Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation

Area of Science:

• Biochemistry
• Pharmacology
• Genetics

Background:

• Gelsolin amyloidosis (AGel) is a systemic and ophthalmic disease caused by gelsolin (GSN) protein deposition.
• Current treatments for AGel are lacking, and specific GSN gene mutations, like D187N/Y, trigger the disease.
• Aberrant proteolysis generates aggregation-prone Gelsolin Amyloidogenic Core (GAC) peptides (5 and 8 kDa).

Purpose of the Study:

• To design and synthesize novel peptidomimetics targeting the GAC peptides.
• To evaluate the efficacy of these peptidomimetics in inhibiting GAC peptide aggregation in vitro.
• To assess the in vivo therapeutic potential of the peptidomimetics in a relevant model.

Main Methods:

• Structure-based design and synthesis of three peptidomimetics (LB-5, LB-6, LB-7) using unnatural amino acids.
• In vitro assessment of peptidomimetic inhibition of GAC_182-192 peptide aggregation at sub-stoichiometric concentrations.
• In vivo evaluation of peptidomimetic efficacy in a *C. elegans* model of GAC_182-192 proteotoxicity.

Main Results:

• Peptidomimetics LB-5 and LB-6 significantly inhibited GAC_182-192 peptide aggregation in vitro.
• LB-7 did not show significant inhibitory effects on GAC_182-192 aggregation.
• LB-5 and LB-6 demonstrated efficacy in vivo, counteracting proteotoxicity in the *C. elegans* model.

Conclusions:

• Novel peptidomimetics, LB-5 and LB-6, represent a promising therapeutic strategy for Gelsolin Amyloidosis.
• These findings validate a new approach for targeting amyloidogenic peptides in AGel.
• The developed peptidomimetic toolbox may be applicable to other amyloidogenic diseases.