Abstract
Non-natural compounds mimicking the actions of proteins and large peptides can find a plethora of applications in modulating protein-protein interactions. In this study, we tested the biological properties of three new tripodal and trifunctional scaffolds designed for the solidphase synthesis of three different peptides on the same scaffold.
Using model peptide sequences derived from receptor-binding epitopes from insulin or peptides derived from previously developed insulin mimetics, we probed the quality of scaffold-derived compounds as binders of the insulin and IGF-1 receptors and as activators of the insulin receptor. We identified two compounds, which can bind insulin receptors with low micromolar affinities.
We found that factors influencing the activities of scaffold-based compounds are complex and that the properties of compounds are due to specific peptide sequences placed on specific arms of the scaffolds. This opens up new avenues for combinatorial libraries of scaffold-based compounds, which could provide new activators or inhibitors of both receptors.
The potential of the scaffold-based compounds is further underlined by a substantially higher metabolic stability of scaffold-linked peptides compared to peptides alone.