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2 results on '"Biancamaria Farina"'

1. Structural and biochemical insights of CypA and AIF interaction

Author

Biancamaria Farina, Gianluigi Di Sorbo, Angela Chambery, Andrea Caporale, Guido Leoni, Rosita Russo, Fabiola Mascanzoni, Domenico Raimondo, Roberto Fattorusso, Menotti Ruvo, and Nunzianna Doti

Subjects
Medicine, Science
Abstract

Abstract The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370–394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed. We show that AIF(370-394) interacts with CypA on the same surface recognized by AIF(Δ1-121) protein and that the region is very close to the CypA catalytic pocket. Such region partially overlaps with the binding site of cyclosporin A (CsA), the strongest catalytic inhibitor of CypA. Our data point toward distinct CypA structural determinants governing the inhibitor selectivity and the differential biological effects of AIF and CsA, and provide new structural insights for designing CypA/AIF selective inhibitors with therapeutic relevance in neurodegenerative diseases.

Published
2017
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2. The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

Author

Laura Zaccaro, Orazio Taglialatela-Scafati, Giuseppina Chianese, Ernesto Fattorusso, Biancamaria Farina, Caterina Fattorusso, Arianna Quintavalla, Roberto Fattorusso, Marco Persico, Claudio Trombini, Marco Lombardo, Francesca Rondinelli, Ivan de Paola, Persico, Marco, Fattorusso, Roberto, TAGLIALATELA SCAFATI, Orazio, Chianese, Giuseppina, de Paola, Ivan, Zaccaro, Laura, Rondinelli, Francesca, Lombardo, Marco, Quintavalla, Arianna, Trombini, Claudio, Fattorusso, Ernesto, Fattorusso, Caterina, Farina, Biancamaria, Taglialatela-Scafati, Orazio, De Paola, Ivan, and Taglialatela Scafati, Orazio

Subjects
Magnetic Resonance Spectroscopy, computational studies, Radical, Molecular Conformation, action mechanism, Heme, ALKYLATION, Alkylation, 010402 general chemistry, METABOLITES, 01 natural sciences, Molecular Docking Simulation, EFFECTIVE CORE POTENTIALS, Molecular conformation, Article, Mass Spectrometry, Synthetic analogue, Dioxanes, chemistry.chemical_compound, Antimalarials, TRIOXANES, ARTEMISININ DERIVATIVES, SIMPLEX, medicine, Ferrous Compounds, Artemisinin, OPTIMIZATION, Plakortin, antimalarial endoperoxides, Multidisciplinary, Binding Sites, PLASMODIUM-FALCIPARUM, biology, 010405 organic chemistry, Chemistry, DRUG ARTEMISININ, Plasmodium falciparum, MOLECULAR CALCULATIONS, biology.organism_classification, Combinatorial chemistry, 0104 chemical sciences, medicine.drug
Abstract

In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

Published
2017
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