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

Area of Science:

• Biochemistry
• Neuroscience
• Endocrinology

Background:

• Human islet amyloid polypeptide (hIAPP), or amylin, regulates blood glucose.
• Amylin aggregation into amyloid deposits is linked to type 2 diabetes and Alzheimer's disease.

Purpose of the Study:

• To investigate 1-benzylamino-2-hydroxyalkyl derivatives as potential inhibitors of amylin aggregation.
• To identify specific compounds that can prevent pathological amylin conformational changes.

Main Methods:

• Thioflavin T (ThT) and Dynamic Light Scattering (DLS) assays were used to assess amylin aggregation inhibition.
• Fluorescence quenching, binding, and thermodynamic analyses were performed.
• In silico molecular simulations were conducted to compare compound efficacy.

Main Results:

• Compounds 18 and 22 were identified as potent amylin aggregation inhibitors with IC50 values of 3.04 μM and 2.71 μM, respectively.
• These compounds stabilized small oligomers, reducing cytotoxicity, and induced conformational changes in amylin without altering Tyr37 fluorescence.
• Molecular dynamics simulations showed compound 18 stabilized alpha-helical fragments, potentially delaying amyloid formation.

Conclusions:

• 1-benzylamino-2-hydroxyalkyl derivatives, particularly compound 18, show promise as amylin aggregation inhibitors.
• These findings provide insights into amylin aggregation mechanisms and inform the design of novel therapeutic agents for T2D and AD.