Journal of Pharmaceutical and Biomedical Analysis 2015-12-10

PEGylated D-serine dehydratase as a D-serine reducing agent.

Tomokazu Ito, Hiroe Takada, Keiko Isobe, Masataka Suzuki, Yasuyuki Kitaura, Hisashi Hemmi, Tsukasa Matsuda, Jumpei Sasabe, Tohru Yoshimura

Index: J. Pharm. Biomed. Anal. 116 , 34-9, (2015)

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Abstract

D-Serine is an endogenous coagonist for N-methyl-D-aspartate (NMDA) receptors and is involved in excitatory neurotransmission. Excessive receptor activation causes excitotoxicity, leading to various acute and chronic neurological disorders. Decrease in D-serine content may provide a therapeutic strategy for the treatment of the neurological disorders in which overstimulation of NMDA receptors plays a pathological role. Saccharomyces cerevisiaed-serine dehydratase (Dsd1p), which acts dominantly on D-serine, may be a useful D-serine reducing agent. We conjugated a linear 5-kDa polyethylene glycol (PEG) to Dsd1p (PEG-Dsd1p) and examined the effects of PEG-conjugation on its biochemical and pharmacokinetic properties. PEG-Dsd1p retained activity, specificity, and stability of the enzyme. The PEG modification extended the serum half-life of Dsd1p in mice 6-fold, from 3.8h to 22.4h. PEG-Dsd1p was much less immunogenic compared to the unmodified enzyme. Intraperitoneal administration of PEG-Dsd1p was effective in decreasing the D-serine content in the mouse hippocampus. These findings suggest that PEG-Dsd1p may be a novel tool for lowering D-serine levels in vivo.Copyright © 2015 Elsevier B.V. All rights reserved.