Foldamer-mediated manipulation of a pre-amyloid toxin

Sunil Kumar, Melissa Birol, Diana E. Schlamadinger, Slawomir P. Wojcik, Elizabeth Rhoades and Andrew D. Miranker ()
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Sunil Kumar: Yale University
Melissa Birol: Yale University
Diana E. Schlamadinger: Yale University
Slawomir P. Wojcik: Yale University
Elizabeth Rhoades: Yale University
Andrew D. Miranker: Yale University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11412

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