Diabetes Mellitus Drug Discovery: Insights into Targeting Feline and Human Amylin with Small Molecules.
Kendall B E MooreNatalie G HorganBrooke LentersJessica S FortinPublished in: The veterinary quarterly (2023)
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. 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. 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 . 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 proteinaceous fibrils. Compound 24 may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.
Keyphrases
- drug discovery
- type diabetes
- endothelial cells
- end stage renal disease
- induced pluripotent stem cells
- chronic kidney disease
- healthcare
- newly diagnosed
- pluripotent stem cells
- cardiovascular disease
- public health
- quality improvement
- ejection fraction
- palliative care
- oxidative stress
- signaling pathway
- induced apoptosis
- adipose tissue
- prognostic factors
- cell death
- amino acid
- protein protein
- current status
- metabolic syndrome
- endoplasmic reticulum stress
- peritoneal dialysis