Search

Your search keyword '"Terruzzi, Luca"' showing total 12 results
Start Over Author "Terruzzi, Luca"
12 results on '"Terruzzi, Luca"'

1. Antimalarial Artefenomel Inhibits Human SARS-CoV-2 Replication in Cells while Suppressing the Receptor ACE2

Author

Massignan, Tania, Boldrini, Alberto, Terruzzi, Luca, Spagnolli, Giovanni, Astolfi, Andrea, Bonaldo, Valerio, Pischedda, Francesca, Pizzato, Massimo, Lolli, Graziano, Barreca, Maria Letizia, Biasini, Emiliano, Faccioli, Pietro, and Pieri, Lidia

Subjects
Quantitative Biology - Biomolecules, Condensed Matter - Soft Condensed Matter, Physics - Biological Physics
Abstract

The steep climbing of victims caused by the new coronavirus disease 2019 (COVID-19) throughout the planet is sparking an unprecedented effort to identify effective therapeutic regimens to tackle the pandemic. The SARS-CoV-2 virus is known to gain entry into various cell types through the binding of one of its surface proteins (spike) to the host Angiotensin-Converting Enzyme 2 (ACE2). Thus, spike-ACE2 interaction represents a major target for vaccines and antiviral drugs. A novel method has been recently described by some of the authors to pharmacologically downregulate the expression of target proteins at the post-translational level. This technology builds on computational advancements in the simulation of folding mechanisms to rationally block protein expression by targeting folding intermediates, hence hampering the folding process. Here, we report the all-atom simulations of the entire sequence of events underlying the folding pathway of ACE2. Our data revealed the existence of a folding intermediate showing two druggable pockets hidden in the native conformation. Both pockets were targeted by a virtual screening repurposing campaign aimed at quickly identifying drugs capable to decrease the expression of ACE2. We identified four compounds capable of lowering ACE2 expression in Vero cells in a dose-dependent fashion. All these molecules were found to inhibit the entry into cells of a pseudotyped retrovirus exposing the SARS-CoV-2 spike protein. Importantly, the antiviral activity has been tested against live SARS-CoV-2 (MEX-BC2/2020 strain). One of the selected drugs (Artefenomel) could completely prevent cytopathic effects induced by the presence of the virus, thus showing antiviral activity against SARS-CoV-2. Ongoing studies are further evaluating the possibility of repurposing these drugs for the treatment of COVID-19., Comment: Manuscript has extended to include the experimental evidence for anti-viral effects on cell colonies

Published
2020

3. Pliability in the m6A-Binding Region Extends Druggability of YTH Domains

Author

Cazzanelli, Giulia, primary, Dalle Vedove, Andrea, additional, Spagnolli, Giovanni, additional, Terruzzi, Luca, additional, Colasurdo, Enrica, additional, Boldrini, Alberto, additional, Patsilinakos, Alexandros, additional, Sturlese, Mattia, additional, Grottesi, Alessandro, additional, Biasini, Emiliano, additional, Provenzani, Alessandro, additional, Quattrone, Alessandro, additional, and Lolli, Graziano, additional

Published
2024
Full Text
View/download PDF

4. Pharmacological inactivation of the prion protein by targeting a folding intermediate

Author

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, and Biasini, Emiliano

Published
2021
Full Text
View/download PDF

7. Pharmacological inactivation of the prion protein by targeting a folding intermediate

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina, 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, López Lorenzo, Nuria, Fernández Flores, Leticia Camila, Bugallo Codeseira, Yaiza, Tosatto, Laura, Linsenmeier, Luise, Vignoli, Beatrice, Petris, Gianluca, Gasparotto, Dino, Pennuto, Maria, Guella, Graziano, Canossa, Marco, Altmeppen, Hermann C., Lolli, Graziano, Biressi, Stefano, Martín Pastor, Manuel, Rodríguez Requena, Jesús, Mancini, Ines, Barreca, Maria L., Faccioli, Pietro, Biasini, Emiliano, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina, 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, López Lorenzo, Nuria, Fernández Flores, Leticia Camila, Bugallo Codeseira, Yaiza, Tosatto, Laura, Linsenmeier, Luise, Vignoli, Beatrice, Petris, Gianluca, Gasparotto, Dino, Pennuto, Maria, Guella, Graziano, Canossa, Marco, Altmeppen, Hermann C., Lolli, Graziano, Biressi, Stefano, Martín Pastor, Manuel, Rodríguez Requena, Jesús, Mancini, Ines, Barreca, Maria L., Faccioli, Pietro, and Biasini, Emiliano

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

Published
2021

8. Pharmacological inactivation of the prion protein by targeting a folding intermediate

Author

Spagnolli, G, Massignan, T, Astolfi, A, Biggi, S, Rigoli, M, Brunelli, P, Libergoli, M, Ianeselli, A, Orioli, S, Boldrini, A, Terruzzi, L, Bonaldo, V, Maietta, G, Lorenzo, N, Fernandez, L, Codeseira, Y, Tosatto, L, Linsenmeier, L, Vignoli, B, Petris, G, Gasparotto, D, Pennuto, M, Guella, G, Canossa, M, Altmeppen, H, Lolli, G, Biressi, S, Pastor, M, Requena, J, Mancini, I, Barreca, M, Faccioli, P, Biasini, E, 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, Spagnolli, G, Massignan, T, Astolfi, A, Biggi, S, Rigoli, M, Brunelli, P, Libergoli, M, Ianeselli, A, Orioli, S, Boldrini, A, Terruzzi, L, Bonaldo, V, Maietta, G, Lorenzo, N, Fernandez, L, Codeseira, Y, Tosatto, L, Linsenmeier, L, Vignoli, B, Petris, G, Gasparotto, D, Pennuto, M, Guella, G, Canossa, M, Altmeppen, H, Lolli, G, Biressi, S, Pastor, M, Requena, J, Mancini, I, Barreca, M, Faccioli, P, Biasini, E, 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, and Biasini, Emiliano

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.

Published
2021

10. PHARMACOLOGICAL PROTEIN INACTIVATION BY TARGETING FOLDING INTERMEDIATES

Author

Spagnolli, Giovanni, primary, Massignan, Tania, additional, Astolfi, Andrea, additional, Biggi, Silvia, additional, Brunelli, Paolo, additional, Libergoli, Michela, additional, Ianeselli, Alan, additional, Orioli, Simone, additional, Boldrini, Alberto, additional, Terruzzi, Luca, additional, Maietta, Giulia, additional, Rigoli, Marta, additional, Lorenzo, Nuria Lopez, additional, Fernandez, Leticia C., additional, Tosatto, Laura, additional, Linsenmeier, Luise, additional, Vignoli, Beatrice, additional, Petris, Gianluca, additional, Gasparotto, Dino, additional, Pennuto, Maria, additional, Guella, Graziano, additional, Canossa, Marco, additional, Altmeppen, Hermann Clemens, additional, Lolli, Graziano, additional, Biressi, Stefano, additional, Pastor, Manuel Martin, additional, Requena, Jesús R., additional, Mancini, Ines, additional, Barreca, Maria Letizia, additional, Faccioli, Pietro, additional, and Biasini, Emiliano, additional

Published
2020
Full Text
View/download PDF

12. Pliability in the m 6 A-Binding Region Extends Druggability of YTH Domains.

Author

Cazzanelli G, Dalle Vedove A, Spagnolli G, Terruzzi L, Colasurdo E, Boldrini A, Patsilinakos A, Sturlese M, Grottesi A, Biasini E, Provenzani A, Quattrone A, and Lolli G

Subjects
Pliability, RNA, Messenger chemistry, RNA, Messenger metabolism, Molecular Conformation, RNA-Binding Proteins chemistry, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism
Abstract

Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the m 6 A mark on mRNA and represent valuable drug targets. Crystallographic structures have been determined for all three family members; however, discrepancies are present in the organization of the m 6 A-binding pocket. Here, we present new crystallographic structures of the YTH domain of YTHDF1, accompanied by computational studies, showing that this domain can exist in different stable conformations separated by a significant energetic barrier. During the transition, additional conformations are explored, with peculiar druggable pockets appearing and offering new opportunities for the design of YTH-interfering small molecules.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results