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 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.

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

“…In support of this idea, insulin has been shown to interfere with lipid-induced IAPP self-assembly, although this inhibitory effect is distinct from that of ENSA on membrane-induced aSyn aggregation because it involves the binding of insulin to IAPP fibril ends rather than the membrane and is markedly greater in the absence than in the presence of lipids [34]. In other studies, peptidomimetics and small molecules that interfered with membrane-induced IAPP aggregation were reported to attenuate IAPP cytotoxicity [23, 35]. These observations and the findings presented herein strongly suggest that stabilizing aggregation-resistant forms of membrane-bound amyloidogenic polypeptides by promoting interactions with their binding partners could be a viable therapeutic strategy not only for synucleinopathy disorders, but also for a broader array of protein misfolding diseases.…”

Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin

“…This inhibition does not appear to be a simple consequence of displacing IAPP from the liposome surface. Using a previously characterized fluorescein tagged variant of ADM-116 24 , we observe that the IAPP:ADM-116 complex and not ADM-116 readily associates with the liposome (Fig. 2c).…”

“…Atomic models of ADM-116 and ADM-3 based on crystal structures 23,24 . Models of ADM-116 and ADM-3 are readily created in which each show two exposed carboxylates held at comparable distances apart.…”

“…The kinetics for lipid catalysed IAPP fibrillation was completely suppressed over the time-frame of the experiment (45 h) in the presence of stoichiometric ADM-116 (Fig. 2a) 24 . ADM-116 is ≫10 fold more effective than our previously reported pentaquinoline, ADM-118 (earlier reported under the name OQ 5 11 ) (Fig.…”

Cell‐Penetrating Peptide Foldamers: Drug‐Delivery Tools

“…Furthermore, Miranker et al. reported quinoline oligoamides that stabilized a pre‐amyloid; α‐helical conformation of islet amyloid polypeptide . Surprisingly, although this oligoamide is a dianionic compound with a molecular weight of around 1000 Da, it crosses the cell membrane.…”