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

Abstract

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.

BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease

“…In a previous study, we reported that the hotspot regions in β1 (Asn159), α2 (Val189, Tyr192, and Lys194), and the α1~α2 loop (Glu196), which are involved in the pathogenic conversion process, are obstructed by binding to the anti-prion compounds. In particular, the α1~α2 salt bridge between Arg156 and Glu196 of the misfolded PrP C returns to the PrP C state in the presence of BMD42-29 [27]; this finding is consistent with other reports [39,47]. BMD42-2910 has hydrogen bonding interactions at Glu196, which are not absent in BMD42-29.…”

“…These aggregates can be detected by western blotting and inhibited by anti-PrP compounds [26]. Additionally, the structural mechanisms of BMD42-29 inhibition have been studied [27]. In the present study, we extended previous research by designing the derivatives of BMD42-29 using in silico feedback, specifically with chemical modifications based on docking pose of BMD42-29; the aim was to elucidate the improved anti-prion activity compared to that achieved by a previous procedure [25].…”

Application of the fragment molecular orbital method to discover novel natural products for prion disease

“… 21 , who proposed one compound, named GN8, which strongly stabilises normal conformation by binding to PrP C . Based on several computational studies, the specific binding site of PrP C can be specified as Asn159, Val189, Thr192, Lys194, and Glu196 15 , 22 , 23 . Therefore, focusing on the hotspot pocket as the interaction site between GN8 and PrP C may be a promising way to develop new antiprion drugs in the future.…”