Diabetes Mellitus Drug Discovery: Insights into Targeting Feline and Human Amylin with Small Molecules

Abstract

In a majority of diabetic feline and human patients, amyloid deposits have been detected in the islets of Langerhans. These deposits originate from islet amyloid polypeptide (IAPP or amylin), a satiety hormone produced and co‐secreted with insulin by beta‐cells. These islet amyloid deposits have been associated with beta‐cell death during the progression of diabetes. Several molecular entities have been shown to inhibit human IAPP aggregation, including silibinin and resveratrol. However, these agents have poor bioavailability and cause multiple pharmacological effects. An effective means to stop or prevent pancreatic amyloidosis in diabetes mellitus with small drug‐like molecules is still not available. The overall objective of this project was to identify selective and general inhibitors of feline and human IAPP fibril formation. The potency of molecules to reduce the formation of feline and human IAPP fibrils and toxic oligomers was monitored in vitrousing biophysical methods such as Thioflavin T (ThT) fluorescence assays, dynamic light scattering (DLS), and transmission electron microscopy (TEM). We then assessed the potency of the JF analogs on both feline and human IAPP, which differ by only 4 amino acids. JF‐19‐033 selectively inhibited feline IAPP fibril formation. JF‐19‐034 selectively inhibited human IAPP fibril formation. In contrast, JF‐19‐029 non‐selectively inhibited all of the human and feline IAPP peptides we tested. By doing this, we identified selective and non‐selective inhibitors of IAPP fibril formation. This project represents a phenotypic‐based drug design strategy for modulating feline and human IAPP fibril formation based on amino acid variations by small molecules. As a result, it has the potential to point towards new therapeutic strategies for type 2 diabetes.