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，这种蛋白质的产生已经被证明是困难的。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。这种转换有可能成为治疗癌症的靶向疗法。此外，我们将在体外和活细胞中制造用作激酶传感器的开关。用作传感器的开关将在一个平台上开发，这样其他蛋白质的传感器将更容易被创造出来。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。我们将开发用于治疗癌症的开关，以及用于在体外和活细胞中检测和定量重要蛋白激酶的传感器开关。

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.