LAUSR

Aggregation of polypeptides and proteins is commonly associated with human and other vertebrate diseases. For example, amyloid plaques consist of amyloid-β proteins (Aβ) are frequently identified in Alzheimer's disease and islet amyloid formed by islet amyloid polypeptide (IAPP, Amylin) can be found in most patients with type-2 diabetes (T2D). Although many fluorescent dyes have been developed to stain amyloid fibrils, very few examples are designed for IAPP. In this study, a series of environmentally sensitive fluorescent probes using flavonoid as a scaffold design is rationally designed and synthesized. One of these probes, namely 3-HF-ene-4'-OMe, can bind to IAPP fibrils but not IAPP monomers by exhibiting a much stronger fluorescent enhancement at 535 nm. In addition, this probe shows better detection sensitivity to IAPP fibrils compared with conventionally used Thioflavin-T. We demonstrate that 3-HF-ene-4'-OMe can be used to monitor the kinetics of IAPP fibril formation in vitro even in the presence amyloid inhibitor. To test the specificity of probe, we attempt to incubate this probe with amyloid fibrils formed from other amyloidogenic proteins. Interestingly, this probe shows different responses when mixing with these fibrils suggesting the binding mode of this probe on these fibrils could be different. Moreover, we show that this probe is not toxic to pancreatic mouse beta cells. Further structural optimization based on the structure of 3-HF-ene-4'-OMe may accomplish a specific probe for imaging islet amyloid in the pancreas. That would improve our understanding on the relationship between islet amyloid and T2D.