# Inhibition of Human Amylin Aggregation: In Silico and In Vitro Studies

## TL;DR

This study identifies new compounds that can inhibit the aggregation of amylin, a protein linked to diabetes and Alzheimer's disease.

## Contribution

The study introduces 1-benzylamino-2-hydroxyalkyl derivatives as novel amylin aggregation inhibitors with strong in vitro and in silico evidence.

## Key findings

- Compounds 18 and 22 inhibited amylin aggregation with IC50 values of 3.04 and 2.71 μM.
- Compound 18 showed stronger interactions with amylin and stabilized α-helical fragments during simulations.
- The compounds reduced cytotoxicity by preserving small oligomers and inducing conformational changes in amylin.

## Abstract

Human islet amyloid polypeptide (hIAPP), also termed
amylin, is
an endocrine hormone that plays a key role in regulating blood glucose
levels. Pathological conformational changes in amylin can lead to
its aggregation into amyloid deposits, which are significant markers
in the development of type 2 diabetes (T2D) and Alzheimer’s
disease (AD). In this study, we explored 1-benzylamino-2-hydroxyalkyl
derivatives as potential amylin aggregation inhibitors. These compounds
have previously demonstrated activity against amyloid-β aggregation
in AD. We conducted ThT and DLS assays to identify compounds 18 and
22 as the most active derivatives, inhibiting amylin aggregation with
IC50 values of 3.04 and 2.71 μM, respectively. These
compounds preserved small-sized oligomers, which exhibited reduced
cytotoxicity compared to controls. The fluorescence quenching assay
revealed that compounds 18 and 22 significantly quenched the intrinsic
fluorescence of amylin without altering the emission spectra, indicating
conformational changes without major modifications in the Tyr37 region.
Binding and thermodynamic analyses indicated strong, spontaneous interactions
dominated by hydrophobic forces. An in silico study
compared the behavior of compound 18 (the most potent) and compound
9 (the least potent) in the ThT assay. Overall, compound 18 formed
more interactions with amylin than compound 9 and remained attached
to the peptide for a longer time during the simulation, more frequently
stabilizing the α-helical fragments. This stabilization may
help delay the transition into intermediate structures associated
with amyloidogenic β-sheet formation. Our findings offer new
insights into the aggregation process and may inform the design of
more effective aggregation inhibitors.