Peptide Morphing: Rational Design of Separase Inhibitors

描述(申请人提供)：分离酶最近被鉴定为一种半胱氨酸蛋白酶，可裂解粘附素的Scc1亚单位，粘附素是一种复杂的蛋白质，在物理上连接姐妹染色单体，在有丝分裂纺锤体动力学中起重要作用。这项建议将最近描述的多肽变形技术应用于合理设计和合成结合和抑制分离酶的非多肽小分子。我们希望这项提议将展示多肽变形的力量，通过呈现一个功能丰富和立体多样化的配基结构给一个具有迫切生物学意义和重要意义的蛋白质靶标。对分离酶的抑制，特别是在活性部位的抑制，应该能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.