Peptide-based inhibitors of amyloid assembly.
This review considers the design, synthesis, and mechanistic assessment of peptide-based fibrillogenesis inhibitors, mainly focusing on beta-amyloid, but generalizable to other aggregating proteins and peptides. In spite of revision of the "amyloid hypothesis," the investigation and development of fibrillogenesis inhibitors remain important scientific and therapeutic goals for at least three reasons. First, it is still premature to dismiss fibrils altogether as sources of cytotoxicity. Second, a "fibrillogenesis inhibitor" is typically identified experimentally as such, but these compounds may also bind to intermediates in the fibrillogenesis pathway and have hard-to-predict consequences, including improved clearance of more cytotoxic soluble oligomers. Third, inhibitors are valuable structural probes, as the entire field of enzymology attests. Screening procedures for selection of random inhibitory sequences are briefly considered, but the bulk of the review concentrates on rationally designed fibrillogenesis inhibitors. Among these are internal segments of fibril-forming peptides, amino acid substitutions and side chain modifications of fibrillogenic domains, insertion of prolines into or adjacent to fibrillogenic domains, modification of peptide termini, modification of peptide backbone atoms (including N-methylation), peptide cyclization, use of D-amino acids in fibrillogenic domains, and nonpeptidic beta-sheet mimics. Finally, we consider methods of assaying fibrillogenesis inhibitors, including pitfalls in these assays. We consider binding of inhibitor peptides to their targets, but because this is a specific application of the more general and much larger problem of assessing protein-protein interactions, this topic is covered only briefly. Finally, we consider potential applications of inhibitor peptides to therapeutic strategies.
Sciarretta
Kimberly L
KL
The University of Chicago, Department of Pathology, Chicago, IL, USA.
Gordon
David J
DJ
Meredith
Stephen C
SC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000187:drug effects; D015195:Drug Design; D008745:Methylation; D045333:Nanotubes, Peptide / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis; D034444:Peptoids / Q000737:chemistry; D020836:Protein Structure, Quaternary / Q000187:drug effects*; D017433:Protein Structure, Secondary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D045333:Nanotubes, Peptide; D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; D034444:Peptoids