Selectively N-Methylated Soluble IAPP Mimics as Potent IAPP Receptor Agonists and Nanomolar Inhibitors of Cytotoxic Self-Assembly of Both IAPP and Aβ40

摘要

The aggregation of islet amyloid polypeptide (IAPP) is linked to (3-cell degeneration and the pathogenesis of type 2 diabetes (T2D). IAPP is a 37-residue polypeptide hormone secreted by the pancreatic β-cells. IAPP amyloid deposits are found in the pancreata of many T2D patients. In its soluble form, however, IAPP acts as a brain-gut neuropeptide regulator of glucose homeostasis. Its main physiological functions comprise delay of gastric emptying by inhibiting gastric contractions and suppression of food intake. IAPP receptors are G protein coupled receptors (GPCRs) that form through heterodimerization of the calcitonin receptor with receptor activity modifying proteins (RAMPs). Due to its extreme insolubility IAPP is not suited for medicinal application. However, a soluble IAPP receptor agonist, the IAPP analogue [P25,P28,P29]-IAPP or pramlintide, was approved for diabetes therapy a few years ago and its use results in improved control of blood sugar levels. Therefore, the application of soluble IAPP receptor agonists has lately become a very promising new approach in diabetes treatment.