Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity

Inhibition
of glutamate carboxypeptidase II (GCPII) is effective
in preclinical models of neurological disorders associated with excessive
activation of glutamatergic systems. Here we report synthesis, structural
characterization, and biological activity of new hydroxamic acid-based
inhibitors with nanomolar affinity for human GCPII. Crystal structures
of GCPII/hydroxamate complexes revealed an unprecedented binding mode
in which the putative P1′ glutarate occupies the spacious entrance
funnel rather than the conserved glutamate-binding S1′ pocket.
This unique binding mode provides a mechanistic explanation for the
structure–activity relationship data, most notably the lack
of enantiospecificity and the tolerance for bulky/hydrophobic functions
as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics
profile of one of the inhibitors will be presented along with analgesic
efficacy data from the rat chronic constrictive injury model of neuropathic
pain.