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

Abstract

Dipeptidyl peptidase IV (DP IV, CD26) plays an essential role in the activation and proliferation of lymphocytes, which is shown by the immunosuppressive effects of synthetic DP IV inhibitors. Similarly, both human immunodeficiency virus‐1 (HIV‐1) Tat protein and the N‐terminal peptide Tat(1–9) inhibit DP IV activity and T cell proliferation. Therefore, the N‐terminal amino acid sequence of HIV‐1 Tat is important for the inhibition of DP IV. Recently, we characterized the thromboxane A2 receptor peptide TXA2‐R(1–9), bearing the N‐terminal MWP sequence motif, as a potent DP IV inhibitor possibly playing a functional role during antigen presentation by inhibiting T cell‐expressed DP IV [Wrenger, S., Faust, J., Mrestani‐Klaus, C., Fengler, A., Stöckel‐Maschek, A., Lorey, S., Kähne, T., Brandt, W., Neubert, K., Ansorge, S. & Reinhold, D. (2000) J. Biol. Chem.275, 22180–22186]. Here, we demonstrate that amino acid substitutions at different positions of Tat(1–9) can result in a change of the inhibition type. Certain Tat(1–9)‐related peptides are found to be competitive, and others linear mixed‐type or parabolic mixed‐type inhibitors indicating different inhibitor binding sites on DP IV, at the active site and out of the active site. The parabolic mixed‐type mechanism, attributed to both non‐mutually exclusive inhibitor binding sites of the enzyme, is described in detail. From the kinetic investigations and molecular modeling experiments, possible interactions of the oligopeptides with specified amino acids of DP IV are suggested. These findings give new insights for the development of more potent and specific peptide‐based DP IV inhibitors. Such inhibitors could be useful for the treatment of autoimmune and inflammatory diseases.

Utilisation of the isobole methodology to study dietary peptide–drug and peptide–peptide interactive effects on dipeptidyl peptidase IV (DPP-IV) inhibition

“…In the case of the Sitagliptin:Ile-Pro-Ile-Gln-Tyr (1:426 and 1:852) mixtures, a synergistic effect was seen with a reduction of the IC 50 value compared to Zt of 7 and 11 %, respectively. Although the peptides studied have different modes 25 of inhibition (competitive, non-competitive, true or substrate-type inhibitor), there did not seem to be a clear trend showing specific types of interactions in the mixtures in one instance or the other. However, it is interesting to note that, the synergistic effect was seen with a mixture of competitive DPP-IV inhibitors (Sitagliptin 30 and Ile-Pro-Ile-Gln-Tyr).…”

“…Similar results have been described where the immunomodulatory properties of an hydrolysate was less than that of its associated isoelectric focusing fractions when tested at the same concentration 26 . This was explained by the fact that 25 some peptides may interact through physicochemical interactions 27 , making them unavailable as bioactive components.…”

“…The five DPP-IV inhibitory peptides studied were selected based on differences in their mode of inhibition and the fact that they were relatively potent food protein-derived DPP-IV inhibitors 25 (IC 50 value < 60 μM) 8,18 . The IC 50 values obtained during this study were of the same order as previously described 8,18 (Supplementary Table S2).…”

“…The increasing global prevalence of type 2 diabetes (T2D) has led 25 the scientific community to investigate different strategies in order to slow down its evolution. Dipeptidyl peptidase IV (DPP-IV) inhibitors belong to a new class of drugs with an antidiabetic action, with Sitagliptin ® (Januvia ® , Merck & Co., Inc. USA) being the first DPP-IV inhibitor launched on the market.…”

Dipeptidyl peptidase IV inhibitory and antioxidative properties of milk protein-derived dipeptides and hydrolysates

“…transactivator Tat has been reported [22]. The non-competitive inhibition was due to peptides binding to a secondary site different from the active site of DPP-IV.…”