# Molecular Mechanisms of Islet Amyloid Polypeptide Aggregation: Towards Chemical Strategies to Prevent Amyloid Formation and to Design Non-Aggregating Peptide Therapeutics

## TL;DR

This review explores how the islet amyloid polypeptide (IAPP) forms harmful amyloid fibrils in type 2 diabetes and discusses strategies to prevent this aggregation for therapeutic development.

## Contribution

The paper provides a comprehensive review of IAPP aggregation mechanisms and proposes chemical strategies to inhibit amyloid formation and design non-aggregating therapeutics.

## Key findings

- IAPP aggregation involves conformational changes from disordered monomers to cross-β-sheet structures.
- Chemical strategies can be developed to prevent amyloid formation and design safe IAPP-based therapeutics.
- Understanding aggregation mechanisms is key to creating non-aggregating peptide agonists for metabolic disorders.

## Abstract

The islet amyloid polypeptide (IAPP) is a peptide hormone playing key biological roles, including glucose homeostasis and regulation of food intake, conferring high therapeutic potential to treat metabolic disorders. Nonetheless, IAPP is mainly known as the major component of the amyloid fibrils observed in the pancreatic islets of patients afflicted with type 2 diabetes, and the accumulation of these insoluble protein deposits correlates closely with the loss of pancreatic β-cells. The inherent aggregation propensity of this peptide hormone is not only associated with the pathogenesis of type 2 diabetes but also complicates the design of IAPP derivatives for the treatment of metabolic disorders. Accordingly, elucidating the molecular mechanisms by which IAPP self-assembles into amyloid fibrils is critical to identify chemical strategies to arrest aggregation, as well as to design safe and stable IAPP-derived therapeutics. This review aims at presenting the different mechanistic models of IAPP aggregation and how to exploit this information to identify inhibitors of amyloid formation and non-aggregating peptide agonists. After discussing the conformational conversions allowing IAPP to undergo a mainly disordered monomeric conformation into ordered cross-β-sheet quaternary supramolecular structures, we present chemical strategies to prevent amyloid deposition and to develop non-aggregating peptide-based therapeutics.