2. Academic Validation
  3. Pharmacological inactivation of the prion protein by targeting a folding intermediate

Pharmacological inactivation of the prion protein by targeting a folding intermediate

  • Commun Biol. 2021 Jan 12;4(1):62. doi: 10.1038/s42003-020-01585-x.
Giovanni Spagnolli 1 2,  Tania Massignan 1 2 3,  Andrea Astolfi 4,  Silvia Biggi 1 2,  Marta Rigoli 5,  Paolo Brunelli 1 2,  Michela Libergoli 1 2,  Alan Ianeselli 1 2,  Simone Orioli 5 6,  Alberto Boldrini 1 3,  Luca Terruzzi 1 3,  Valerio Bonaldo 1 2,  Giulia Maietta 1 2,  Nuria L Lorenzo 7,  Leticia C Fernandez 7,  Yaiza B Codeseira 7,  Laura Tosatto 8,  Luise Linsenmeier 9,  Beatrice Vignoli 5,  Gianluca Petris 1,  Dino Gasparotto 1 2,  Maria Pennuto 10 11,  Graziano Guella 5,  Marco Canossa 1,  Hermann C Altmeppen 9,  Graziano Lolli 1,  Stefano Biressi 1 2,  Manuel M Pastor 12,  Jesús R Requena 7,  Ines Mancini 5,  Maria L Barreca 13,  Pietro Faccioli 14 15,  Emiliano Biasini 16 17
Affiliations

Affiliations

  • 1 Department of Cellular, Computational and Integrative Biology, University of Trento, 38123, Povo, TN, Italy.
  • 2 Dulbecco Telethon Institute, University of Trento, 38123, Povo, TN, Italy.
  • 3 Sibylla Biotech SRL, 37121, Verona, VR, Italy.
  • 4 Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, PG, Italy.
  • 5 Department of Physics, University of Trento, Povo, Trento, TN, Italy.
  • 6 INFN-TIFPA, University of Trento, Povo, Trento, TN, Italy.
  • 7 CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.
  • 8 Institute of Biophysics, National Council of Research, 38123 Povo, Trento, TN, Italy.
  • 9 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
  • 10 Department of Biomedical Sciences (DBS), University of Padova, 35131, Padova, Italy.
  • 11 Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy.
  • 12 RIAIDT, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.
  • 13 Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, PG, Italy. maria.barreca@unipg.it.
  • 14 Department of Physics, University of Trento, Povo, Trento, TN, Italy. pietro.faccioli@unitn.it.
  • 15 INFN-TIFPA, University of Trento, Povo, Trento, TN, Italy. pietro.faccioli@unitn.it.
  • 16 Department of Cellular, Computational and Integrative Biology, University of Trento, 38123, Povo, TN, Italy. emiliano.biasini@unitn.it.
  • 17 Dulbecco Telethon Institute, University of Trento, 38123, Povo, TN, Italy. emiliano.biasini@unitn.it.
PMID: 33437023 DOI: 10.1038/s42003-020-01585-x
Abstract

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular Prion Protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

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