JP6682221B2 - Tacc3阻害剤のスクリーニング方法 - Google Patents
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Description
することから、末梢性ニューロパシーのような重篤な副作用を生じることが知られている(例えば、特許文献2)。
1.スクリーニング方法の概略
図1にTACC3とTOGpとの結合を指標とするスクリーニング方法の概略を示す。
TACC3、TOGpともに、全長が含まれるタンパク質を用いてもよいが、タンパク質精製、検出感度の点から、結合領域が含まれるなるべく狭い領域をスクリーニングに用いた方がよい。そこで、両者の結合領域の特定を行った。
TACC3を3分割したフラグメントd1(アミノ酸配列番号1〜332)、d3(アミノ酸配列番号327〜600)、d4(アミノ酸配列番号593〜838)をpcDNA3にクローニングし、HA-タグを付与し(図2A)、293細胞で発現させ、内因性のTOGpとの相互作用を解析した。
TOGpを4分割したフラグメントF1(アミノ酸配列番号1〜619)、F2(アミノ酸配列番号620〜1094)、F3(アミノ酸配列番号1095〜1509)、F4(アミノ酸配列番号1502〜2032)をpcDNAにクローニングし、FLAG-タグを付与し(図3A)、293細胞で発現させ、内因性のTACC3との相互作用を解析した。
内因性のTOGp、又はTACC3と、各フラグメントの結合が観察されたことから、in vivoでこれらフラグメント同士が結合するか解析した。
上述のin vivoアッセイで相互作用が確認されたTOGp-F4−3(アミノ酸配列番号1890〜2032)をさらに分割したF4−4(アミノ酸配列番号1890〜1963)、F4−5(アミノ酸配列番号1956〜2032)(図5A)とTACC3-d4フラグメントを用いて、in vitro pull-downアッセイにより結合解析を行った(図5B)。
上記アッセイより、in vivo、in vitroで結合が確認できたTACC3-d4、TOGp-F4-3を用いて理研NPDepo化合物ライブラリーを用いて化合物のスクリーニングを行った。ここでは、化合物のスクリーニングを例に挙げて説明するが、抗体、ペプチドなど医薬候補となるものであればどのようなものを用いてもよい。
Claims (2)
- TACC3活性を阻害する化合物のスクリーニング方法であって、
TACC3のアミノ酸配列番号593〜838の領域と
TOGpのアミノ酸配列番号1890〜2032の領域との結合を阻害することを指標とする化合物のスクリーニング方法。 - 前記TACC3のアミノ酸配列番号593〜838の領域が
TACC3のアミノ酸配列番号593〜838からなる領域を含む組換えタンパク質であり、
前記TOGpのアミノ酸配列番号1890〜2032の領域が、
TOGpのアミノ酸配列番号1890〜2032からなる領域を含む組換えタンパク質であり、少なくともいずれか一方の前記組換えタンパク質が検出に必要な配列を含むことを特徴とする請求項1記載の化合物のスクリーニング方法。
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