Soluble neutral metallopeptidases: physiological regulators of peptide action

Classically, the pre- and post-secretory processing of peptide signals appears to be mediated primarily by subtilisin-like peptidases in secretory vesicles and/or membrane-associated neutral endopeptidases in the extracellular environment. This article presents both biochemical and physiological evidence to support a role for soluble neutral metallopeptidases in the mediation of cell-to-cell communication by the selective generation and termination of peptide signals. These soluble peptidases have been implicated in the normal and disease-state processing of peptides involved in neurological, endocrine and cardiovascular functions. In this context, specific inhibitors of these enzymes could selectively modulate peptide levels and thus have considerable therapeutic potential. The aim of this review is to discuss the design and development of specific inhibitors of soluble neutral metallopeptidases that have been instrumental in identifying the roles of these enzymes. It will also review the evidence and present a case for the involvement of soluble neutral metallopeptidases in the regulation of peptide signalling in both central nervous system (CNS) and peripheral tissues.