Pharmacological inactivation of the prion protein by targeting a folding intermediate
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Pharmacological inactivation of the prion protein by targeting a folding intermediate. / Spagnolli, Giovanni; Massignan, Tania; Astolfi, Andrea; Biggi, Silvia; Rigoli, Marta; Brunelli, Paolo; Libergoli, Michela; Ianeselli, Alan; Orioli, Simone; Boldrini, Alberto; Terruzzi, Luca; Bonaldo, Valerio; Maietta, Giulia; Lorenzo, Nuria L; Fernandez, Leticia C; Codeseira, Yaiza B; Tosatto, Laura; Linsenmeier, Luise; Vignoli, Beatrice; Petris, Gianluca; Gasparotto, Dino; Pennuto, Maria; Guella, Graziano; Canossa, Marco; Altmeppen, Hermann C; Lolli, Graziano; Biressi, Stefano; Pastor, Manuel M; Requena, Jesús R; Mancini, Ines; Barreca, Maria L; Faccioli, Pietro; Biasini, Emiliano.
in: COMMUN BIOL, Jahrgang 4, Nr. 1, 62, 12.01.2021.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pharmacological inactivation of the prion protein by targeting a folding intermediate
AU - Spagnolli, Giovanni
AU - Massignan, Tania
AU - Astolfi, Andrea
AU - Biggi, Silvia
AU - Rigoli, Marta
AU - Brunelli, Paolo
AU - Libergoli, Michela
AU - Ianeselli, Alan
AU - Orioli, Simone
AU - Boldrini, Alberto
AU - Terruzzi, Luca
AU - Bonaldo, Valerio
AU - Maietta, Giulia
AU - Lorenzo, Nuria L
AU - Fernandez, Leticia C
AU - Codeseira, Yaiza B
AU - Tosatto, Laura
AU - Linsenmeier, Luise
AU - Vignoli, Beatrice
AU - Petris, Gianluca
AU - Gasparotto, Dino
AU - Pennuto, Maria
AU - Guella, Graziano
AU - Canossa, Marco
AU - Altmeppen, Hermann C
AU - Lolli, Graziano
AU - Biressi, Stefano
AU - Pastor, Manuel M
AU - Requena, Jesús R
AU - Mancini, Ines
AU - Barreca, Maria L
AU - Faccioli, Pietro
AU - Biasini, Emiliano
PY - 2021/1/12
Y1 - 2021/1/12
N2 - 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.
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.
U2 - 10.1038/s42003-020-01585-x
DO - 10.1038/s42003-020-01585-x
M3 - SCORING: Journal article
C2 - 33437023
VL - 4
JO - COMMUN BIOL
JF - COMMUN BIOL
SN - 2399-3642
IS - 1
M1 - 62
ER -