JP2019094271A - アンジオテンシン変換酵素阻害剤、食品、飲料、およびサプリメント - Google Patents
アンジオテンシン変換酵素阻害剤、食品、飲料、およびサプリメント Download PDFInfo
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Abstract
Description
本発明のACE阻害剤を構成するトリペプチドは、Ile−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Gly、またはこれらの塩である。C末端がGlyであるトリペプチドのACE阻害活性を評価したところ、N末端から2番目のアミノ酸残基がHypの場合にはProの場合よりもACE阻害活性が著しく高いことが判明した。例えば、後記する実施例に示すように、N末端がAlaの場合、Ala−Pro−GlyのIC50は985.7μMであるが、Ala−Hyp−GlyのIC50は159.2μMと、ACE阻害活性が6倍も相違した。特に、N末端がValの場合は約9倍、Leuの場合は約90倍もACE阻害活性が高い。非特許文献1では、Hip−HL(ヒプリルヒスチジルロイシン)を用いてAla−Hyp−GlyのACE阻害活性を測定し、そのIC50を711μMと記載している。そこで、Ala−Hyp−Glyを陽性対照として種々トリペプチドのACE阻害活性を評価したところ、前記N末端がValやLeu、IleであるトリペプチドがAla−Hyp−Glyに比べて10〜40倍ものACE阻害活性を有することが判明した。これら3つのN末端アミノ酸は全て脂肪族かつ疎水性度の高いアミノ酸であり、その性質がACE阻害活性に寄与していると考えられる。本発明では、Ile−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Glyおよびこれらの塩の中から選択される1種のトリペプチドを使用する場合であってもよく、2種以上を混合して使用する場合であってもよい。
本発明のACE阻害剤は、Ile−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Gly、およびこれらの塩のいずれか1以上のトリペプチドを含む。例えば、前記した特許文献6記載の方法に準じて、Ile−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Gly、およびこれらの塩を含むペプチド組成物を調製し、このペプチド組成物をそのままACE阻害剤として使用することができる。一方、単離したIle−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Gly、およびこれらの塩のいずれか1以上、または前記ペプチド組成物に更に、賦形剤、希釈剤、乳化分散剤、矯味剤、矯臭剤などを添加してACE阻害剤としてもよい。このような賦形剤や希釈剤として、澱粉、ステアリン酸マグネシウム、ラクトースなどを例示することができる。これらは、ACE阻害活性を損なわない範囲で適宜混合することができる。なお、ACE阻害剤として投与する場合の投与量は、被投与者の血圧の程度、患者の年齢、体重、または投与方法などに応じて適宜調整することができる。好ましくは0.001〜100mg/kg/日、より好ましくは0.1〜20mg/kg/日である。
0.35mUのブタ腎臓由来ACE(シグマアルドリッチ社製)を含む75mM Tris−HCl緩衝液(pH8.3)275μlに被検物質の水溶液25μlを加え全量300μlとした後、予め37℃、10分間加温した。同じ緩衝液に溶解し、同様に37℃としたHip−His−Leu(HHL;株式会社ペプチド研究所社製)溶液(0.7μmol/ml)50μlをこれに添加し反応を開始した。反応開始後5分、10分、20分および30分時点で反応液70μlを取り、反応停止液(内部標準として4ng/mlのN−benzoyl−d5−glycine(d5Hip;CDN Isotopes社製)を含む1%ギ酸溶液)70μlと混合して反応を停止し、LC/MS測定用サンプルとした。同様に、被検物質無添加の対照サンプルを調製した。ACEの作用によりHHLから遊離したHipおよび内部標準として添加したd5Hipを下記LC/MS測定条件で測定した後、d5Hipで補正して定量したHip量を反応時間に対してプロットし、Hipの生成曲線を求めた。同曲線から1分間あたりのHip生成量を算出してACE活性とした。検量線は0.5〜50ng/mlのHip(シグマアルドリッチ社製)溶液を75mM Tris−HCl緩衝液(pH8.3)で調製後、70μlを取り、反応液と同様70μlの反応停止液を混合して調製した。被検物質を含まない対照の活性と被検物質を加えたサンプルの活性を比較し、以下の式により阻害率を算出した。
阻害率(%)=100×(対照の活性−サンプルの活性)/対照の活性
IC50値(対照の活性を50%阻害するのに要する被検物質量)は、縦軸に阻害率、横軸に被検物質濃度をプロットして阻害曲線の式を求めた後、50%阻害に対応する被検物質の濃度を算出して求めた。
高速液体クロマトグラフ:1200Series(アジレント・テクノロジー株式会社製)、
質量分析装置:3200 QTRAP(株式会社エービー・サイエックス社製)、
分析カラム:Ascentis Express C18 5μm, 2.1mmi.d.×150mm(SUPLECO社製)、
カラム温度:25℃
移動相:A液;0.1%ギ酸、B液;100%アセトニトリル、
グラジエント条件:
0〜2分:A液100%、
2〜6分:A液100〜30%;B液0〜70%、
6〜8分:A液10%;B液90%、
8〜10分:A液100%、
流速:0.5mL/min、
イオン化:ESI、ポジティブ、
分析モード:Multiple Reaction Monitoring(MRM)モード、
イオンスプレー電圧:5.5kV、
イオンソース温度:500℃
pH4.0の0.1M酢酸ナトリウムバッファーにウシ由来ゼラチンを溶解して2質量%溶液を調製し、この溶液にショウガ根茎をアセトン中で粉砕して作製したショウガ粉末をウシ由来ゼラチンに対して質量換算で1/10倍量、ジチオスレイトール(和光純薬工業株式会社製)を最終濃度2mMとなるように加え、50℃で振盪、攪拌しながら16h反応させた。反応終了後静置し、上清を回収してペプチド溶液を得た。得られたペプチド溶液を下記LC/MS測定条件で測定した。結果を表1に示す。コラーゲンをショウガ根茎由来酵素で分解することで、Val−Hyp−Gly(VOG)、Val−Pro−Gly(VPG)、Ala−Hyp−Gly(AOG)、Ala−Pro−Gly(APG)、Leu−Hyp−Gly(LOG)、Leu−Pro−Gly(LPG)、およびIle−Hyp−Gly(IOG)が生成されることが確認された。
高速液体クロマトグラフ:1200Series(アジレント・テクノロジー株式会社製)、
質量分析装置:3200 QTRAP(株式会社エービー・サイエックス社製)、
分析カラム:Ascentis Express F5 5μm, 4.6mmi.d.×250mm(SUPELCO社製)、
カラム温度:40℃
移動相:A液;0.1%ギ酸、B液;100%アセトニトリル、
グラジエント条件:
0〜7.5分:A液100%、
7.5〜20分:A液100〜10%;B液0〜90%、
20〜25分:A液10%;B液90%、
25〜30分:A液100%、
流速:0.4mL/min、
イオン化:ESI、ポジティブ、
分析モード:MRMモード、
イオンスプレー電圧:3kV、
イオンソース温度:500℃
製造例1でショウガ粉末によるコラーゲンの分解により生成が確認されたトリペプチドについて、Anygen社のカスタム合成サービスにより化学合成(VOG、VPG、AOG、LOG、LPGおよびIOG)、またはBachem社より市販品を購入(APG)し、上記測定法にてそのACE阻害活性を測定した。結果を表2に示す。
比較例2のAOGは非特許文献1に開示され、そのIC50は711μMと記載されている。AOGを陽性対照として、製造例1で生成の確認された種々のトリペプチドを本願のACE阻害活性の測定方法によって測定したところ、VOG(実施例1)、LOG(実施例2)、およびIOG(実施例3)は、AOG(比較例2)より極めて高いACE阻害活性を有することが判明した。
Claims (4)
- Ile−Hyp−Gly、Leu−Hyp−Gly、Val−Hyp−Gly、およびこれらの塩からなる群から選択される1以上のトリペプチドを含む、アンジオテンシン変換酵素阻害剤。
- 請求項1記載のアンジオテンシン変換酵素阻害剤を含む食品。
- 請求項1記載のアンジオテンシン変換酵素阻害剤を含む飲料。
- 請求項1記載のアンジオテンシン変換酵素阻害剤を含むサプリメント。
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