Evaluation of small-molecule compounds as modulators of mitochondrial membrane interactions with the human islet amyloid polypeptide

Abstract

The human islet amyloid polypeptide (hIAPP) is a neuroendocrine hormone known to misfold and partake in an aberrant aggregation process, involving the formation of a soluble toxic oligomeric species. Oligomers play an important role in the pathogenesis of type-2 Diabetes Mellitus (T2DM), a metabolic disorder impacting millions worldwide. Mitochondrial organelles and their phospholipid membranes are being increasingly recognised as key targets of hIAPP toxicity; however, this avenue of research requires further attention. In this study, fluorescence polarisation assays revealed that membrane-active hIAPP oligomers decreased the mobility of DPH (1,6-diphenyl1,3,5-hexatriene) fluorophore in both artificial mito-mimetic vesicles and isolated mitochondria. Hence, the oligomers manifested a membrane-rigidifying effect on synthetic and biological mitochondrial membranes, possibly reflecting a carpeting action or formation of transmembrane pores by the inserted peptide. A group of two natural (scutellarein and epigallocatechin-gallate) and five synthetic compounds possessing a diphenyl-pyrazole scaffold (anle253b, anle138b, anle145c, sery315b, and sery335b) that satisfy the Lipinski criteria, were investigated for their capacity to mitigate the membrane-rigidifying effects of oligomeric hIAPP. Interestingly, a general trend was observed in that pre-incubation with a compound that led to a more rigid lipid environment, correlated with the mitigation of hIAPP-induced membrane fluidity changes. Remarkably, anle138b demonstrated the ability to effectively inhibit such alterations in phospholipid-packing in both liposome and mitochondrial experiments. In light of these results, anle138b is an attractive candidate for further investigation as a modulator of the physicochemical properties of mitochondrial-like membranes, making them more resistant to hIAPP aggregates. Such a strategy may provide a novel therapeutic approach to combat T2DM, and other amyloidogenic disorders.