Small molecules breaking down islet amyloid polypeptide self‐assembly

Abstract

Amyloid deposition is a recognised feature of the islets in the majority of type 2 diabetic patients. These deposits originate from islet amyloid polypeptide (IAPP). Normally, IAPP is secreted along with insulin from pancreatic β‐cells and has hormonal functions related to satiety. However, IAPP is one of the most potent amyloidogenic proteins. Deposition of IAPP is associated with β‐cell death and diabetes progression. Drugs to inhibit pancreatic amyloidosis are not available. We have prepared a small molecule screening library to inhibit pancreatic amyloidosis. Our central hypothesis is that IAPP fibril formation (fibrillization) and deposition can be modulated by IAPP‐interactive compounds. We aim to establish structure‐activity relationships by which our small molecules impede IAPP fibrillization. Our primary approach, thioflavin T (ThT) assay, represented a major tool for the determination of IAPP fibrillization and inhibition by small molecules. For the most potent molecules, the abrogation of cytotoxic intermediate species (i.e. oligomerization leading to fibril formation) was determined with photo‐induced cross‐linking of unmodified protein. To confirm the inhibitory effect morphologically, electron microscopy analysis was performed to detect IAPP fibrils directly. Disaggregation of preformed fibrils by different compounds was studied with ThT assays and electron microscopy. The 1st‐tier screening method (ThT assay) identified several lead compounds to target IAPP. The oligomerization of IAPP was abrogated by JF‐19‐029. JF‐19‐029 and NBMI‐19‐013 deteriorated preformed fibrils. Few molecules have been reported to break down mature fibrils. We hope to open a new therapeutic approach to reduce type 2 diabetes progression.