Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor

Abstract

We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure.

Insulin-like Growth Factor 1 Analogs Clicked in the C Domain: Chemical Synthesis and Biological Activities

“…Subsequently, the free −SH groups were “liberated” from the Ag + salt by the gaseous H 2 S, and the precipitated Ag 2 S was removed by centrifugation. We followed here our successful application of such an approach for the removal of copper from synthesized compounds after click reactions. − Finally, the dilution of the supernatant, and the removal of an excess of the reductive H 2 S gas, was followed by a slow air oxidation of the peptide, and its biomimetic folding, and the products 2 , 3 , and 4 were isolated by RP-HPLC. The typical yields of this last synthetic step were about 8% (0.5 mg) for 2 , 5.7% (0.27 mg) for 3 , and 1.7% (0.12 mg) for 4 (Figures S2–S4), which provided sufficient material for their biological characterization.…”

Tri‐Orthogonal Scaffolds for the Solid‐Phase Synthesis of Peptides

“…The library was tested for binding to the receptor for insulin. We identified few weak insulin receptor binders and activators . Nevertheless, it was clear that much larger compound diversity and complexity would be necessary for the discovery of more potent insulin receptor binders.…”

A Trifunctional Linker for Palmitoylation and Peptide and Protein Localization in Biological Membranes

“…Trifunctional linkers and scaffolds are ubiquitous in chemistry and serve a great variety of purposes. Even the simplest linkers bearing three identical reactive groups can be used, taking advantage of stochastic coupling or clever (sub‐stoichiometric) introduction of the test molecules . Trifunctional linkers bearing three different reactive groups are more challenging to synthesize .…”