合成含有仿磷酸酪胺酸的三胜肽和四胜肽作為蛋白質SH2 結構區的抑制劑

Abstract

蛋白質SH2結構區在蛋白質-蛋白質相互作用上扮演關鍵的角色，而此類作用主要是透過SH2結構區與特定位置的磷酸化酪胺酸來進行。因此我們設計並合成出仿磷酸酪胺酸的單體分子，利用Fmoc 方法進行組合式固相胜肽合成，用以建構包含此仿磷酸酪胺酸單體的三胜肽和四胜肽分子庫，作為篩選蛋白質SH2結構區的抑制劑。其中，三胜肽是以Grb2 SH2結構區所對應的YXN序列，而四胜肽則是以STAT SH2結構區所對應的YXXQ序列來設計。此外，這些胜肽分子庫N 端上涵蓋有三種不同基團，以增加其分子庫的規模。

The Src-homology 2 (SH2) domains play an important role in protein-protein interaction, and are specific for the phosphotyrosine-containing peptides. Herein, we design and synthesis the phosphotyrosyl mimetic as a building block to set up the compound library using Fmoc solid phase peptide synthesis. And the library is composed of the phosphotyrosyl mimetic-containing tri- and tetrapeptides as SH2 domain inhibitors. In this library, the Grb2-SH2 domain preferably binds phosphotyrosyl peptides with the consensus sequence YXN, and the STAT-SH2 domain recognizes YXXQ tetrapeptides sequence. Additionally, in order to increase the scope of the library, we perform three different N-terminal modification in this peptides.