Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
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Oefner C, Pierau S, Schulz H, Dale GE
Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
Acta Crystallogr D Biol Crystallogr. 2007 Sep;63(Pt 9):975-81. Epub 2007 Aug 17.
- PubMed ID
- 17704566 [ View in PubMed]
- Abstract
Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a number of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor, as well as the incretin hormone glucagon-like peptide 1 (GLP-1), which is a potent stimulator of insulin secretion. The activity of GLP-1 is also rapidly abolished by the serine protease dipeptidyl peptidase IV (DPP-IV), which led to an elevated interest in inhibitors of this enzyme for the treatment of type II diabetes. A dual NEP/DPP-IV inhibitor concept is proposed, offering an alternative strategy for the treatment of type 2 diabetes. Here, the synthesis and crystal structures of the soluble extracellular domain of human NEP (residues 52-749) complexed with the NEP, competitive and potent dual NEP/DPP-IV inhibitor MCB3937 are described.