Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation

Gelsolin amyloidosis (AGel) is characterized by multiple systemic and ophthalmic features
resulting from pathological tissue deposition of the gelsolin (GSN) protein. To date, no cure is available
for the treatment of any form of AGel. More than ten single-point substitutions in the GSN gene
are responsible for the occurrence of the disease and, among them, D187N/Y is the most widespread
variant. These substitutions undergo an aberrant proteolytic cascade, producing aggregation-prone
peptides of 5 and 8 kDa, containing the Gelsolin Amyloidogenic Core, spanning residues 182–192
(GAC182–192). Following a structure-based approach, we designed and synthesized three novel
sequence-specific peptidomimetics (LB-5, LB-6, and LB-7) built on a piperidine-pyrrolidine unnatural
amino acid. LB-5 and LB-6, but not LB-7, efficiently inhibit the aggregation of the GAC182–192 amyloidogenic
peptides at sub-stoichiometric concentrations. These peptidomimetics resulted also effective
in vivo, in a C. elegans-based assay, in counteracting the proteotoxicity of aggregated GAC182–192.
These data pave the way to a novel pharmacological strategy against AGel and also validate a toolbox
exploitable in other amyloidogenic diseases.