Soluble neutral metallopeptidases: Physiological regulators of peptide action

Classically, the pre- and post-secretory processing of peptide signals appe ars to be mediated primarily by subtilisin-like peptidases in secretory ves icles and/or membrane-associated neutral endopeptidases in the extracellula r environment. This article presents both biochemical and physiological evi dence to support a role for soluble neutral metallopeptidases in the mediat ion of cell-to-cell communication by the selective generation and terminati on 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 inhibitor s of these enzymes could selectively modulate peptide levels and thus have considerable therapeutic potential. The aim of this review is to discuss th e design and development of specific inhibitors of soluble neutral metallop eptidases that have been instrumental in identifying the roles of these enz ymes. It will also review the evidence and present a case for the involveme nt of soluble neutral metallopeptidases in the regulation of peptide signal ling in both central nervous system [CNS) and peripheral tissues. Copyright (C) 2000 European Peptide Society and John Wiley gr Sons, Ltd.