Foldamer-mediated manipulation of a pre-amyloid toxin

Nat Commun. 2016 Apr 25:7:11412. doi: 10.1038/ncomms11412.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / metabolism*
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Islet Amyloid Polypeptide / chemistry*
  • Islet Amyloid Polypeptide / metabolism
  • Islet Amyloid Polypeptide / toxicity
  • Molecular Structure
  • Quinolines / chemistry*
  • Rats

Substances

  • Amides
  • Islet Amyloid Polypeptide
  • Quinolines
  • quinoline