title: Effect of PEGylation of N-WASP181-200 on the inhibitory potency for renal aminoglycoside accumulation.
abstract: 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.
authors: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors: Kenji
authors: K
authors: Fujii
authors: Junya
authors: J
authors: Nagai
authors: Takeshi
authors: T
authors: Sawada
authors: Ryoko
authors: R
authors: Yumoto
authors: Mikihisa
authors: M
authors: Takano
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D003982:Dibekacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005839:Gentamicins / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010446:Peptide Fragments; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D011092:Polyethylene Glycols; D003982:Dibekacin; C031986:arbekacin