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