Design of peptidyl compounds that affect beta-amyloid aggregation: importance of surface tension and context.
Self-association of beta-amyloid (Abeta) peptide into cross-beta-sheet fibrils induces cellular toxicity in vitro and is linked with progression of Alzheimer's disease. Previously, we demonstrated that hybrid peptides, containing a recognition domain that binds to Abeta and a disrupting domain consisting of a chain of charged amino acids, inhibited Abeta-associated toxicity in vitro and increased the rate of Abeta aggregation. In this work we examine the design parameter space of the disrupting domain. Using KLVFFKKKKKK as a base case, we tested hybrid compounds with a branched rather than linear lysine oligomer, with l-lysine replaced by d-lysine, and with lysine replaced by diaminopropionic acid. We synthesized a compound with a novel anionic disrupting domain that contained cysteine thiols oxidized to sulfates, as well as other compounds in which alkyl or ether chains were appended to KLVFF. In all cases, the hybrid compound's ability to increase solvent surface tension was the strongest predictor of its effect on Abeta aggregation kinetics. Finally, we investigated the effects of arginine on Abeta aggregation. Arginine is a well-known chaotrope but increases surface tension of water. Arginine modestly decreased Abeta aggregation. In contrast, RRRRRR slightly, and KLVFFRRRRRR greatly, increased Abeta aggregation. Thus, the influence of arginine on Abeta aggregation depends strongly on the context in which it is presented. The effect of arginine, RRRRRR, and KLVFFRRRRRR on Abeta aggregation was examined in detail using laser light scattering, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence, and transmission electron microscopy.
Gibson
Todd J
TJ
Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, Wisconsin 53706, USA.
Murphy
Regina M
RM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013500:Surface Tension
D016229:Amyloid beta-Peptides; D007202:Indicators and Reagents; D009842:Oligopeptides; D010455:Peptides