Inhibition of dipeptidyl peptidase IV by fluoroolefin-containingN-peptidyl-O-hydroxylamine peptidomimetics

Abstract

Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leukocyte differentiation antigen CD26 when found as an extracellular membrane-bound proline specific serine protease, cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline residue in the penultimate position. Here we report that known (Z)-Ala-[CF‫؍‬C]-Pro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, were isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of each diastereomeric pair as an inhibitor of human placental dipeptidyl peptidase DPP IV has been examined. The inhibition of DPP IV by these compounds is rapid and efficient. The diastereomeric pair u-1 exhibits very potent inhibitory activity with a K i of 188 nM. Fluoroolefin containing N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of their inhibitory potency and stability, are superior to N-peptidyl-O-hydroxylamine inhibitors derived from an Ala-Pro dipeptide.

The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism

“…As highlighted by our inhibitor structure, only a peptide in the trans conformation is able to productively bind to the active site, in agreement with earlier observations (40). Expectedly, locking the trans conformation of an N-alanyl-prolyl, O-acyl hydroxamine by the substitution of the P 2 -P 1 peptide bond with a fluoroolefin group results in a superior irreversible DP IV-inhibitor (41)(42)(43). Contrasting their fluoroolefin mimetics, the ''normal'' N-aminoacyl-prolyl, O-acyl hydoxylamines are processed by DP IV to Ͼ99.9% as substrates, whereas they inhibit other proteases very potently (44,45).…”

The Therapeutic Potential of Inhibitors of Dipeptidyl Peptidase IV (DPP IV) and Related Proline-Specific Dipeptidyl Aminopeptidases

“…Similar to the (Z)-fluoro-olefin nitrile 21, a (Z)-fluoroolefin N-peptidyl-O-(4-nitrobenzoyl)hydroxylamine 34 was isolated as two pairs of diastereomers [139]. In this example, it was proven that introduction of a (Z)-fluoro-olefin as a peptidomimetic of a trans amide bond, enhances both potency and chemical stability.…”

Fluorinated Pseudopeptide Analogues of the Neuropeptide 26RFa: Synthesis, Biological, and Structural Studies

“…[10] Moreover, in terms of metabolic stability, the fluoro-olefin moiety increases the resistance of a pseudopeptide to proteolysis. [11,12] To study the importance of the configuration of the double bond, it also seemed interesting to synthesize both Z (transoid) and E (cisoid) analogues in order to obtain information about the bioactive conformation of the heptapeptides.…”