Peptide Morphing: Rational Design of Separase Inhibitors

描述（由申请人提供）：分离酶最近被确定为一种半胱氨酸蛋白酶，可切割内聚蛋白的Scc1亚基，内聚蛋白是一种复杂的蛋白质，在物理上连接姐妹染色单体，并在有丝分裂纺锤体动力学中起重要作用。这一建议将最近描述的肽变形技术应用于合理设计和合成小的非肽分子来结合和抑制分离酶。我们希望这一提议将通过向具有迫切生物学意义的蛋白质靶标提供功能丰富和立体多样化的配体结构来展示肽变形的力量。分离酶的抑制，特别是在活性位点的抑制，应该揭示染色体生物学的关键方面。

DESCRIPTION (provided by applicant): Separase has recently been identified as a cysteine protease that cleaves the Scc1 subunit of cohesin, a complex protein that physically connects sister chromatids and serves important functions in mitotic spindle dynamics. This proposal applies the recently described technique of peptide morphing in the rational design and synthesis of small nonpeptidic molecules to bind and inhibit separase. It is our hope that this proposal will demonstrate the power of peptide morphing by presenting a functionally rich and stereo diversified ligand structure to a protein target of urgent biologic interest and significance. Inhibition of separase, particularly at the active site, should shed light on key aspects of chromosome biology.