Pharmacological inactivation of the prion protein by targeting a folding intermediate
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Published:2021-01-12
Issue:1
Volume:4
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Spagnolli GiovanniORCID, Massignan Tania, Astolfi Andrea, Biggi Silvia, Rigoli MartaORCID, Brunelli Paolo, Libergoli Michela, Ianeselli Alan, Orioli Simone, Boldrini AlbertoORCID, Terruzzi LucaORCID, Bonaldo ValerioORCID, Maietta Giulia, Lorenzo Nuria L., Fernandez Leticia C., Codeseira Yaiza B., Tosatto Laura, Linsenmeier Luise, Vignoli Beatrice, Petris GianlucaORCID, Gasparotto Dino, Pennuto MariaORCID, Guella GrazianoORCID, Canossa Marco, Altmeppen Hermann C.ORCID, Lolli Graziano, Biressi StefanoORCID, Pastor Manuel M., Requena Jesús R., Mancini Ines, Barreca Maria L.ORCID, Faccioli Pietro, Biasini EmilianoORCID
Abstract
AbstractRecent 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.
Funder
Fondazione Telethon
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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