Spagnolli, GiovanniMassignan, TaniaAstolfi, AndreaBiggi, SilviaRigoli, MartaBrunelli, PaoloLibergoli, MichelaIaneselli, AlanOrioli, SimoneBoldrini, AlbertoTerruzzi, LucaBonaldo, ValerioMaietta, GiuliaLópez Lorenzo, NuriaFernández Flores, Leticia CamilaBugallo Codeseira, YaizaTosatto, LauraLinsenmeier, LuiseVignoli, BeatricePetris, GianlucaGasparotto, DinoPennuto, MariaGuella, GrazianoCanossa, MarcoAltmeppen, Hermann C.Lolli, GrazianoBiressi, StefanoMartín Pastor, ManuelRodríguez Requena, JesúsMancini, InesBarreca, Maria L.Faccioli, PietroBiasini, Emiliano2021-02-222021-02-222021Communications Biology volume 4, Article number: 62 (2021)http://hdl.handle.net/10347/24542Recent 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 expressioneng© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Computational biophysicsPrionsVirtual screeningjournal article10.1038/s42003-020-01585-x2399-3642open access