Stoichiometric Inhibition of Amyloid -Protein Aggregation with Peptides Containing Alternating ,-Disubstituted Amino Acids - Analytical Methods & Tools for Lyophilization

Stoichiometric Inhibition of Amyloid -Protein Aggregation with Peptides Containing Alternating ,-Disubstituted Amino Acids
Received January 4, 2006
Web Release Date: March 1, 2006
Marcus A. Etienne, Jed P. Aucoin, Yanwen Fu, Robin L. McCarley, and Robert P. Hammer*
J. Am. Chem. Soc.,
ACS Publications
Copyright © 2006 American Chemical Society
Department of Chemistry, Choppin Hall, Louisiana State University, Baton Rouge, Louisiana 70803
rphammer@lsu.edu
Abstract:
We have prepared two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid -protein (A) that contain ,-disubstituted amino acids at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus). We have studied the effects of AMY-1 and AMY-2 on the aggregation of A and find that, at stoichiometric concentrations, both peptides completely stop A fibril growth. Equimolar mixtures of AMY-1 and A form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillar or fibrillar material even after prolonged periods of time (4.5 months). Also, 10 mol % of AMY-1 prevents A self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillar or fibrillar aggregates. Circular dichroism spectroscopy of equimolar mixtures of AMY-1 and A show that the secondary structure of the mixture changes over time and progresses to a predominantly -sheet structure, which is consistent with the design of these inhibitors preferring a sheet-like conformation. Changing the position of the charged tail on the peptide, AMY-2 interacts with A differently in that equimolar mixtures form large (~1 m) globular aggregates which do not progress to fibrils, but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the inhibitors act as cosurfactants that interfere with the native ability of A to self-assemble by disrupting hydrophobic interactions either at the C-terminus or N-terminus of A.
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