IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

Abstract

In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea β-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.

Food-derived peptides with inhibitory capacity for HMG-CoA reductase activity: a potential nutraceutical for hypercholesterolemia

“…In addition, peptides with the highest inhibitory activity have hydrophilic character, in accordance with Pak et al who showed an inverse correlation between hydrophobicity (Ho) of peptides and inhibitory capacity of the HMG-CoAR activity (86). This aspect is somewhat disputed, because other authors have shown a better activity for the hydrophobic peptides (44,67,84). Therefore, the hydrophobic/hydrophilic character of peptides is not the only factor involved in HMG-CoA activity inhibition but also the other physicochemical characteristics of peptides.…”

“…The R3 and C3 fractions decrease the HMG-CoA velocity reaction by 90% and 83%, respectively (43), pointing out that the thermal process negatively affects the bioactivity of peptides on the cholesterol-lowering effect. Another study demonstrated that the length of peptides is a major factor responsible for this biological activity (44). In this line, 82 peptide sequences with HMG-CoAR inhibitory activity were identified from the hydrolysis of cowpea beans using pepsin (37 ℃ for 3 h, pH = 2) and pancreatin (37 ℃ for 3 h, pH = 7).…”

“…Finally, 13 peptides were studied based on their lower molecular weight (MW), presence of hydrophobic residues (phenylalanine, tyrosine, or leucine) and aromatic rings, and their peptide ranker score. After a docking study in which the probability of interacting within the substrate-binding site of HMG-CoAR was evaluated, the tripeptides IAF, QGF, and QDF were identified as inhibitors of the HMG-CoAR activity (reduction of 69%, 77%, and 78% respectively, at 500 μmol/L) (Figure 3) (44,45). Other peptides such as MPNY and GCTLN decreased the HMG-CoAR activity by 38.1%, and 17.9%, respectively, at 100 μmol/L (45).…”

Selected Soybean Varieties Regulate Hepatic LDL-Cholesterol Homeostasis Depending on Their Glycinin:β-Conglycinin Ratio

“…Previous reports also described that peptic/tryptic soybean hydrolysates might inhibit HMGCR [16]. Other legume hydrolysates and pure peptides have also demonstrated HMGCR activity inhibition [44,45].…”

Special Issue “Peptides for Health Benefits 2021”

“…Several studies have proposed that bioactive peptides, particularly those released from legume seed, represent a possible alternative to statin drugs. In the work of Silva et al [4], an in silico approach was used to elucidate the mechanism underlying the binding of cowpea β-vignin-derived peptides and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The results of this study guided the synthesis of three peptides, IAF, QGF, and QDF, capable of reducing cholesterol synthesis through a mechanism similar to that of statins.…”