{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kumar S"],"funding":["NIGMS NIH HHS"],"pagination":["11412"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4848510"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7"],"pubmed_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."],"journal":["Nature communications"],"pubmed_title":["Foldamer-mediated manipulation of a pre-amyloid toxin."],"pmcid":["PMC4848510"],"funding_grant_id":["R01 GM094693","R01 GM102815"],"pubmed_authors":["Schlamadinger DE","Miranker AD","Birol M","Wojcik SP","Kumar S","Rhoades E"],"additional_accession":[]},"is_claimable":false,"name":"Foldamer-mediated manipulation of a pre-amyloid toxin.","description":"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.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Apr","modification":"2024-11-13T17:00:02.676Z","creation":"2019-03-27T02:12:36Z"},"accession":"S-EPMC4848510","cross_references":{"pubmed":["27108700"],"doi":["10.1038/ncomms11412"]}}