RT Journal Article
T1 Pharmacological inactivation of the prion protein by targeting a folding intermediate
A1 Spagnolli, Giovanni
A1 Massignan, Tania
A1 Astolfi, Andrea
A1 Biggi, Silvia
A1 Rigoli, Marta
A1 Brunelli, Paolo
A1 Libergoli, Michela
A1 Ianeselli, Alan
A1 Orioli, Simone
A1 Boldrini, Alberto
A1 Terruzzi, Luca
A1 Bonaldo, Valerio
A1 Maietta, Giulia
A1 López Lorenzo, Nuria
A1 Fernández Flores, Leticia Camila
A1 Bugallo Codeseira, Yaiza
A1 Tosatto, Laura
A1 Linsenmeier, Luise
A1 Vignoli, Beatrice
A1 Petris, Gianluca
A1 Gasparotto, Dino
A1 Pennuto, Maria
A1 Guella, Graziano
A1 Canossa, Marco
A1 Altmeppen, Hermann C.
A1 Lolli, Graziano
A1 Biressi, Stefano
A1 Martín Pastor, Manuel
A1 Rodríguez Requena, Jesús
A1 Mancini, Ines
A1 Barreca, Maria L.
A1 Faccioli, Pietro
A1 Biasini, Emiliano
K1 Computational biophysics
K1 Prions
K1 Virtual screening
AB 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
PB Springer Nature
YR 2021
FD 2021
LK http://hdl.handle.net/10347/24542
UL http://hdl.handle.net/10347/24542
LA eng
NO Communications Biology volume 4, Article number: 62 (2021)
NO L.To. is supported by Fondazione Caritro (Bando Post Doc 2017) and Kennedy’s Disease Association (Research Grant 2018). Research of HCA was supported by the CJD Foundation, Inc. and the Alzheimer Forschung Initiative e.V. (AFI). J.R.R. was funded by a grant (BFU2017-86692-P) from the Spanish Ministry of Economy and Competitiveness, partially funded by FEDER funds. The work was also supported by grants from Fondazione Telethon and Provincia Autonoma di Trento to S.B. (TCP13007), from Fondazione Telethon to E.B. (TCP14009), and by a fellowship from Fondazione Telethon to G.S. S.B. and E.B. are Assistant Telethon Scientists at the Dulbecco Telethon Institute
DS Minerva
RD 24 abr 2026