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36 results on '"Favretto, Filippo"'

3. Evaluating the potential of non‐immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.

Author

Favretto, Filippo, Jiménez‐Faraco, Eva, Catucci, Gianluca, Di Matteo, Adele, Travaglini‐Allocatelli, Carlo, Sadeghi, Sheila J., Dominici, Paola, Hermoso, Juan A., and Astegno, Alessandra

Abstract

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X‐ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein–ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Catalytic specificity and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa

Author

Pedretti, Marco, primary, Fernández-Rodríguez, Carmen, additional, Conter, Carolina, additional, Oyenarte, Iker, additional, Favretto, Filippo, additional, Matteo, Adele di, additional, Dominici, Paola, additional, Petrosino, Maria, additional, Martinez-Chantar, Maria Luz, additional, Majtan, Tomas, additional, Astegno, Alessandra, additional, and Martinez-Cruz, Luis Alfonso, additional

Published
2024
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8. Role of myristoylation in modulating PCaP1 interaction with calmodulin

Author

Pedretti, Marco, primary, Favretto, Filippo, additional, Troilo, Francesca, additional, Giovannoni, Moira, additional, Conter, Carolina, additional, Mattei, Benedetta, additional, Dominici, Paola, additional, Travaglini-Allocatelli, Carlo, additional, Di Matteo, Adele, additional, and Astegno, Alessandra, additional

Published
2023
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11. Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

Author

Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Università degli Studi di Verona, Jiménez-Faraco, Eva [0000-0002-5548-3252], Hermoso, Juan A. [0000-0002-1862-8950], Astegno, Alessandra [0000-0002-7341-0970], Favretto, Filippo, Jiménez-Faraco, Eva, Conter, Carolina, Dominici, Paola, Hermoso, Juan A., Astegno, Alessandra, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Università degli Studi di Verona, Jiménez-Faraco, Eva [0000-0002-5548-3252], Hermoso, Juan A. [0000-0002-1862-8950], Astegno, Alessandra [0000-0002-7341-0970], Favretto, Filippo, Jiménez-Faraco, Eva, Conter, Carolina, Dominici, Paola, Hermoso, Juan A., and Astegno, Alessandra

Abstract

Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. A possible mechanism of action involves CsA binding to T. gondii cyclophilins, although much remains to be understood. Herein, we characterize the functional and structural properties of a conserved (TgCyp23) and a more divergent (TgCyp18.4) cyclophilin isoform from T. gondii. While TgCyp23 is a highly active cis-trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at the atomic resolution showing the molecular details of CsA recognition by the protein. Computational and structural studies revealed relevant differences at the CsA-binding site between TgCyp18.4 and TgCyp23, suggesting that the two cyclophilins might have distinct functions in the parasite. These studies highlight the extensive diversification of TgCyps and pave the way for antiparasite interventions based on selective targeting of cyclophilins.

Published
2023

29. Human cyclophilin 40 unravels neurotoxic amyloids

Author

Baker, Jeremy D., primary, Shelton, Lindsey B., additional, Zheng, Dali, additional, Favretto, Filippo, additional, Nordhues, Bryce A., additional, Darling, April, additional, Sullivan, Leia E., additional, Sun, Zheying, additional, Solanki, Parth K., additional, Martin, Mackenzie D., additional, Suntharalingam, Amirthaa, additional, Sabbagh, Jonathan J., additional, Becker, Stefan, additional, Mandelkow, Eckhard, additional, Uversky, Vladimir N., additional, Zweckstetter, Markus, additional, Dickey, Chad A., additional, Koren, John, additional, and Blair, Laura J., additional

Published
2017
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30. Understanding promiscuous and selective ligand binding by liver FABP

Author

D'Onofrio, Mariapina, Favretto, Filippo, Zanzoni, Serena, Perez Santero, Silvia, Assfalg, Michael, Molinari, Henriette, Santambrogio, Carlo, and Grandori, Rita

Subjects
FABP, ligand binding, FABP, NMR, mass spectrometry, ligand binding, NMR, mass spectrometry
Published
2015

32. Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L-FABP to malaria sporozoite protein UIS3

Author

Favretto, Filippo, Assfalg, Michael, Molinari, Henriette, and D'Onofrio, Mariapina

Subjects
Models, Molecular, fatty acid binding protein, UIS3, malaria, Protozoan Proteins, Membrane Proteins, Fatty Acid-Binding Proteins, Models, Biological, protein-protein interaction, NMR spectroscopy, Accelerated Communications, Humans, lipids (amino acids, peptides, and proteins), lipid transfer, Fatty acid binding protein, Lipid transfer, Malaria, Protein-protein interaction, Nuclear Magnetic Resonance, Biomolecular, Protein Binding
Abstract

UIS3 is a malaria parasite protein essential for liver stage development of Plasmodium species, presumably localized to the membrane of the parasitophorous vacuole formed in infected cells. It has been recently proposed that the soluble domain of UIS3 interacts with the host liver fatty acid binding protein (L-FABP), providing the parasite with a pathway for importing exogenous lipids required for its rapid growth. This finding may suggest novel strategies for arresting parasite development. In this study, we have investigated the interaction between human L-FABP and the soluble domain of Plasmodium falciparum UIS3 by NMR spectroscopy. The amino acid residue-specific analysis of (1)H,(15) N-2D NMR spectra excluded the occurrence of a direct interaction between L-FABP (in its unbound and oleate-loaded forms) and Pf-UIS3. Furthermore, the spectrum of Pf-UIS3 was unchanged when oleate or phospholipids were added. The present investigation entails a reformulation of the current model of host-pathogen lipid transfer, possibly redirecting research for early intervention against malaria.

Published
2012
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35. Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–TransIsomerization and the Chameleonic Roles of Calcium

Author

Gray, Amber L. H., Steren, Carlos A., Haynes, Isaac W., Bermejo, Guillermo A., Favretto, Filippo, Zweckstetter, Markus, and Do, Thanh D.

Abstract

Falling outside of Lipinski’s rule of five, macrocyclic drugs have accessed unique binding sites of their target receptors unreachable by traditional small molecules. Cyclosporin(e) A (CycA), an extensively studied macrocyclic natural product, is an immunosuppressant with undesirable side effects such as electrolytic imbalances. In this work, a comprehensive view on the conformational landscape of CycA, its interactions with Ca2+, and host–guest interactions with cyclophilin A (CypA) is reported through exhaustive analyses that combine ion-mobility spectrometry–mass spectrometry (IMS–MS), nuclear magnetic resonance (NMR) spectroscopy, distance-geometry modeling, and NMR-driven molecular dynamics. Our IMS–MS data show that CycA can adopt extremely compact conformations with significantly smaller collisional cross sections than the closed conformation observed in CDCl3. To adopt these conformations, the macrocyclic ring has to twist and bend via cis–transisomerization of backbone amides, and thus, we termed this family of structures the “bent” conformation. Furthermore, NMR measurements indicate that the closed conformation exists at 19% in CD3OD/H2O and 55% in CD3CN. However, upon interacting with Ca2+, in addition to the bent and previously reported closed conformations of free CycA, the CycA:Ca2+complex is open and has all-transpeptide bonds. Previous NMR studies using calcium perchlorate reported only the closed conformation of CycA (which contains one cispeptide bond). Here, calcium chloride, a more biologically relevant salt, was used, and interestingly, it helps converting the cis-MeLeu9–MeLeu10 peptide bond into a transbond. Last, we were able to capture the native binding of CycA and CypA to give forth evidence that IMS–MS is able to probe the solution-phase structures of the complexes and that the Ca2+:CycA complex may play an essential role in the binding of CycA to CypA.

Published
2021
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36. Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.

Author

Favretto F, Jiménez-Faraco E, Catucci G, Di Matteo A, Travaglini-Allocatelli C, Sadeghi SJ, Dominici P, Hermoso JA, and Astegno A

Subjects
Crystallography, X-Ray, Protozoan Proteins chemistry, Protozoan Proteins metabolism, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins genetics, Models, Molecular, Binding Sites, Cyclosporins chemistry, Cyclosporins pharmacology, Toxoplasma drug effects, Cyclophilins chemistry, Cyclophilins antagonists & inhibitors, Cyclophilins metabolism, Cyclosporine chemistry, Cyclosporine pharmacology
Abstract

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response., (© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Published
2024
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