The Combinatorial Design of Protein Molecular Switches

描述(申请人提供)：蛋白质开关作为选择性蛋白质疗法和诊断和基础科学应用的生物传感器具有很大的前景；然而，事实证明，创造这样的蛋白质是困难的。我们建议使用我们开发的组合方法来创建用于这些应用的蛋白质开关，该方法将所有现有的蛋白质视为所需开关的潜在输入和输出模块。我们将创造一个蛋白质开关，它只会激活癌细胞中的前药。这种转变有可能成为癌症治疗的靶向治疗方法。此外，我们将创造开关，用于在体外和活细胞中作为激酶的传感器。用作传感器的开关将在一个平台上开发，这样就可以更容易地创建其他蛋白质的传感器。建议的实验也将为研究如何最好地创造开关提供信息。与公共健康相关：工程蛋白质开关作为选择性蛋白质疗法以及诊断和基础科学应用的生物传感器前景广阔。我们将开发用于癌症治疗的开关，以及用于在体外和活细胞中检测和量化重要蛋白激酶的传感器的开关。

DESCRIPTION (provided by applicant): Protein switches hold great promise as selective protein therapeutics and as biosensors for diagnostic and basic science applications; however, the creation of such proteins has proven difficult. We propose to create protein switches for these applications using a combinatorial method we developed that views all existing proteins as potential input and output modules for the desired switch. We will create a protein switch that will activate a prodrug only in cancer cells. Such a switch would have potential as a targeted therapeutic for the treatment of cancer. In addition, we will create switches to be used as sensors for kinases in vitro and in live cells. Switches to be used as sensors will be developed on a platform such that sensors for other proteins will be more readily created. Experiments proposed will also inform the study of how best to create switches. PUBLIC HEALTH RELEVANCE: Engineered protein switches hold great promise as selective protein therapeutics and as biosensors for diagnostic and basic science applications. We will develop switches designed for the treatment of cancer and switches designed to be used as sensors for the detection and quantification of important protein kinases in vitro and in live cells.