Enantiomers of the prion protein degrader SM875: Production and configurational assignment, in silico analysis and in vitro evaluation




Innocenti, Nicole; Tähtinen, Petri; Spagnolli, Giovanni; Perrucci, Cecilia; Bellini, Martina; Parolin, Eleonora; Bonaldo, Valerio; Biasini, Emiliano; Mancini, Ines

PublisherACADEMIC PRESS INC ELSEVIER SCIENCE

SAN DIEGO

2025

Bioorganic Chemistry

BIOORGANIC CHEMISTRY

BIOORG CHEM

108489

161

9

0045-2068

1090-2120

DOIhttps://doi.org/10.1016/j.bioorg.2025.108489

https://doi.org/10.1016/j.bioorg.2025.108489

https://research.utu.fi/converis/portal/detail/Publication/491874845



Prion diseases are rare and fatal neurodegenerative conditions affecting humans and animals caused by the misfolding of the cellular prion protein (PrP). Recently, the molecule 1-(4-bromophenyl)-1,4,5,7-tetrahydro-4-(4hydroxy-3)-6H-pyrazolo[3,4-b]pyridin-6-one, named SM875, was identified as a promising PrP degrader through a computational approach targeting folding intermediates. The racemic mixture of SM875 showed biological activity but also exhibited variable toxicity. In this study, we optimized the synthesis of racemic SM875 and achieved high-purity enantiomeric separation via chiral HPLC. The docking calculation data of each enantiomer with a simplified model of Chiralpak IA (R), used as the chiral stationary phase, were in line with their relative elution time. The electronic circular dichroic (ECD) spectra acquired for each isomer compared with the TD-DFT calculated spectrum for (R)-SM875 allowed the assignment of their absolute configuration. The biological evaluation revealed that the (R)-enantiomer solely reduces PrP levels, with associated toxicity, while the (S)- enantiomer is inactive. Molecular dynamics simulations corroborate the (R)-enantiomer's stronger interaction with PrP. These findings provide a foundation for therapeutic development targeting prion diseases.



This work was partially supported by grants from Fondazione Telethon (GGP20043), the American CJD Foundation and the Italian Association for Prion Encephalopathies (Aienp) to E.B.


Last updated on 2025-02-06 at 15:44