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Foldamer-mediated manipulation of a pre-amyloid toxin

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Item Type:Article
Title:Foldamer-mediated manipulation of a pre-amyloid toxin
Creators Name:Kumar, S. and Birol, M. and Schlamadinger, D.E. and Wojcik, S.P. and Rhoades, E. and Miranker, A.D.
Abstract:Disordered proteins, such as those central to Alzheimer's and Parkinson's, are particularly intractable for structure-targeted therapeutic design. Here we demonstrate the capacity of a synthetic foldamer to capture structure in a disease relevant peptide. Oligoquinoline amides have a defined fold with a solvent-excluded core that is independent of its outwardly projected, derivatizable moieties. Islet amyloid polypeptide (IAPP) is a peptide central to β-cell pathology in type II diabetes. A tetraquinoline is presented that stabilizes a pre-amyloid, α-helical conformation of IAPP. This charged, dianionic compound is readily soluble in aqueous buffer, yet crosses biological membranes without cellular assistance: an unexpected capability that is a consequence of its ability to reversibly fold. The tetraquinoline docks specifically with intracellular IAPP and rescues β-cells from toxicity. Taken together, our work here supports the thesis that stabilizing non-toxic conformers of a plastic protein is a viable strategy for cytotoxic rescue addressable using oligoquinoline amides.
Keywords:Amides, Cell Line, Insulin-Secreting Cells, Islet Amyloid Polypeptide, Molecular Structure, Type 2 Diabetes Mellitus, Quinolines, Animals, Rats
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:7
Page Range:11412
Date:25 April 2016
Official Publication:https://doi.org/10.1038/ncomms11412
PubMed:View item in PubMed

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