Potent Inhibitors of Dipeptidyl Peptidase iv and Their Mechanisms of Inhibition

Abstract

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.

Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N‐terminus of HIV‐1 Tat indicate at least two inhibitor binding sites

“…For DP IV/CD26 several inhibition modes are known: competitive, noncompetitive, mixed-type, irreversible, etc. [28]. In all these cases, the enzyme inhibition takes place by binding to one site located in or out of the active site.…”

Dipeptidyl peptidase IV inhibition downregulates Na+-H+exchanger NHE3 in rat renal proximal tubule

“…The purpose of this study was to test the hypothesis that DPPIV, by virtue of its oligomeric association with NHE3, directly or indirectly affects NHE3 activity in the intact proximal tubule in vivo. We demonstrate that administration of the reversible DPPIV inhibitor Lys[Z(NO 2 )]-pyrrolidide (34,37,39,40) is associated with inhibition of NHE3-mediated NaHCO 3 reabsorption in the rat renal proximal tubule. Furthermore, our data demonstrate that there exists an in vivo functional interaction between NHE3 and DPPIV.…”

“…For this study, we administered to experimental rats an injection of 60 mg⅐kg Ϫ1 ⅐day Ϫ1 ip of the highly specific DPPIV inhibitor I40 (34,37,39,40). Rats injected with equal amounts of the noninhibitory compound Lys [Z(NO 2 )]-OH served as controls (39).…”

“…As mentioned earlier, DPPIV is a serine protease that cleaves NH 2 -terminal dipeptides from peptides with a penultimate proline or alanine (19). Based on the structural similarity of pyrrolidide to proline, I40 is a dipeptide product analog with high affinity (K i ϭ 0.271 Ϯ 0.012 M) for binding to the active site and inhibiting DPPIV (37,40).…”

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

“…The rigidity of this pocket was probed by several groups through modification of the ring size of P1 fragments. In isoleucine analogues of the non-covalent inhibitor 8 an order of magnitude lower affinity was observed when the pyrrolidine moiety was replaced by a piperidine or azetidine [32]. The low tolerance for larger rings was confirmed for the covalent 2-ketopyrrolidine 12 while the 2-ketoazetidine analogues were equipotent [26].…”