Pharmacological inactivation of the prion protein by targeting a folding intermediate

  • Giovanni Spagnolli (Shared first author)
  • Tania Massignan (Shared first author)
  • Andrea Astolfi (Shared first author)
  • Silvia Biggi
  • Marta Rigoli
  • Paolo Brunelli
  • Michela Libergoli
  • Alan Ianeselli
  • Simone Orioli
  • Alberto Boldrini
  • Luca Terruzzi
  • Valerio Bonaldo
  • Giulia Maietta
  • Nuria L Lorenzo
  • Leticia C Fernandez
  • Yaiza B Codeseira
  • Laura Tosatto
  • Luise Linsenmeier
  • Beatrice Vignoli
  • Gianluca Petris
  • Dino Gasparotto
  • Maria Pennuto
  • Graziano Guella
  • Marco Canossa
  • Hermann C Altmeppen
  • Graziano Lolli
  • Stefano Biressi
  • Manuel M Pastor
  • Jesús R Requena
  • Ines Mancini
  • Maria L Barreca
  • Pietro Faccioli
  • Emiliano Biasini

Related Research units

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.

Bibliographical data

Original languageEnglish
Article number62
ISSN2399-3642
DOIs
Publication statusPublished - 12.01.2021
PubMed 33437023