Design of Peptidyl Compounds That Affect β-Amyloid Aggregation:  Importance of Surface Tension and Context

• Published in: Biochemistry (Easton) Vol. 44; no. 24; pp. 8898 - 8907
• Main Authors: Gibson, Todd J, Murphy, Regina M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21-06-2005
• Subjects: Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Circular Dichroism; Indicators and Reagents; Kinetics; Models, Molecular; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Peptides - chemical synthesis; Peptides - pharmacology; Protein Conformation; Protein Structure, Secondary; Surface Tension
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi050225s

Self-association of β-amyloid (Aβ) peptide into cross-β-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 Aβ and a disrupting domain consisting of a chain of charged amino acids, inhibited Aβ-associated toxicity in vitro and increased the rate of Aβ 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 Aβ aggregation kinetics. Finally, we investigated the effects of arginine on Aβ aggregation. Arginine is a well-known chaotrope but increases surface tension of water. Arginine modestly decreased Aβ aggregation. In contrast, RRRRRR slightly, and KLVFFRRRRRR greatly, increased Aβ aggregation. Thus, the influence of arginine on Aβ aggregation depends strongly on the context in which it is presented. The effect of arginine, RRRRRR, and KLVFFRRRRRR on Aβ aggregation was examined in detail using laser light scattering, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence, and transmission electron microscopy.