Small Peptides for Inhibiting Serum Amyloid A Aggregation

Deposition of human Serum Amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis and eventually organ damage, are a commonly seen as a consequence of certain cancers and inflammatory diseases. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils, and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the life-time of peptide drugs can be increased by replacing L-amino acids with their mirror D- amino acids, we have also studied corresponding D-peptides. We find that DRI-SAA1-5, formed of D-amino acids with the sequence of the peptide reversed, has similar inhibitory properties than the original L-peptide, and therefore may be a promising candidate for drugs targeting SAA amyloidosis.