Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16206-11. doi: 10.1073/pnas.1102803108. Epub 2011 Sep 19.
The exquisite specificity of proteins is a key feature driving their application to anticancer therapies. The therapeutic potential of another fundamental property of proteins, their ability to be regulated by molecular cues in their environment, is unknown. Here, we describe a synthetic biology strategy for designing protein therapeutics that autonomously activate a therapeutic function in response to a specific cancer marker of choice. We demonstrate this approach by creating a prodrug-activating enzyme that selectively kills human cancer cells that accumulate the marker hypoxia-inducible factor 1α. This property arises primarily through increased cellular accumulation of the enzyme in the presence of the marker. Our strategy offers a platform for the development of inherently selective protein therapeutics for cancer and other diseases.
蛋白质的高度特异性是驱动其应用于抗癌疗法的关键特征。蛋白质的另一个基本特性——能够被环境中的分子信号调节——的治疗潜力尚不清楚。在这里，我们描述了一种用于设计蛋白质治疗药物的合成生物学策略，该策略可以自主激活治疗功能，以响应特定的癌症标志物。我们通过创建一种前药激活酶来证明这种方法，该酶可以选择性地杀死积累标志物缺氧诱导因子 1α 的人类癌细胞。这种特性主要是由于在标志物存在的情况下，酶在细胞内的积累增加所致。我们的策略为开发用于癌症和其他疾病的固有选择性蛋白治疗药物提供了一个平台。
