Futami Junichiro, Yamada Hidenori
Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.
Curr Pharm Biotechnol. 2008 Jun;9(3):180-4. doi: 10.2174/138920108784567326.
The cytotoxic properties of naturally occurring or engineered RNases correlate well with their efficiency of cellular internalization and digestion level of cellular RNA. Cationized RNases are considered to adsorb to the anionic cellular surface by Coulombic interactions, and then become efficiently internalized into cells by an endocytosis-like pathway. The design of cytotoxic RNases by chemical modification of surface carboxylic residues is one of the powerful strategies for enhancing cellular internalization and is accompanied with a decreased sensitivity for the cytoplasmic RNase inhibitor. Although chemically modified cationized RNases showed decreased ribonucleolytic activity, improved endocytosis and decreased affinity to the endogenous RNase inhibitor conclusively contribute to their ability to digest cellular RNA. Furthermore, the cytotoxicity of cationized RNases can be drastically enhanced by co-endocytosis with an endosome-destabilizing peptide. Since efficient cellular internalization of proteins into living cells is an important technology for biotechnology, studies concerning the design of cytotoxic RNases provided general perceptions for protein-based drug design.
天然存在的或经工程改造的核糖核酸酶（RNases）的细胞毒性特性与其细胞内化效率和细胞RNA的消化水平密切相关。阳离子化核糖核酸酶被认为通过库仑相互作用吸附到阴离子细胞表面，然后通过类似内吞作用的途径有效地内化到细胞中。通过对表面羧基残基进行化学修饰来设计细胞毒性核糖核酸酶是增强细胞内化的有效策略之一，同时伴随着对细胞质核糖核酸酶抑制剂敏感性的降低。尽管化学修饰的阳离子化核糖核酸酶显示出核糖核酸酶活性降低，但改善的内吞作用和对内源性核糖核酸酶抑制剂的亲和力降低最终有助于它们消化细胞RNA的能力。此外，阳离子化核糖核酸酶与内体不稳定肽的共内吞作用可显著增强其细胞毒性。由于蛋白质有效内化到活细胞中是生物技术的一项重要技术，因此有关细胞毒性核糖核酸酶设计的研究为基于蛋白质的药物设计提供了一般认识。
