JP2020505060A - 腫瘍壊死因子αの高親和性ペプチド及びその適用 - Google Patents
腫瘍壊死因子αの高親和性ペプチド及びその適用 Download PDFInfo
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Abstract
Description
1.ペプチド配列の取得と修飾
TNF−αタンパク質に親和性を有する所望のペプチドを化学的方法によって人工的に合成した。
(1)TNF−αタンパク質へのペプチド632の親和性の実験結果
96ウェルELISAプレートを4℃で一晩、2μg/mlTNF−αタンパク質でコートした。BSAでブロッキングした後、異なる濃度のFITCでラベルしたペプチド632を各ウェルに加え、2時間インキュベーションした。
インキュベーション後、HRP結合抗FITCモノクローナル抗体を加え、1時間インキュベーションし、ABTS着色溶液を加えた。1時間発色展開の後、410nmでのOD値をマイクロプレートリーダーを用いて測定し、GraphPad Prism5をプロッティング及び解析のために用いた。この結果は、ペプチド632が138nMの解離定数(Kd)を有し、TNF−αタンパク質に高親和性を有することを立証した。
実験動物を3群:ブランク群、非関連ペプチド対照群、及びアンタゴニストペプチド(ペプチド632)群に分けた。6週齢の雄の昆明マウスに3日間連続で、ペプチドを右腹部に皮下注射した。最後の注射から30分後、各群のマウスの右の耳介の両側をp−キシレン(0.03ml/マウス)でスメアし炎症を誘導し、左の耳介は正常コントロールとした。炎症1時間後、動物を屠殺し、マウスの耳を完全に切断し、同一マウスの左右の耳を識別するためにマークした。マウスの耳の両側を同一の紙片でコートした。直径8mmの耳膨張パンチャーを用いて、左右の耳の同一部分を切断し、耳断片を得た。この耳断片を紙と一緒に重量を測定し、その結果を記録した。マウス耳の膨張度=炎症の誘導されている耳断片の重量−炎症のない耳断片の重量
重要な炎症性因子として、TNF−αは、炎症の発生及び発達に重要な役割を奏している。炎症によって誘導された免疫疾患において、TNF−αの増加したレベルは、組織損傷を生じる、一連の病原性反応及び関連サイトカインの発現を誘導する。TNF−αの拮抗作用は、関節リウマチ及び乾癬のような種々の炎症性疾患における有効な処置であることが証明されている。しかしながら、現在のアンタゴニストは、モノクローナル抗体及びその誘導体に焦点を併せている。モノクローナル抗体及びその誘導体は、強い副作用、特に薬剤における用途を制限する高い免疫原性を有する。したがって、ここで提供されるTNF−αに高い親和性を有するペプチドは、TNF−αに強い親和性を有するのみならず、TNF−αの生物学的活性も阻害する。よって、本発明のペプチドは、関連する炎症性損傷を予防することができ、有望なTNF−αアンタゴニスト薬として用いることができる。さらに、修飾ペプチド632は、TNF−αタンパク質の発現を検出するための検出試薬として用いることができる。
配列番号1(N末端→C末端):HYIDFRW
配列番号2:CATTATATTGATTTTAGGTGG
配列番号3(N末端→C末端):KASGSPSGFWPS
配列番号4(N末端→C末端):HYIDFRWDMKASGSPSGFWPS
実験動物を3群:ブランク群、非関連ペプチド対照群、及びアンタゴニストペプチド(ペプチド632)群に分けた。6週齢の雄の昆明マウスに3日間連続で、ペプチドを右腹部に皮下注射した。最後の注射から30分後、各群のマウスの右の耳介の両側をp−キシレン(0.03ml/マウス)でスメアし炎症を誘導し、左の耳介は正常コントロールとした。炎症1時間後、動物を屠殺し、マウスの耳を完全に切断し、同一マウスの左右の耳を識別するためにマークした。マウスの耳の両側を同一の紙片でコートした。直径8mmの耳膨張パンチャーを用いて、左右の耳の同一部分を切断し、耳断片を得た。この耳断片を紙と一緒に重量を測定し、その結果を記録した。マウス耳の膨張度=炎症の誘導されている耳断片の重量−炎症のない耳断片の重量
図1及び図2に示されるとおり、ペプチド632は、TNF−αタンパク質に高い結合親和性を有する。動物実験は、ペプチド632を注射した実験群の耳膨張度が対照群に比べて有意に低かったことを示した。上記の結果は、ペプチド632がTNF−αの活性をアンタゴナイズすることによって炎症ダメージを防止する効果を達成することができることを示している。
Claims (7)
- TNF−αに高親和性を有するペプチドであって、該ペプチドは、配列番号1又は配列番号3のアミノ酸配列を有するか、又は該ペプチドは、配列番号1及び配列番号3の単一リピート又は複数リピートを有するタンデム又は分岐ペプチドであり、配列番号4のアミノ酸配列を有する、該ペプチド。
- TNF−αに高親和性を有するペプチドをコードする遺伝子であって、該ペプチドは、配列番号1のアミノ酸配列を有し、該遺伝子は、配列番号2に記載のヌクレオチド配列を有する、該遺伝子。
- コア配列として請求項1に記載のTNF−αに高親和性を有するペプチドを含み、抗原又は薬物と連結するか又はそのC末端、N末端又は側鎖基においてPEGによって修飾されるか又は他の分子基によって共有結合によって修飾された構造的に特徴のある分子である、生物学的材料又は化学基によって修飾されたペプチド。
- 請求項1に記載のTNF−αに高親和性を有するペプチドを含む、修飾されたペプチドであって、該修飾されたペプチドが、TNF−α検出のためのFITCフルオロフォア、アイソトープ、化学発光基又は酵素試薬でラベルされている、該修飾されたペプチド。
- TNF−αアンタゴニストの調製における、請求項1に記載のTNF−αに高親和性を有するペプチドの使用。
- TNF−α発現の検出のための薬剤又は臨床試験薬剤の調製における、請求項1に記載のTNF−αに高親和性を有するペプチドの使用。
- TNF−αアンタゴニストの調製又はトレーサー検出における、請求項2に記載のTNF−αに高親和性を有するペプチドをコードする遺伝子の使用。
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PCT/CN2018/072194 WO2018130170A1 (zh) | 2017-01-12 | 2018-01-11 | 一种肿瘤坏死因子alpha的高亲和性肽及其应用 |
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JP2005145884A (ja) * | 2003-11-14 | 2005-06-09 | Peptide Door Co Ltd | TNF−αに結合性を有するペプチド又はタンパク質、及び該ペプチド又はタンパク質を用いたTNF−α吸着体、TNF−α検査試薬、TNF−α中和剤 |
JP2012509312A (ja) * | 2008-11-20 | 2012-04-19 | パナセア バイオテック リミテッド | 腫瘍壊死因子α阻害ペプチドおよびその使用方法 |
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