GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator

Joseph R. Moskal*, Amy G. Kuo, Craig Weiss, Paul L. Wood, Amy O'Connor Hanson, Stephen Kelso, Robert B. Harris, John F. Disterhoft

*Corresponding author for this work

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

We previously created a monoclonal antibody (MAb), B6B21, that acts as a partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor [Moskal, J.R., Schaffner, A.E., 1986. Monoclonal antibodies to the dentate gyrus: immunocytochemical characterization and flow cytometric analysis of hippocampal neurons bearing a unique cell-surface antigen. J. Neurosci. 6, 2045-2053.]. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [ 3H]MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of NMDA receptor [Moskal, J.R., Yamamoto, H., Colley, P.A., 2001. The use of antibody engineering to create novel drugs that target N-methyl-d-aspartate receptors. Curr. Drug Targets 2, 331-345.]. Peptides that were able to increase [3H]MK-801 binding in a dose-dependent manner under these conditions were named Glyxins. Here we report that GLYX-13, a tetrapeptide (TPPT-amide), was found to readily cross the blood-brain barrier and modulate the NMDA receptor in a glycine-like fashion when examined pharmacologically and electrophysiologically. When GLYX-13 was administered to rats at 0.5-1.0 mg/kg i.v., a significant enhancement in learning was observed using a hippocampus-dependent trace eyeblink conditioning paradigm. These data indicate that the Glyxins are a new class of NMDA receptor modulators that may have therapeutic potential. Based on the broad agonist range in vitro and the potent cognitive-enhancing properties in a valid in vivo model of learning, GLYX-13 is a new drug candidate with potential for the treatment of cognitive disorders.

Original languageEnglish (US)
Pages (from-to)1077-1087
Number of pages11
JournalNeuropharmacology
Volume49
Issue number7
DOIs
StatePublished - Dec 1 2005

Keywords

  • Glycine
  • Hippocampus
  • Monoclonal antibody
  • N-methyl-D-aspartate receptor
  • Partial agonist
  • Peptide

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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