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Dive into the research topics where Claudia Del Vecchio is active.

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Featured researches published by Claudia Del Vecchio.


Antimicrobial Agents and Chemotherapy | 2003

New anti-human immunodeficiency virus type 1 6-aminoquinolones: Mechanism of action

Cristina Parolin; Claudia Del Vecchio; Teresa Pecere; Enzo Tramontano; Violetta Cecchetti; Arnaldo Fravolini; Sara Masiero; Manlio Palumbo; Giorgio Palù

ABSTRACT A 6-aminoquinolone derivative, WM5, which bears a methyl substituent at the N-1 position and a 4-(2-pyridyl)-1-piperazine moiety at position 7 of the bicyclic quinolone ring system, was previously shown to exhibit potent activity against replication of human immunodeficiency virus type 1 (HIV-1) in de novo-infected human lymphoblastoid cells (V. Cecchetti et al., J. Med. Chem. 43:3799-3802, 2000). In this report, we further investigated WM5s mechanism of antiviral activity. WM5 inhibited HIV-1 replication in acutely infected cells as well as in chronically infected cells. The 50% inhibitory concentrations were 0.60 ± 0.06 and 0.85 ± 0.05 μM, respectively. When the effects of WM5 on different steps of the virus life cycle were analyzed, the reverse transcriptase activity and the integrase and protease activities were not impaired. By using a transient trans-complementation assay to examine the activity of WM5 on the replicative potential of HIV-1 in a single round of infection, a sustained inhibition of Tat-mediated long terminal repeat (LTR)-driven transcription (>80% of controls) was obtained in the presence of 5 μM WM5. Interestingly, the aminoquinolone was found to efficiently complex TAR RNA, with a dissociation constant in the nanomolar range (19 ± 0.6 nM). These data indicate that WM5 is a promising lead compound for the development of a new class of HIV-1 transcription inhibitors characterized by recognition of viral RNA target(s).


Antimicrobial Agents and Chemotherapy | 2004

Inhibition of Human Immunodeficiency Virus Type 1 Tat-trans-Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative

Sara N. Richter; Cristina Parolin; Claudia Del Vecchio; Egidio Brocca-Cofano; Arnaldo Fravolini; Giorgio Palù; Manlio Palumbo

ABSTRACT WM5, a 6-aminoquinolone derivative, binds with high affinity to the bulge of the trans-activation-responsive region (TAR), whereas it displays low binding affinity for the loop and stem regions of TAR and for random RNA and DNA sequences. Furthermore, WM5 disrupts the natural protein-nucleic acid complex with a 50% inhibitory concentration in the low micromolar range in both in vitro and in vivo assays.


Biochemical Pharmacology | 2011

Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype

Elena Piccoli; Matteo Nadai; Carla Mucignat Caretta; Valeria Bergonzini; Claudia Del Vecchio; Huy Riem Ha; Laurent Bigler; Daniele Dal Zoppo; Elisabetta Faggin; Andrea Pettenazzo; Rocco Orlando; Cristiano Salata; Arianna Calistri; Giorgio Palù; Aldo Baritussio

Abstract Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control.


Journal of Microbiology | 2015

From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors

Lijia Xu; Nicole Grandi; Claudia Del Vecchio; Daniela Mandas; Angela Corona; Dario Piano; Francesca Esposito; Cristina Parolin; Enzo Tramontano

HIV-1 reverse transcriptase (RT) is still an extremely attractive pharmaceutical target for the identification of new inhibitors possibly active on drug resistant strains. Medicinal plants are a rich source of chemical diversity and can be used to identify novel scaffolds to be further developed by chemical modifications. We investigated the ability of the main lignans from Schisandra chinensis (Turcz.) Baill. fruits, commonly used in Traditional Chinese Medicine, to affect HIV-1 RT functions. We purified 6 lignans from Schisandra chinensis fruits and assayed their effects on HIV-1 RT and viral replication. Among the S. chinensis fruit lignans, Schisandrin B and Deoxyschizandrin selectively inhibited the HIV-1 RT-associated DNA polymerase activity. Structure activity relationship revealed the importance of cyclooctadiene ring substituents for efficacy. In addition, Schisandrin B was also able to impair HIV-1 RT drug resistant mutants and the early phases of viral replication. We identified Schisandrin B and Deoxyschizandrin as new scaffold for the further development of novel HIV-1 RT inhibitors.


Virology Journal | 2011

Herpes simplex virus type 2 infection increases human immunodeficiency virus type 1 entry into human primary macrophages.

Elena Sartori; Arianna Calistri; Cristiano Salata; Claudia Del Vecchio; Giorgio Palù; Cristina Parolin

Epidemiological and clinical data indicate that genital ulcer disease (GUD) pathogens are associated with an increased risk of human immunodeficiency virus type 1 (HIV-1) acquisition and/or transmission. Among them, genital herpes simplex virus type 2 (HSV-2) seems to play a relevant role. Indeed, the ability of HSV-2 to induce massive infiltration at the genital level of cells which are potential targets for HIV-1 infection may represent one of the mechanisms involved in this process. Here we show that infection of human primary macrophages (MDMs) by HSV-2 results in an increase of CCR5 expression levels on cell surface and allows higher efficiency of MDMs to support entry of R5 HIV-1 strains. This finding could strengthen, at the molecular level, the evidence linking HSV-2 infection to an increased susceptibility to HIV-1 acquisition.


ChemMedChem | 2014

Design, Synthesis, and Biological Evaluation of 1,3‐Diarylpropenones as Dual Inhibitors of HIV‐1 Reverse Transcriptase

Rita Meleddu; Valeria Cannas; Simona Distinto; Giorgia Sarais; Claudia Del Vecchio; Francesca Esposito; Giulia Bianco; Angela Corona; Filippo Cottiglia; Stefano Alcaro; Cristina Parolin; Anna Artese; Daniela Scalise; Massimo Fresta; A. Arridu; Francesco Ortuso; Elias Maccioni; Enzo Tramontano

A small library of 1,3‐diarylpropenones was designed and synthesized as dual inhibitors of both HIV‐1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) associated functions. Compounds were assayed on these enzyme activities, which highlighted dual inhibition properties in the low‐micromolar range. Interestingly, mutations in the non‐nucleoside RT inhibitor binding pocket strongly affected RNase H inhibition by the propenone derivatives without decreasing their capacity to inhibit DP activity, which suggests long‐range RT structural effects. Biochemical and computational studies indicated that the propenone derivatives bind two different interdependent allosteric pockets.


Bioorganic & Medicinal Chemistry Letters | 2009

Synthesis and biological evaluation of 2-phenylquinolones targeted at Tat/TAR recognition

Giuseppe Manfroni; Oriana Tabarrini; Stefano Sabatini; Violetta Cecchetti; Giulia Giaretta; Cristina Parolin; Claudia Del Vecchio; Arianna Calistri; Manlio Palumbo; Arnaldo Fravolini

Tat (transactivator of transcription) is a small HIV protein rich in arginines that interacts with a viral RNA structure called TAR (trans-activation responsive region). Tat-TAR interaction is essential for viral gene expression, replication and pathogenesis. Small molecules able to interfere with TAR and to compete for Tat binding possess antiviral activity due to inhibition of viral transcription and expression, thus impairing formation of infectious virions. We report here, the synthesis and biological evaluation of a new series of quinolone derivatives, namely 2-phenylquinolones, designed with the aim of interfering with the protein/RNA complex. These new derivatives are able to efficiently interfere with Tat/TAR complex in vitro depending on precise structural requirements as demonstrated by fluorescence quenching assay analysis.


Phytomedicine | 2016

Sennoside A, derived from the traditional chinese medicine plant Rheum L., is a new dual HIV-1 inhibitor effective on HIV-1 replication.

Francesca Esposito; Ilaria Carli; Claudia Del Vecchio; Lijia Xu; Angela Corona; Nicole Grandi; Dario Piano; Elias Maccioni; Simona Distinto; Cristina Parolin; Enzo Tramontano

BACKGROUND Despite the availability of effective antiretroviral therapies, drugs for HIV-1 treatment with new mode of action are still needed. An innovative approach is aimed to identify dual HIV-1 inhibitors, small molecules that can inhibit two viral functions at the same time. Rhubarb, originated from Rheum palmatum L. and Rheum officinale Baill., is one of the earliest and most commonly used medicinal plants in Traditional Chinese Medicine (TCM) practice. We wanted to explore TCM for the identification of new chemical scaffolds with dual action abilities against HIV-1. METHODS R. palmatum L. and R. officinale Baill. extracts along with their main single isolated constituents anthraquinone derivatives were tested on both HIV-1 Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities in biochemical assays. Active compounds were then assayed for their effects on HIV-1 mutated RTs, integrase (IN) and viral replication. RESULTS Both R. palmatum L. and R. officinale Baill. extracts inhibited the HIV-1 RT-associated RNase H activity. Among the isolated constituents, Sennoside A and B were effective on both RDDP and RNase H RT-associated functions in biochemical assays. Sennoside A was less potent when tested on K103N, Y181C, Y188L, N474A and Q475A mutated RTs, suggesting the involvement of two RT binding sites for its antiviral activity. Sennoside A affected also HIV-1 IN activity in vitro and HIV-1 replication in cell-based assays. Viral DNA production and time of addition studies showed that Sennoside A targets the HIV-1 reverse transcription process. CONCLUSION Sennoside A is a new scaffold for the development of HIV-1 dual RT inhibitors.


Journal of NeuroVirology | 2009

Nef and cell signaling transduction: a possible involvement in the pathogenesis of human immunodeficiency virus–associated dementia

Valeria Bergonzini; Arianna Calistri; Cristiano Salata; Claudia Del Vecchio; Elena Sartori; Cristina Parolin; Giogio Palù

Although the introduction of highly active antiretroviral therapy (HAART) has resulted in a significant decrease of acquired immunodeficiency syndrome (AIDS) morbidity and mortality, the prevalence of human immunodeficiency virus (HIV)-associated dementia (HAD) has actually risen, due to the increasing life expectancy of the infected subjects. To date, several aspects of the HAD pathogenesis remain to be dissected. In particular, the viral-cellular protein interplay is still under investigation. Given their specific features, two viral proteins, Tat and Nef, have been mainly hypothesized to play a role in HIV neuropathology. Here we show that HIV-1 Nef has an effect on the transcriptional levels of a cellular protein, anaplastic lymphoma kinase (ALK), that is preferentially expressed in the central and peripheral nervous system at late embryonic stages. By its overexpression along with Nef, the authors demonstrate ALK ability to influence, at least in the U87MG astrocytic glioma cells, the mytogen-activated protein kinase (MAP-K) dependent pathway. Moreover, although in the absence of a physical direct interaction, Nef and ALK activate matrix metalloproteinases (MMPs), which are likely to contribute to blood-brain barrier (BBB) damage in HAD. Finally, in the in vitro model of glioblastoma cells adopted, Nef and ALK show similar effects by increasing different cytochines/chemokines that may be relevant for HAD pathogenesis. If confirmed in vivo, these data may indicate that, thanks to its ability to interfere with specific cellular pathways involved in BBB damage and in central nervous system (CNS) integrity, Nef, along with specific cellular counterparts, could be one of the viral players implicated in HAD development.


ChemMedChem | 2009

2-Phenylquinolones as Inhibitors of the HIV-1 Tat–TAR Interaction

Oriana Tabarrini; Serena Massari; Giulia Giaretta; Stefano Sabatini; Claudia Del Vecchio; Cristina Parolin; Arnaldo Fravolini; Manlio Palumbo; Violetta Cecchetti

Novel 2‐phenylquinolones aimed at the Tat–TAR complex were synthesized and tested. Derivatives characterized by precise modifications of the quinolone nucleus and to the side chain of the 2‐phenyl ring allowed a thorough structure–activity study, confirming 2‐phenylquinolone as a suitable scaffold for inhibition of the Tat–TAR interaction.

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