The Combinatorial Design of Protein Molecular Switches

描述（由申请人提供）：蛋白质开关作为选择性蛋白质治疗剂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，已经证明创建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为这些应用创建蛋白质开关，该方法将所有现有蛋白质视为所需开关的潜在输入和输出模块。我们将创造一种蛋白质开关，只在癌细胞中激活前药。这种开关将具有作为治疗癌症的靶向治疗剂的潜力。此外，我们将创建开关作为传感器激酶在体外和活细胞。将在平台上开发用作传感器的开关，以便更容易创建其他蛋白质的传感器。提出的实验也将为如何最好地创建开关的研究提供信息。公共卫生相关性：工程蛋白质开关作为选择性蛋白质治疗剂和诊断和基础科学应用的生物传感器具有很大的前景。我们将开发设计用于治疗癌症的开关和设计用于检测和定量体外和活细胞中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.