Benzofuranone Derivatives as Effective Small Molecules Related to Insulin Amyloid Fibrillation: A Structure-Function Study

Abstract

Amyloids are protein fibrils of nanometer size resulting from protein self-assembly. They have been shown to be associated with a wide variety of diseases such as Alzheimer's and Parkinson's and may contribute to various other pathological conditions, known as amyloidoses. Insulin is prone to form amyloid fibrils under slightly destabilizing conditions in vitro and may form amyloid structures when subcutaneously injected into patients with diabetes. There is a great deal of interest in developing novel small molecule inhibitors of amyloidogenic processes, as potential therapeutic compounds. In this study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin-T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds. Amyloids are protein fibrils resulting from protein self-assembly and contribute to pathological conditions known as amyloidoses. Insulin is prone to form amyloid fibrils under in vivo conditions when injected in diabetic patients. In this study, the effects of five new synthetic benzofuranone derivatives were investigated on in vitro insulin amyloid formation. Despite high structural similarity, one of the five compounds tested was observed to enhance amyloid fibrillation while the others inhibited the process when used at micro molar concentrations. © 2011 John Wiley & Sons A/S.