In Silico Approaches Applied to the Study of Peptide Analogs of Ile-Pro-Ile in Relation to Their Dipeptidyl Peptidase IV Inhibitory Properties.

Alice B Nongonierma,Luca Dellafiora,Gianni Galaverna,Pietro Cozzini,Richard J Fitzgerald,Sara Paolella

doi:10.3389/fendo.2018.00329

Abstract

Inhibition of dipeptidyl peptidase IV (DPP-IV) may be exploited to maintain the incretin effect during the postprandial phase. As a result, glycemic regulation and energy homeostasis may be improved. Food protein-derived peptides have been identified as natural agents capable of inhibiting DPP-IV. Ile-Pro-Ile is the most potent DPP-IV inhibitory peptide identified to date. A minimum analog peptide set approach was used to study peptide analogs of Ile-Pro-Ile. The DPP-IV half maximal inhibitory concentration (IC50) values of the 25 peptides evaluated ranged from 3.9 ± 1.0 µM (Ile-Pro-Ile) to 247.0 ± 32.7 µM (Phe-Pro-Phe). The presence of Pro at position 2 of tripeptides was required to achieve high DPP-IV inhibition. Most peptides behaved as competitive inhibitors of DPP-IV with the exception of peptides with a N-terminal Trp, which were mixed-type inhibitors. While possessing the structure of preferred DPP-IV substrates, most peptides studied were particularly stable during 30 min incubation with DPP-IV. Molecular docking revealed that Ile-Pro-Ile and its peptide analogs interacted in a very similar manner with the active site of DPP-IV. In addition, no correlation was found between the Hydropathic INTeraction score and the DPP-IV IC50 values of the peptides studied. This outcome suggests that free energy may not be directly responsible for enzyme inhibition by the peptides. Finally, novel DPP-IV inhibitory peptides were identified using the strategy employed herein. These results may be relevant for the development of food protein-derived peptides with serum glucose lowering and food intake regulatory properties in humans.

Highlights

The inhibition of dipeptidyl peptidase IV (DPP-IV) is one of the numerous therapeutic strategies used for the management of type 2 diabetes
The partial least squares regression (PLSR) analysis linking the DPP-IV IC50 value to the amino acid descriptors of the peptides was statistically significant with a p model and p lack of fit value of 0.01 and 0.15, respectively (Table 3)
The coefficients of the PLSR model, which were significant (p < 0.05) were the constant (c), a1,3 and b2,3 (Figure 1A). This indicated that the hydrophobicity of the amino acids located at the N-terminal and next to the C-terminal positions of peptides were important for the DPP-IV inhibitory potency of peptides

Summary

Introduction

The inhibition of dipeptidyl peptidase IV (DPP-IV) is one of the numerous therapeutic strategies used for the management of type 2 diabetes. DPP-IV can cleave incretins such as glucagon-like peptide-1 (GLP-1) and glucose inhibitory polypeptide, resulting in a loss of their insulinotropic activity during the postprandial phase. The inhibition of DPP-IV has been shown to result in a better regulation of glycemia in type 2 diabetic subjects [1, 2]. For this reason, several DPP-IV inhibitory drugs, known as gliptins, have been developed as antidiabetic agents [1]. GLP-1 has been shown to modulate energy homeostasis by slowing down gastric emptying, inducing satiety, and reducing food intake [3].

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