Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
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.
Oefner
Christian
C
Morphochem AG, CH-4058, Basel, Switzerland.
Pierau
Sabine
S
Schulz
Henk
H
Dale
Glenn E
GE
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry
D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; C523562:MCB3937; D009842:Oligopeptides; D010446:Peptide Fragments; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin; D000243:Adenosine Deaminase; D015032:Zinc