Modulation of early aggregation events by flexible peptidomimetics inhibits gelsolin amyloid formation

Gelsolin amyloidosis (Agel) is a hereditary systemic disorder caused by point mutations in the gelsolin (GSN) gene that promote aberrant proteolytic processing and deposition of amyloidogenic fragments. The most prevalent variant, D187N, destabilizes the G2 domain of the protein and exposes a cleavage site, ultimately generating fragments containing the GSN amyloidogenic core. Targeting this sequence represents a promising therapeutic strategy. Here, we report a comprehensive structural and mechanistic characterization of LB6, a rationally designed peptidomimetic inhibitor of gelsolin aggregation, together with selected analogues. Biophysical, computational, and structure-activity relationship analyses reveal that LB6 populates a dynamic ensemble of conformations whose flexibility is critical for activity. LB6 and its reverse-sequence analogue MC35 effectively inhibit fibril formation and promote remodelling of pre-formed aggregates of the pathogenic G2 domain, carrying D187N mutation (G2_D187N). Mechanistic studies indicate that these compounds interfere with early events of G2_D187N aggregation and counteract the toxicity of aggregated G2_D187Nin vivo in C. elegans. Collectively, our results identify conformational adaptability as an important determinant of inhibitory potency and establish LB6 as a promising lead scaffold for the development of therapeutic agents targeting AGel.