Potent inhibitors of dipeptidyl peptidase IV and their mechanisms of inhibition.
Dipeptidyl peptidase IV (DP IV) is a proline specific serine protease which cleaves Xaa-Pro-dipeptides from the N-terminus of longer peptides. A series of product analogous amino acid amides containing different structure modifications like substitution of a ring atom, variation of the ring size and/or the introduction of a thioxo amide bond, phosphono amide bond or reduced amide bond were done to characterize these compounds as inhibitors of DP IV. These compounds are mostly classical reversible inhibitors of DP IV. In contrast amino acyl-2-cyanopyrrolidides inhibit DP IV according to a slow-binding mechanism with inhibition constants in the nanomolare range. On the other hand, diaryl dipeptide phosphonates inhibit irreversibly. In conclusion, this work shows, that the mechanism of inhibition of DP IV depends on the structure of the investigated compounds.
Stöckel-Maschek
A
A
Martin-Luther-University Halle-Wittenberg, Department of Biochemistry and Biotechnology, Germany.
Stiebitz
B
B
Born
I
I
Faust
J
J
Mögelin
W
W
Neubert
K
K
D000818:Animals; D001667:Binding, Competitive; D004151:Dipeptides / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
D004151:Dipeptides; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D018819:Dipeptidyl Peptidase 4