Effect of PEGylation of N-WASP181-200 on the Inhibitory Potency for Renal Aminoglycoside Accumulation

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• 作者：Kenji Fujii ; Junya Nagai ; Takeshi Sawada ; Ryoko Yumoto ; Mikihisa Takano
• 刊名：Bioconjugate Chemistry
• 出版年：2009
• 出版时间：August 19, 2009
• 年：2009
• 卷：20
• 期：8
• 页码：1553-1558
• 全文大小：225K
• 年卷期：v.20,no.8(August 19, 2009)
• ISSN：1520-4812

文摘

We previously showed that a 20-residue basic peptide, N-WASP181-200 (NISHTKEKKKGKAKKKRLTK), inhibits renal accumulation of aminoglycoside antibiotics such as gentamicin and arbekacin. The aim of this study is to determine whether PEGylation of N-WASP181-200 enhances its inhibitory potency for renal accumulation of aminoglycosides. N-terminally PEGylated peptide (PEG1k-N-W) was synthesized by conjugating N-WASP181-200 with PEG of approximately 1 kDa using the Fmoc protection/deprotection method. PEG1k-N-W decreased gentamicin binding to isolated rat renal brush-border membrane in a concentration-dependent manner, but the in vitro inhibitory potency of PEG1k-N-W was weaker than that of N-WAP181-200. On the other hand, under in vivo conditions, PEG1k-N-W decreased the renal accumulation of arbekacin more potently than N-WASP181-200. When injected intravenously, PEG1k-N-W showed a 1.7-fold longer plasma half-life relative to N-WASP181-200. In addition, the stability of N-WASP181-200 in renal brush-borer membrane suspension was found to be increased by PEGylation. Our findings suggest that PEGylation of N-WASP181-200 is a useful strategy for reducing dosage of the concomitant with which to decrease renal accumulation in the kidney, leading to prevention of aminoglycoside-induced nephrotoxicity.