Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV

✍ Scribed by Oefner, Christian ;Pierau, Sabine ;Schulz, Henk ;Dale, Glenn E.

• Book ID: 104478347
• Publisher: International Union of Crystallography
• Year: 2007
• Tongue: English
• Weight: 528 KB
• Volume: 63
• Category: Article
• ISSN: 0907-4449
• DOI: 10.1107/s0907444907036281

✦ Synopsis

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.