリヌクレオチド
(e)上記(c)のポリヌクレオチドと80%以上相同するDNA配列からなり、且つ発現可能なポリヌクレオチド
であって、その発現物が標的細胞においてカルシウムイオンリーク抑制作用を有するポリヌクレオチドである。
本発明DNA分子は、本明細書に開示された本発明のポリヌクレオチドのRyR2遺伝子の部分核酸配列断片の具体例についての配列情報に基づいて、或いはRyR2アミノ酸配列の部分配列の情報に基づいて、該配列がコードする核酸配列に相当するDNA分子をそのまま合成する化学的DNA合成法、或いは一般的遺伝子工学的手法により容易に製造、取得することができる〔Molecular Cloning 2d Ed, Cold Spring Harbor Lab. Press (1989);続生化学実験講座「遺伝子研究法I、II、III」、日本生化学会編(1986)など参照〕。
本発明ポリペプチド(発現物)は、本発明遺伝子を利用して、通常の遺伝子工学的手法(例えばScience, 224, 1431 (1984); Biochem. Biophys. Res. Comm., 130, 692 (1985); Proc. Natl. Acad. Sci., USA., 80, 5990 (1983)など)に従って、該遺伝子の発現物として又はこれを含む蛋白質として、容易に、大量に且つ安定して製造することができる。より詳細には、所望の蛋白質をコードする遺伝子が宿主細胞中で発現できる組換えDNA(発現ベクター)を作成し、これを宿主細胞に導入して形質転換し、該形質転換体を培養し、次いで得られる培養物から目的蛋白質を回収することにより、本発明ポリペプチド(発現物)を得ることができる。
本発明医薬組成物において有効成分とする本発明ポリヌクレオチドの発現物(及び本発明スクリーニング方法に利用する同発現物)(以下、単に「本発明発現物」という)は、前記〔4〕に示した遺伝子工学的手法により得ることができる。
本発明ポリペプチドは、配列番号3〜9に示すアミノ酸配列情報に従って、一般的な化学合成法により製造することもできる。該方法には、通常の液相法及び固相法によるペプチド合成法が包含される。
本発明医薬組成物は、本発明ポリペプチド又は本発明発現物を有効成分とする。該医薬組成物は、例えば標的細胞のカルシウムイオンリーク抑制作用(特に筋小胞体におけるカルシウムイオンリーク抑制作用)を有する医薬組成物として、又はカルシウムハンドリング(制御)改善剤として有用である。また、上記カルシウムイオンリーク抑制剤及びカルシウムハンドリング(制御)改善剤としての作用により、心不全、心筋症、弁膜症、虚血性心疾患、心筋梗塞、狭心症、不整脈、高血圧症、末梢循環障害、糖尿病、記憶障害、脳梗塞、悪性高熱症などに対する治療剤及び予防剤としても有用である。
本発明は、標的細胞の小胞体におけるカルシウムイオンリーク抑制作用(又はカルシウムハンドリング異常改善作用)を促進又は阻害する候補化合物をスクリーニングする方法をも提供する。
(1)筋小胞体からのカルシウムイオンのリーク及びその抑制作用は、例えば、M. Yano ら、Circulation, 102, 2131−2136 (2000)に記載の方法に従って測定することができる。
(1)本発明ポリペプチドをコードするポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞の小胞体にFK506を添加して、カルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での標的細胞の小胞体からのカルシウムイオンリークをカルシウムイオン・インディケーターにより計測し、小胞体からのカルシウムイオン流出の変化量をそれぞれ求める工程
(4)被験物質の非存在下に、非形質転換細胞の小胞体にFK506を添加して、カルシウムイオンリークを誘導させた小胞体からのカルシウムイオンリークをカルシウムイオン・インディケーターにより計測し、小胞体の外側におけるカルシウムイオンの値を基準値として、上記(3)で求められた各値と該基準値との差を求める工程
(5)被験物質の存在下における基準値との差が、被験物質の非存在下における基準値との差と比べて、小である場合に、該被験物質を候補物質として選択する工程
(1)本発明ポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞に小胞体にFK506を添加してカルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での上記標的細胞の小胞体におけるポリヌクレオチド発現量を、RT−PCR法を用いて、それぞれ求める工程
(4)被験物質の存在下における上記発現量を、被験物質の非存在下における同発現量と対比する工程
(5)被験物質の存在下における発現量が、非存在下における発現量に比して増加している場合に、該被験物質を候補物質として選択する工程
(1)本発明のポリペプチドをコードするポリヌクレオチドの発現ベクターで形質転換した標的細胞を準備する工程
(2)被験物質の存在下及び非存在下に、該標的細胞の小胞体にFK506を添加してカルシウムイオンリークを誘導する工程
(3)被験物質の存在下及び非存在下での標的細胞におけるポリペプチド産生量を、該ポリペプチドに対する抗体を用いて、それぞれ求める工程
(4)被験物質の非存在下における産生量と、被験物質の存在下における産生量とを対比する工程
(5)被験物質の存在下における産生量が非存在下におけるそれに比して増加している場合に、該被験物質を候補物質として選択する工程
更に本発明は、標的細胞における本発明ポリペプチド及び本発明ポリヌクレオチドの発現物からなる群から選ばれる少なくとも1種と、FK506とを構成成分として含有することを特徴とする、該ポリペプチド又は発現物の標的細胞の小胞体におけるカルシウムイオンリーク抑制作用に対するアゴニスト又はアンタゴニストをスクリーニングするためのスクリーニング用キットを提供する。
構成2. 小胞体におけるカルシウムイオンリーク誘導物(FK506)
構成3. カルシウム取り込み誘導物(例えば、ATPなど)及びカルシウムイオン指示薬(例えば、fluo3など)
構成4. カルシウムATPアーゼ阻害剤(例えば、タプシガーギンなど)
ポリペプチドの合成は、Fmoc(9−フルオレニルメチルオキシカルボニル:9−fluorenylmethyloxycarbonyl)法による固相合成法により合成した。
DR3−2 :ペプチド配列番号1861−1880 配列番号18
DR3−3 :ペプチド配列番号1871−1890 配列番号19
R2 2068/87 :ペプチド配列番号2068−2087 配列番号13
R2JN28 :ペプチド配列番号2086−2113 配列番号14
R2JF :ペプチド配列番号2086−2133 配列番号15
R2P :ペプチド配列番号2114−2149 配列番号 3
R2 2150/85:ペプチド配列番号2150−2185 配列番号16
カルシウムイオンリーク抑制活性の測定は、ヤノ(Yano, M.)らの方法に従って実施した〔Yano, et al., Circulation, 102, 2131−2136 (2000)〕。
上記実験において、ヒトリアノジン受容体2のペプチド配列番号2114−2149に相当する配列番号3で示されるR2Pにカルシウムイオンリーク抑制効果が確認されたことから、本発明者らは、さらにR2Pの部分ペプチド、あるいはR2Pの変異体として以下に示される配列のペプチドを合成し、それらのカルシウムイオンリーク抑制効果の有無について、カルシウムイオンリーク抑制効果を検討した。
MSV−R2P :ペプチド配列番号M+2112−2149 配列番号 4
RP1−30 :ペプチド配列番号2114−2143 配列番号 5
RP1−25 :ペプチド配列番号2114−2138 配列番号 6
RP1−20 :ペプチド配列番号2114−2133 配列番号 7
RP13−32 :ペプチド配列番号2126−2145 配列番号 8
RP17−36 :ペプチド配列番号2130−2149 配列番号 9
RP1−20REV:ペプチド配列番号2133−2114 配列番号10
RP1−10 :ペプチド配列番号2114−2123 配列番号11
R2MP :ペプチド配列番号2114−2149(V2132M)
配列番号12
Claims (9)
- 配列番号3で示されるアミノ酸配列からなるポリペプチド。
- 配列番号3で示されるアミノ酸配列からなるポリペプチドをコードするポリヌクレオチド。
- 請求項1記載のポリペプチドを有効成分として含有する医薬組成物。
- 請求項2記載のポリヌクレオチドの発現物を有効成分として含有する医薬組成物。
- 心不全、心筋症、弁膜症、虚血性心疾患、心筋梗塞、狭心症、不整脈及び高血圧症からなる群より選ばれる疾患の治療剤である請求項3又は4記載の医薬組成物。
- 被験物質の存在下及び非存在下に、請求項1記載のポリペプチドによる、標的細胞としてのヒト心筋細胞又はヒト平滑筋細胞の小胞体におけるカルシウムイオンリーク抑制作用の程度を測定し、被験物質の存在下における測定値を被験物質の非存在下における測定値と対比して、該抑制作用を増強するアゴニスト又は該抑制作用を低減させるアンタゴニストを選択することを特徴とする、標的細胞の小胞体におけるカルシウムイオンリーク抑制作用に対するアゴニスト又はアンタゴニストのスクリーニング方法(ただし、被験物質をヒトに投与する場合を除く)。
- ポリペプチドによる標的細胞の小胞体におけるカルシウムイオンリーク抑制作用の程度が、被験物質の存在下及び非存在下に小胞体にFK506を添加して、カルシウムイオンリークをカルシウムイオン・インディケーターにより計測し、小胞体からのカルシウムイオン流出の減少量として求められるものである請求項6記載のスクリーニング方法。
- 被験物質の存在下及び非存在下に、請求項2記載のポリヌクレオチドの発現物による、標的細胞としてのヒト心筋細胞又はヒト平滑筋細胞の小胞体におけるカルシウムイオンリーク抑制作用の程度を測定し、被験物質の存在下における測定値を被験物質の非存在下における測定値と対比して、該抑制作用を増強するアゴニスト又は該抑制作用を低減させるアンタゴニストを選択することを特徴とする、標的細胞の小胞体におけるカルシウムイオンリーク抑制作用に対するアゴニスト又はアンタゴニストのスクリーニング方法(ただし、被験物質をヒトに投与する場合を除く)。
- ヒト心筋細胞又はヒト平滑筋細胞のいずれかの標的細胞における請求項1記載のポリペプチドと、FK506とを構成成分として含有することを特徴とする、該ポリペプチドによる標的細胞の小胞体におけるカルシウムイオンリーク抑制作用に対するアゴニスト又はアンタゴニストをスクリーニングするためのスクリーニング用キット。
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