Noncovalent modulation of protein energy landscapes with an emerging class of cyclic-peptide chaperones

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the deterioration of motor neurons that abates essential biol. functions and exhibits survival times of 3 - 5 years after diagnosis. One driver of this disease derives from inherited mutations to the protein superoxide dismutase 1 (SOD1), which hinder proper folding and result in the accumulation of toxic aggregates. We identified cyclic peptides that target precise epitopes on SOD1 through a new high-throughput screening platform that furnishes high-affinity binders against regions of a protein independent of secondary and tertiary structure. Binding these epitopes both stabilizes the native state and accelerates folding. In this context, these small peptides function as mol. chaperones and mitigate the impact of deleterious mutations to SOD1. They also display the traditional benefits of small mols., such as straightforward chem. modifications and long-term stability. Overall, this method provides a route to rationally perturb the energy landscape of any protein through noncovalent binding, making it useful in fundamental studies of protein folding as well as designing therapeutics for misfolding diseases.