Foldamer-mediated manipulation of a pre-amyloid toxin.

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 ?-cell pathology in type II diabetes. A tetraquinoline is presented that stabilizes a pre-amyloid, ?-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 ?-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.

SUBMITTER: Kumar S 

PROVIDER: S-EPMC4848510 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature