Small Molecule Targeting of Feline Islet Amyloid Polypeptide for the Management of Feline Diabetes Mellitus

Abstract

In a majority of feline diabetic patients, amyloid deposits have been detected in the islets of Langerhans. These deposits originate from islet amyloid polypeptide (IAPP), a satiety hormone produced and co-secreted with insulin by beta-cells. Islet amyloid deposits have been associated with beta-cell death during 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 feline diabetes mellitus with small drug-like molecules is still not available. We hypothesize that it is possible to inhibit the aggregation of feline IAPP selectively by small molecules. The overall objective of this project is to establish the structure-activity relationship of our in-house designed small molecules to impede feline IAPP aggregation and to prepare new analogs for further drug development.We evaluated the effect of 250 newly synthetized small molecules to reduce the formation of feline IAPP fibrils in vitro using Thioflavin T (ThT) fluorescence assays. Screening of small molecules were performed on human IAPP to identify selective inhibitors of feline IAPP. The inhibition of oligomer formation was assessed with photo-induced cross-linking of unmodified protein (PICUP) assays. Inhibition of feline IAPP was confirmed with transmission electron microscopy. Based on the screening of newly synthesized molecules, we discovered selective inhibitors, including JF-19-33, of feline IAPP. Identifying selective inhibitors of feline IAPP aggregation will open up a new therapeutic approach to reducing β-cell death and slowing progression of feline diabetes mellitus.