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| Item Type: | Article |
|---|---|
| Title: | Foldamer-mediated manipulation of a pre-amyloid toxin |
| Creators Name: | Kumar, S., Birol, M., Schlamadinger, D.E., Wojcik, S.P., 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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