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

Abstract

Inhibition of dipeptidyl peptidase-IV (DPP-IV) is used as a means to regulate post-prandial serum glucose in type 2 diabetics. The effect of drug (Sitagliptin®)/peptide and binary peptide mixtures on DPP-IV inhibition was studied using an isobole approach. Five peptides (Ile-Pro-Ile-Gln-Tyr, Trp-Lys, Trp-Pro, Trp-Arg and Trp-Leu), having DPP-IV half maximum inhibitory concentration values (IC₅₀) < 60 μM and reported to act through different inhibition mechanisms, were investigated. The dose response relationship of Sitagliptin : peptide (1 : 0, 0 : 1, 1 : 852, 1 : 426 and 1 : 1704 on a molar basis) and binary Ile-Pro-Ile-Gln-Tyr : peptide (1 : 0, 0 : 1, 1 : 1, 1 : 2 and 2 : 1 on a molar basis) mixtures for DPP-IV inhibition was characterised. Isobolographic analysis showed, in most instances, an additive effect on DPP-IV inhibition. However, a synergistic effect was observed with two Sitagliptin : Ile-Pro-Ile-Gln-Tyr (1 : 426 and 1 : 852) mixtures and an antagonistic effect was seen with one Sitagliptin : Trp-Pro (1 : 852) mixture, and three binary peptide mixtures (Ile-Pro-Ile-Gln-Tyr : Trp-Lys (1 : 1 and 2 : 1) and Ile-Pro-Ile-Gln-Tyr : Trp-Leu (1 : 2)). The results show that Sitagliptin and food protein-derived peptides can interact, thereby enhancing overall DPP-IV inhibition. Combination of Sitagliptin with food protein-derived peptides may help in reducing drug dosage and possible associated side-effects.