Neprilysin Inhibitors Provide Insight into its Specificity and Therapeutic Potential
Pp. 598-622 (25)
Darrick Pope and Michael Cascio
Neprilysin (NEP) is one of the enzymes in the zinc-metalloendopeptidase
family that displays a broad specificity in degrading small bioactive peptides. Crystal
structures of seven NEP-inhibitor complexes as well as biochemical characterization of
NEP activity have highlighted amino acid interactions that are crucial to the binding of
various ligands. Studies also indicate that NEP is one of a select group of
metalloenzymes that degrade the amyloid beta peptide (Aβ) in vivo and in situ. The
accumulation of neurotoxic Aβ aggregates in the brain appears to be a causative agent
in the pathophysiology of Alzheimer’s Disease (AD). For this reason the enzymatic
degradation of Aβ has been studied extensively, but little is currently known about the
specific interactions underlying NEP degradation of Aβ. Research that pertains to these
interactions may lead to critical insights for utilizing NEP inhibition of Aβ
accumulation as a safe, beneficial AD therapy.
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282, USA.