Peptide Morphing: Rational Design of Separase Inhibitors

描述（由申请人提供）：分离酶最近被鉴定为一种半胱氨酸蛋白酶，其切割粘附素的Scc1亚基，粘附素是一种物理连接姐妹染色单体并在有丝分裂纺锤体动力学中发挥重要功能的复杂蛋白质。该建议将最近描述的肽变形技术应用于小的非肽分子的合理设计和合成，以结合和抑制分离酶。这是我们的希望，这一建议将展示肽变形的力量，提出了一个功能丰富和立体多样化的配体结构的蛋白质目标的迫切生物学利益和意义。分离酶的抑制，特别是在活性位点的抑制，应该能阐明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.