title: 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.
authors.affiliation: Department of Life Sciences and Food for Health Ireland (FHI), University of Limerick, Castletroy, Limerick, Ireland. dick.fitzgerald@ul.ie.
authors.forename: Alice B
authors.initials: AB
authors.lastname: Nongonierma
authors.forename: Richard J
authors.initials: RJ
authors.lastname: FitzGerald
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D004044:Dietary Proteins / Q000737:chemistry / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004336:Drug Antagonism; D004357:Drug Synergism; D005103:Expert Systems; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D034421:Sus scrofa; D014230:Triazoles / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D004044:Dietary Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D011719:Pyrazines; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate