Exploiting Cross-Amyloid Interactions To Inhibit Insulin Aggregation but not Function: Nanomolar Affinity Inhibition of Insulin Aggregation by an IAPP Mimic

Angewandte Chemie, 2008, 47, 10.1002/anie.200801499 published on 08.08.2008
Angewandte Chemie, online article
In vivo protein aggregation is strongly linked to the pathogenesis of several incurable celland neurodegenerative diseases including Alzheimer’s disease (AD) and type II diabetes (T2D). In vitro protein aggregation leads to a loss of function and complicates therapeutic application of a number of bioactive proteins or polypeptides such as insulin. Designing potent inhibitors of aggregation of such proteins is however a difficult task as these compounds should not affect protein function. Here we present a novel chemical strategy to generate inhibitors of protein aggregation that do not affect protein function by mimicking natively occuring cross-amyloid peptide interactions. We exemplify the validity of this approach by demonstrating that IAPP-GI, a designed soluble and non-amyloidogenic mimic of islet amyloid polypeptide (IAPP), which is a native insulin interaction partner and a key amyloidogenic polypeptide of T2D, is a nanomolar affinity inhibitor of non-native aggregation of insulin without affecting its biological function. As IAPP-GI also blocks with nanomolar activity cytotoxic aggregation of both IAPP and the key amyloidogenic peptide of AD Aβ, it could become a unique lead compound for the development of novel therapeutic strategies targeting both AD and T2D. In addition, our cross-amyloid-inhibitor-design approach may be applicable to other aggregation-prone polypeptides or proteins.

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