2. Academic Validation
  3. Enantiomers of the prion protein degrader SM875: Production and configurational assignment, in silico analysis and in vitro evaluation

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

  • Bioorg Chem. 2025 Jul 1:161:108489. doi: 10.1016/j.bioorg.2025.108489.
Nicole Innocenti 1,  Petri Tähtinen 2,  Giovanni Spagnolli 3,  Cecilia Perrucci 4,  Martina Bellini 5,  Eleonora Parolin 1,  Valerio Bonaldo 3,  Emiliano Biasini 6,  Ines Mancini 7
Affiliations

Affiliations

  • 1 Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology, University of Trento, via Sommarive 9, I-38123 Povo, Trento, Italy; Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, via Sommarive 14, I-38123, Povo, Trento, Italy.
  • 2 Department of Chemistry, University of Turku, Henrikinkatu 2, 20014 Turku, Finland.
  • 3 Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology, University of Trento, via Sommarive 9, I-38123 Povo, Trento, Italy.
  • 4 Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, via Sommarive 14, I-38123, Povo, Trento, Italy.
  • 5 Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology, University of Trento, via Sommarive 9, I-38123 Povo, Trento, Italy; Department of Chemistry, University of Turku, Henrikinkatu 2, 20014 Turku, Finland.
  • 6 Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology, University of Trento, via Sommarive 9, I-38123 Povo, Trento, Italy. Electronic address: [email protected].
  • 7 Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, via Sommarive 14, I-38123, Povo, Trento, Italy. Electronic address: [email protected].
PMID: 40286470 DOI: 10.1016/j.bioorg.2025.108489
Abstract

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-(4-hydroxy-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®, 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.

Keywords

Chiral stationary phase; Density functional theory; Dynamic simulation; Enantiomeric separation; Molecular docking; Prion protein; Synthesis.

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