Modified-peptide inhibitors of amyloid beta-peptide polymerization

Cellular toxicity resulting from nucleation-dependent polymerization of amy loid beta-peptide (A beta) is considered to be a major and possibly the pri mary component of Alzheimer's,disease (AD). Inhibition of A beta polymeriza tion has thus been identified as a target for the development of therapeuti c agents for the treatment of AD. The intrinsic affinity of A beta for itse lf suggested that A beta-specific interactions could be adapted to the deve lopment of compounds that would bind to A beta and prevent it from polymeri zing. A beta-derived peptides of fifteen residues were found to be inhibito ry of A beta polymerization. The activity of these peptides was subsequentl y enhanced through modification of their amino termini with specific organi c reagents. Additional series of compounds prepared to probe structural req uirements for activity allowed reduction of the size of the inhibitors and optimization of the A beta-derived peptide portion to afford a lead compoun d, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI-368), with potent polymerization inhi bitory activity but limited biochemical stability. The corresponding all-D- amino acyl analogue peptide acid (PPI-433) and amide (PPI-457) retained inh ibitory activity and were both stable in monkey cerebrospinal fluid for 24 h.