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首页> 外文期刊>Biochemistry >Preparation of Potent Cytotoxic Ribonucleases by Cationization: Enhanced Cellular Uptake and Decreased Interaction with Ribonuclease Inhibitor by Chemical Modification of Carboxyl Groups
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Preparation of Potent Cytotoxic Ribonucleases by Cationization: Enhanced Cellular Uptake and Decreased Interaction with Ribonuclease Inhibitor by Chemical Modification of Carboxyl Groups

机译：通过阳离子化制备有效的细胞毒性核糖核酸：通过羧基的化学修饰增强细胞摄取并减少与核糖核酸酶抑制剂的相互作用

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Carboxyl groups of bovine RNase A were amidated with ethylenedianrine (to convert negative charges of carboxylate anions to positive ones), 2-aminoethanol (to eliminate negative charges), and taurine (to keep negative charges), respectively, by a carbodiimide reaction. Human RNase 1 was also modified with ethylenediamine. Surprisingly, the modified RNases were all cytotoxic toward 3T3-SV -40 cells despite their decreased ribonucleolytic activity. However, their enzymatic activity was not completely eliminated by the presence of excess cytosolic RNase inhibitor (RI). As for native RNase A and RNase 1 which were not cytotoxic, they were completely inactivated by RI. More interestingly, within the cytotoxic RNase derivatives, cytotoxicity correlated well with the net positive charge. RNase land RNaseA modified with ethylenediamine were more cytotoxic than naturally occurring cytotoxic bovine seminal RNase. An experiment using the fluorescence-labeled RNase derivatives indicated that the more cationic RNases were more efficiently adsorbed to the cells. Thus, it is suggested that the modification of carboxyl groups could change complementarity of RNase to RI and as a result endow RNase cytotoxicity and that cationization enhances the efficiency of cellular uptake of RN ase so as to strengthen its cytotoxicity. The finding .that an extracellular human enzyme such as RNase 1 could be effectively internalized into the cell by cationization suggests that cationization is a simple strategy for efficient delivery of a protein into cells and may open the way of the development of new therapeutics.
机译：牛核糖核酸酶A的羧基分别通过碳二亚胺反应分别与亚乙基二胺（将羧酸根阴离子的负电荷转换为正电荷），2-氨基乙醇（以消除负电荷）和牛磺酸（保持负电荷）酰胺化。人RNase 1也用乙二胺修饰。出人意料的是，尽管核糖核酸分解活性降低，但修饰的RNase对3T3-SV -40细胞均具有细胞毒性。但是，它们的酶促活性并未因过量胞质RNase抑制剂（RI）的存在而被完全消除。至于没有细胞毒性的天然RNase A和RNase 1，它们被RI完全灭活了。更有趣的是，在细胞毒性RNase衍生物中，细胞毒性与净正电荷相关性很好。乙二胺修饰的RNase地RNaseA比天然存在的细胞毒性牛精RNase具有更高的细胞毒性。使用荧光标记的RNase衍生物进行的实验表明，更多的阳离子RNase更有效地吸附到细胞中。因此，暗示羧基的修饰可以改变RNase与RI的互补性，并因此赋予RNase细胞毒性，并且阳离子化增强细胞摄取RNase的效率，从而增强其细胞毒性。细胞外人类酶（如RNase 1）可以通过阳离子化有效地内化到细胞中的发现表明，阳离子化是将蛋白质有效递送到细胞中的简单策略，并可能为开发新的疗法开辟道路。

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