Structural insight into the antiprion compound inhibition mechanism of native prion folding over misfolding.

Transition of a physiological folded prion (PrP ) into a pathogenic misfolded prion (PrP ) causes lethal neurodegenerative disorders and prion diseases. Antiprion compounds have been developed to prevent this conversion; however, their mechanism of action remains unclear. Recently, we reported two antiprion compounds, BMD29 and BMD35, identified by in silico and in vitro screening. In this study, we used extensive explicit-solvent molecular dynamics simulations to investigate ligand-binding inhibition by antiprion compounds in prion folding over misfolding behavior at acidic pH. The two antiprion compounds and the previously reported GN8 compound resulted in a remarkably stabilized intermediate by binding to the hotspot region of PrP , whereas free PrP and the inactive compound BMD01 destabilized the structure of PrP leading to the misfolded form. The results uncovered a secondary structural transition of free PrP and transition suppression by the antiprion compounds. One of the major misfolding processes in PrP , alternation of hydrophobic core residues, disruption of intramolecular interactions, and the increase in residue solvent exposure were significantly inhibited by both antiprion compounds. These findings provide insights into prion misfolding and inhibition by antiprion compounds.