Using Small Molecules and Peptides as Chemical Tools to Study Metal-Amyloid, Membrane-Amyloid, and Peptide-Amyloid Interactions.

[摘要] Amyloid proteins are a family a proteins that are characterized by the misfolding an intrinsically disordered monomer subunit into an ordered beta-sheet fibril. Recent evidence has suggested that the monomer and fibril species are relatively inert; however, aggregates along the misfolding pathway are directly linked to cytotoxicity. It is known that biological cofactors and membranes may play a part in these deleterious events. Specifically metal ions and lipid bilayers may have a role in amyloid-associated toxicity through misregulation of metal ions and generation of oxidative stress with redox active metal ions or disruption of membrane integrity through pore formation and fragmentation of the bilayer. In order to better understand how metal ions and lipid bilayers are involved with amyloid aggregation and toxicity, small molecules can be used as chemical tools. A series of diphenylpropynone derivatives were developed to study the interaction of bifunctional ligands on metal-Aβ aggregation. Both DPP1 and DPP2 showed reactivity toward metal–Aβ species over metal-free Aβ species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal–Aβ species than DPP1. Small molecules can also be applied as chemical modulators for lipid-associated amyloid aggregation. A curcumin derivative, CurDAc, was developed to investigate the mitigation of hIAPP aggregation in the absence and presence of lipid membrane. CurDAc showed tremendous inhibitory propensity for both lipid-free and lipid-assisted IAPP aggregation in vitro, making it an ideal candidate for further SAR studies.To gain insights into the misfolding pathway and oligomerization of amyloid proteins, the self-assembly of TK9, a nine-residue peptide and its variants were characterized through biophysical, spectroscopic, and simulated studies, and it was confirmed that the structure of these peptides influences their aggregation propensity, hence, mimicking amyloid proteins. This peptide also showed promise as a chemical inhibitor for hIAPP aggregation.Through this work, insights into effective structural scaffold to modify amyloid aggregation in the presence of biological cofactors are understood. Moreover, the discovery of a structural scaffold to monitor oligomer and fibril formation in order to elucidate species along the misfolding pathway has also been made.

[发布机构] University of Michigan

[效力级别] small molecule

[关键词] Amyloid;small molecule;Chemistry;Science;Chemistry