チオアミド置換は,治療用ペプチドホルモンのタンパク質分解と受容体の活動を選択的に調節する

Xing Chen¹, Elizabeth G Mietlicki-Baase², Taylor M Barrett¹

¹Department of Chemistry, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States.

Journal of the American Chemical Society

|November 14, 2017

まとめ

チオアミドの改変は,分解に対するペプチドの安定性を高め,治療の可能性を向上させます. この改変は,より効果的なペプチドベースの薬剤とイメージング剤を開発するための新しいアプローチを提供します.

科学分野:

生物化学
薬剤化学
薬理学について

背景:

ペプチドホルモンは有価な治療薬ですが,in vivoでは急速に分解されます.
ミュタゲネシスや化学合成のような既存の改変は広範囲に及ぶことが多いのです
チオアミデーションはペプチドの安定性を高めるための選択的改変戦略を提供します.

研究の目的:

ペプチドホルモンのチオアミド置換の有用性を実証する.
グルカゴン類ペプチド-1 (GLP-1) と胃抑制ポリペプチド (GIP) の安定性を高めるため
Proteaseの相互作用とシグナルバイアスの thioamidationの影響を調査する.

主な方法:

ペプチド骨のチオアミデーションの単原子OからSへの改変.
GLP-1とGIPを原理証明ペプチドとして利用した.
ディペプチジルペプチダゼ4 (DPP-4) 分裂に対する安定性を評価した.
評価されたサイクルAMP (cAMP) アクティベーションとベータアレスティンの効能.

主要な成果:

チオアミドの置換は,DPP-4に対するGLP-1とGIPの安定性を750倍まで高めました.
安定したアナログは,親ペプチドと比較してほぼ同位体のcAMP活性化を示した.
GLP- 1チオペプチドはベータアレスティンの効能が低下し,シグナルバイアスの変化を示した.
チオアミドGLP-1アナログはネズミの体内血糖値に優れていることが示された.

結論:

チオアミド改変は,ペプチド治療薬のタンパク質分解の安定性を高める有効な戦略です.
このアプローチは選択的にタンパク質の相互作用を調節し,治療効果を高めることができます.
チオアミドは,調節されたシグナルバイアスと改善された薬理学プロファイルを持つペプチドアゴニストを開発する可能性を秘めています.

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