Synthetic deformylated α-helical PSMα3 as a selective inhibitor of human amyloid aggregation

The α-helical peptide PSMα3 belongs to the family of phenol-soluble modulins (PSMs) produced by the Staphylococcus aureus bacteria. Synthetic deformylated PSMα3 was previously reported to not form amyloid fibrils and maintain α-helical conformation in a monomeric form for several days of incubation. In this study, we showed that deformylated PSMα3 (dfPSMα3) attenuates fibrillation of wild type human islet amyloid polypeptide (hIAPP) and protects endothelial cells from its cytotoxicity. Kinetic assays revealed a concentration-dependent delay in the lag phase, while microscopy confirmed fewer fibrils upon co-incubation of dfPSMα3 with hIAPP. ATR-FTIR analysis further indicated that dfPSMα3 prevents the β-sheet transition of hIAPP, thereby disrupting fibril formation. On the other hand, we have not observed a similar effect of dfPSMα3 on aggregation of amyloid prone region of serum amyloid A (SAA27) and hIAPP deamidated at the C-terminus (dhIAPP). Molecular modelling suggested that dfPSMα3 could interact with a broader range of amyloidogenic peptides. We showed the key role of hydrophobic interactions in mediating molecular interactions between dfPSMα3 and other short amyloid peptides. Predicted structures indicated that hydrophobic interactions between the dfPSMα3 amino acids: Phe, Leu, and Val and those of the partner protein: Ala, Phe, Ile, Leu, and Val are likely to dominate the process of dfPSMα3 binding to other peptides. In addition, we found that the anti-fibrillation efficacy of dfPSMα3 is highly selective, dependent on the target protein sequence, and extremely sensitive to its terminal alterations.