The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)

Amyloid self‐assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, β‐cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host‐defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial and immunomodulatory polypeptide human cathelicidin LL‐37 binds IAPP with nanomolar affinity and effectively suppresses its amyloid self‐assembly and related pancreatic β‐cell damage in vitro. In addition, we identify key LL‐37 segments that mediate its interaction with IAPP. Our results suggest a possible protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of LL‐37‐derived peptides that combine antimicrobial, immunomodulatory, and T2D‐related anti‐amyloid functions as promising candidates for multifunctional drugs. One for all: A high‐affinity amyloid‐suppressing interaction between the human antimicrobial and immunomodulatory polypeptide cathelicidin LL‐37 and the key type 2 diabetes (T2D) amyloid polypeptide IAPP was identified. The results suggest a protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of novel molecules combining antimicrobial, immunomodulatory, and anti‐amyloid functions as multifunctional drug candidates.