Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

Abstract

This paper describes studies of a series of macrocyclic β-sheet peptides <b>1</b> that inhibit the aggregation of a tau-protein-derived peptide. The macrocyclic β-sheet peptides comprise a pentapeptide “upper” strand, two δ-linked ornithine turn units, and a “lower” strand comprising two additional residues and the β-sheet peptidomimetic template “Hao”. The tau-derived peptide Ac-VQIVYK-NH₂ (AcPHF6) aggregates in solution through β-sheet interactions to form straight and twisted filaments similar to those formed by tau protein in Alzheimer’s neurofibrillary tangles. Macrocycles <b>1</b> containing the pentapeptide VQIVY in the “upper” strand delay and suppress the onset of aggregation of the AcPHF6 peptide. Inhibition is particularly pronounced in macrocycles <b>1a</b>, <b>1d</b>, and <b>1f</b>, in which the two residues in the “lower” strand provide a pattern of hydrophobicity and hydrophilicity that matches that of the pentapeptide “upper” strand. Inhibition varies strongly with the concentration of these macrocycles, suggesting that it is cooperative. Macrocycle <b>1b</b> containing the pentapeptide QIVYK shows little inhibition, suggesting the possibility of a preferred direction of growth of AcPHF6 β-sheets. On the basis of these studies, a model is proposed in which the AcPHF6 amyloid grows as a layered pair of β-sheets and in which growth is blocked by a pair of macrocycles that cap the growing paired hydrogen-bonding edges. This model provides a provocative and appealing target for future inhibitor design