CHEMICAL PROBES FOR STUDYING EUKARYOTIC CELL BIOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们开发了一种结构生物信息学方法来设计高选择性的蛋白激酶抑制剂。我们使用人类基因组的基于结构的序列比对来识别靠近或在ATP结合口袋内的非保守半胱氨酸。然后，我们确定具有适度亲和力和选择性的可逆抑制剂。我们设计和合成了在非保守的半胱氨酸附近具有亲电取代基的衍生物。在另一个项目中，我们发现了一类被称为辅酶转运蛋白的环解脂肽家族，它们能有效地抑制原代人类细胞中几种促炎和促血管生成因子的表达。这些化合物作用于内质网，阻止人类分泌蛋白质子集的共翻译易位。我们目前正在合成环肽变体，并确定结构-活性关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have developed a structural bioinformatics method for designing highly selective inhibitors of protein kinases. We use a structure-based sequence alignment of the human kinome to identify non-conserved cysteines near or within the ATP binding pocket. We then identify reversible inhibitors that bind with modest affinity and selectivity. We design and synthesize derivatives with electrophilic substituents at positions predicted to be proximal to the non-conserved cysteine. In another project, we have discovered a family of cyclodepsipeptides, termed 'cotransins', which potently inhibit the expression of several pro-inflammatory and pro-angiogenic factors in primary human cells. These compounds act at the endoplasmic reticulum and block the cotranslational translocation of a subset of human secretory proteins. We are currently synthesizing cyclopeptide variants and determining structure-activity relationships.