Modified-Peptide Inhibitors of Amyloid β-Peptide Polymerization

Abstract

Cellular toxicity resulting from nucleation-dependent polymerization of amyloid β-peptide (Aβ) is considered to be a major and possibly the primary component of Alzheimer's disease (AD). Inhibition of Aβ polymerization has thus been identified as a target for the development of therapeutic agents for the treatment of AD. The intrinsic affinity of Aβ for itself suggested that Aβ-specific interactions could be adapted to the development of compounds that would bind to Aβ and prevent it from polymerizing. Aβ-derived peptides of fifteen residues were found to be inhibitory of Aβ polymerization. The activity of these peptides was subsequently enhanced through modification of their amino termini with specific organic reagents. Additional series of compounds prepared to probe structural requirements for activity allowed reduction of the size of the inhibitors and optimization of the Aβ-derived peptide portion to afford a lead compound, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI-368), with potent polymerization inhibitory activity but limited biochemical stability. The corresponding all-d-amino acyl analogue peptide acid (PPI-433) and amide (PPI-457) retained inhibitory activity and were both stable in monkey cerebrospinal fluid for 24 h.