Design of cytotoxic ribonucleases by cationization to enhance intracellular protein delivery.
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.
Futami
Junichiro
J
Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan. futamij@cc.okayama-u.ac.jp
Yamada
Hidenori
H
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002412:Cations; D003959:Diamines / Q000737:chemistry; D015195:Drug Design; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000737:chemistry; D015202:Protein Engineering; D012260:Ribonucleases / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002412:Cations; D003959:Diamines; D011108:Polymers; D012260:Ribonucleases