Lomax Jo E, Eller Chelcie H, Raines Ronald T
Graduate Program in Cellular & Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Methods Enzymol. 2012;502:273-90. doi: 10.1016/B978-0-12-416039-2.00014-8.
Mammalian pancreatic-type ribonucleases (ptRNases) comprise an enzyme family that is remarkably well suited for therapeutic exploitation. ptRNases are robust and prodigious catalysts of RNA cleavage that can naturally access the cytosol. Instilling cytotoxic activity requires endowing them with the ability to evade a cytosolic inhibitor protein while retaining other key attributes. These efforts have informed our understanding of ptRNase-based cytotoxins, as well as the action of protein-based drugs with cytosolic targets. Here, we address the most pressing problems encountered in the design of cytotoxic ptRNases, along with potential solutions. In addition, we describe assays that can be used to evaluate a successful design in vitro, in cellulo, and in vivo. The emerging information validates the continuing development of ptRNases as chemotherapeutic agents.
哺乳动物胰腺型核糖核酸酶（ptRNases）构成了一个非常适合用于治疗开发的酶家族。ptRNases是强大且高效的RNA切割催化剂，能够自然地进入细胞质溶胶。赋予其细胞毒性活性需要使其具备逃避细胞质抑制剂蛋白的能力，同时保留其他关键特性。这些研究成果增进了我们对基于ptRNase的细胞毒素以及具有细胞质靶点的蛋白质类药物作用机制的理解。在此，我们阐述了在设计细胞毒性ptRNases过程中遇到的最紧迫问题以及潜在的解决方案。此外，我们还描述了可用于在体外、细胞内和体内评估成功设计的检测方法。新出现的信息证实了ptRNases作为化疗药物的持续开发价值。
