Cross-seeding enables repurposing of aurein antimicrobial peptides as a promoter of human islet amyloid polypeptide (hIAPP).

Since hIAPP (human islet amyloid polypeptide) aggregation and microbial infection are recognized as significant risk factors that contribute to the pathogenesis of type II diabetes (T2D), targeting these catastrophic processes simultaneously may have a greater impact on the prevention and treatment of T2D. Different from the well-studied hIAPP inhibitors, here we propose and demonstrate a repurposing strategy for an antimicrobial peptide, aurein, which can simultaneously modulate hIAPP aggregation and inhibit microbial infection. Collective data from protein, cell, and bacteria assays revealed multiple functions of aurein including (i) promotion of hIAPP aggregation at a low molar ratio of aurein:hIAPP = 0.5 : 1-2 : 1, (ii) reduction of hIAPP-induced cytotoxicity in RIN-m5F cells, and (iii) preservation of original antimicrobial activity against E. coli. , S.A. , and S.E. strains in the presence of hIAPP. These functions of aurein are mainly derived from its strong binding to different hIAPP seeds through conformationally similar β-sheet association. Our study provides a promising avenue for the repurposing of antimicrobial peptides (such as aurein) as amyloid modulators for blocking at least two pathological pathways in T2D.