Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules

Abstract

Background

Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of β-cells to produce insulin and further perpetuating disease.

Objective

Our team’s drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D.

Material and methods

We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro.

Results

The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils.

Conclusion

Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

Keywords:

• Amylin
• cat
• drug discovery
• islet amyloid polypeptide
• pancreatic amyloidosis
• type 2 diabetes
• small molecule therapeutics
• veterinary medicine

Acknowledgment

The authors would like to acknowledge the professional services of Alicia Withrow at the Michigan State University Center for Advanced Microscopy and Prasanth Saraswati for the technical expertise.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This project was funded by the EveryCat Health Foundation (W20-020). Kendall B. E. Moore and Natalie G. Horgan were part of the American Society for Investigative Pathology (ASIP) Summer Research Opportunity Program in Pathology (SROPP). Brooke Lenters was part of the Purdue Veterinary Scholar Summer Research Program supported by Boehringer Ingelheim.