@article{Romeo2020,
title = {Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors},
author = {A Romeo and F Iacovelli and M Falconi
},
editor = {Elsevier},
doi = {10.1016/j.virusres.2020.198068},
year = {2020},
date = {2020-09-01},
journal = {Virus Research},
volume = {286},
number = {198068},
abstract = {The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.},
keywords = {A Romeo, F. Iacovelli, M. Falconi},
pubstate = {published},
tppubtype = {article}
}

@article{Raniolo2019,
title = {Cellular uptake of covalent and non-covalent DNA nanostructures with different sizes and geometries},
author = {S Raniolo and S Croce and RP Thomsen and AH Okholm and V Unida and F Iacovelli and A Manetto and J Kiems and A Desideri and S Biocca},
doi = {10.1039/c9nr02006c},
year = {2019},
date = {2019-06-14},
journal = {Nanoscale},
volume = {11},
pages = {10808-10818},
abstract = {DNA nanostructures with different sizes and shapes, assembled through either covalent or non-covalent bonds, namely tetrahedral and octahedral nanocages, rod-shaped chainmails, square box and rectangular DNA origami structures, were compared for their stability in serum, cell surface binding, internalization efficiency, and intracellular degradation rate. For cell internalization a specific cell system, highly expressing the scavenger receptor LOX-1 was used. The results indicate that LOX-1 binds and internalizes a broad family of DNA structures of different sizes that, however, have a different fate and lifetime inside the cells. Covalently linked tetrahedra, octahedra or chainmails are intact inside cells for up to 18 hours whilst the same DNA nanostructures without covalent bonds along with square box and rectangular origami are rapidly degraded. These data suggest that non-covalently linked structures may be useful for fast drug release whilst the covalently-linked structures could be appropriate vehicles for slow release of molecules.},
keywords = {A. Desideri, F. Iacovelli, S Raniolo},
pubstate = {published},
tppubtype = {article}
}

@article{Pietrucci2019,
title = {Dysbiosis of gut microbiota in a selected population of Parkinson's patients},
author = {D Pietrucci and R Cerroni and V Unida and A Farcomeni and M Pierantozzi and NB Mercuri and S Biocca and A Stefani and A Desideri},
doi = {10.1016/j.parkreldis.2019.06.003},
year = {2019},
date = {2019-06-03},
journal = {Parkinsonism and Related Disorders},
abstract = {Introduction: In recent years the hypothesis that gut microbiota associates with Parkinson's disease (PD)has gained importance, although it has not been possible to define a specific microbiota composition as a predictive biomarker of this disease. We have investigated dysbiosis of gut microbiota in a selected population of PD patients from Central Italy, and examined the weight of specific confounders and predictors, in order to identify potential correlations with clinical phenotypes. Methods: 152 fecal samples were collected from 80 patients and 72 healthy controls. Patients were enrolled according to tight inclusion criteria. Microbiota composition was studied through 16s ribosomal RNA gene amplicon sequencing analysis in combination with data on dietary/life habits. Age, loss of weight, and sex were recognized as confounding factors, whereas PD-status, age, Body Mass Index, “eat cereals”, “gain of weigth” and “physical activity” as predictors. The presence of Lactobacillaceae, Enterobacteriaceae and Enterococcaceae families was significantly higher in feces from PD patients compared to healthy controls, while Lachnospiraceae were significantly reduced. Lower levels of Lachnospiraceae and higher levels of Enterobacteriaceae families also correlated with increased disease severity and motor impairment (Hoehn & Yahr stage, MDS-UPDRS Part III). Predictive metagenomics indicated a significant variation of genes involved in the metabolism of short chain fatty acids and amino acids, and in lipopolysaccharide biosynthesis. Conclusions: PD showed a distinctive microbiota composition. Functional predictions suggest changes in pathways favoring a pro-inflammatory environment in the gastrointestinal tract, and a reduction in the biosynthesis of amino acids acting as precursors of physiological transmitters.},
keywords = {A. Desideri, D. Pietrucci},
pubstate = {forthcoming},
tppubtype = {article}
}

@article{Palombo2019,
title = {Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes},
author = {R Palombo and S Caporali and M Falconi and F Iacovelli and B Morozzo Della Rocca and A Lo Surdo and E Campione and E Candi and G Melino and S Bernardini and A. Terrinoni},
doi = {10.3390/ijms20112689},
year = {2019},
date = {2019-05-31},
journal = {International journal of molecular sciences},
volume = {20},
abstract = {Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.},
keywords = {F. Iacovelli, M. Falconi},
pubstate = {published},
tppubtype = {article}
}

@article{Iacovelli2019,
title = {Probing the Functional Topology of a pH-Dependent Triple Helix DNA Nanoswitch Family through Gaussian Accelerated MD Simulation},
author = {F Iacovelli and KC Hernandez and A Desideri and M Falconi},
doi = {10.1021/acs.jcim.9b00133},
year = {2019},
date = {2019-05-10},
journal = {Journal of Chemical Information and Modelling},
volume = {59},
pages = {2746-2752},
abstract = {The topology of a pH-dependent triple helix DNA nanoswitch family has been characterized through simulative analysis to evaluate the efficiency of the switching mechanism varying the length of the loop connecting the two strands forming the double helix portion. In detail, the system is formed by a double helix made by two six base complementary sequences, connected by one loop having an increasing number of thymidines, namely 5, 7, or 9. The triplex-forming sequence made by six bases, connected to the double helix through a constant 25 base loop, interacts at pH 5.0 through Hoogsteen hydrogen bonds with one strand of the double helical region. We demonstrate, through molecular dynamics simulation, that the thymidine loop length exerts a fine regulatory role for the stability of the triple helix structure and is critical in modulating the switching mechanism triggered by the pH increase.},
keywords = {A. Desideri, F. Iacovelli, M. Falconi},
pubstate = {published},
tppubtype = {article}
}

@article{Ferrara2018,
title = {DNA-based biosensor on flexible nylon substrate by dip-pen lithography for topoisomerase detection},
author = {V Ferrara and A Ottaviani and F Cavaleri and G Arrabito and P Cancemi and YP Ho and BR Knudsen and MS Hede and C Pellerito and A Desideri and S Feo and G Marletta and B Pignataro},
year = {2019},
date = {2019-01-18},
booktitle = {Lecture Notes in Electrical Engineering},
volume = {539},
pages = {309-316},
organization = {4th National Conference on Sensors},
abstract = {Dip-pen lithography (DPL) technique has been employed to develop a new flexible biosensor realized on nylon with the aim to detect the activity of human topoisomerase. The sensor is constituted by an ordered array of a DNA substrate on flexible nylon supports that can be exploited as a drug screening platform for anticancer molecules. Here, we demonstrate a rapid protocol that permits to immobilize minute quantities of DNA oligonucleotides by DPL on nylon surfaces. Theoretical and experimental aspects have been investigated to successfully print DNA oligonucleotides by DPL on such a porous and irregular substrate.},
keywords = {A. Desideri},
pubstate = {published},
tppubtype = {article}
}

@article{Satta2018,
title = {Design, selection and optimization of an anti-TRAIL-R2/anti-CD3 bispecific antibody able to educate T cells to recognize and destroy cancer cells},
author = {A Satta and D Mezzanzanica and F Caroli and B Frigerio and M Di Nicola and RE Kontermann and F Iacovelli and A Desideri and A Anichini and S Canevari and AM Gianni and M Figini },
doi = {10.1080/19420862.2018.1494105},
year = {2018},
date = {2018-10-03},
journal = {mAbs},
volume = {10},
pages = {1084-1097},
abstract = {Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or TRAIL-receptor agonistic monoclonal antibodies promote apoptosis in most cancer cells, and the differential expression of TRAIL-R2 between tumor and normal tissues allows its exploitation as a tumor-associated antigen. The use of these antibodies as anticancer agents has been extensively studied, but the results of clinical trials were disappointing. The observed lack of anticancer activity could be attributed to intrinsic or acquired resistance of tumor cells to this type of treatment. A possible strategy to circumvent drug resistance would be to strike tumor cells with a second modality based on a different mechanism of action. We therefore set out to generate and optimize a bispecific antibody targeting TRAIL-R2 and CD3. After the construction of different bispecific antibodies in tandem-scFv or single-chain diabody formats to reduce possible immunogenicity, we selected a humanized bispecific antibody with very low aggregates and long-term high stability and functionality. This antibody triggered TRAIL-R2 in an agonistic manner and its anticancer activity proved dramatically potentiated by the redirection of cytotoxic T cells against both sensitive and resistant melanoma cells. The results of our study show that combining the TRAIL-based antitumor strategy with an immunotherapeutic approach in a single molecule could be an effective addition to the anticancer armamentarium. },
keywords = {A. Desideri, F. Iacovelli},
pubstate = {published},
tppubtype = {article}
}

@article{Ottaviani2018,
title = {Engineering a responsive DNA triple helix into an octahedral DNA nanostructure for a reversible opening/closing switching mechanism: A computational and experimental integrated stud},
author = {A Ottaviani and F Iacovelli and A Idili and M Falconi and F Ricci and A Desideri},
doi = {10.1093/nar/gky857},
year = {2018},
date = {2018-09-22},
journal = {Nucleic Acids Research},
volume = {46},
pages = {9951-9959},
abstract = {We propose an experimental and simulative approach to study the effect of integrating a DNA functional device into a large-sized DNA nanostructure. We selected, as a test bed, a well-known and characterized pH-dependent clamp-switch, based on a parallel DNA triple helix, to be integrated into a truncated octahedral scaffold. We designed, simulated and experimentally characterized two different functionalized DNA nanostructures, with and without the presence of a spacer between the scaffold and the functional elements. The experimental and simulative data agree in validating the need of a spacer for the occurrence of the pH dependent switching mechanism. The system is fully reversible and the switching can be monitored several times without any perturbation, maintaining the same properties of the isolated clamp switch in solution.},
keywords = {A. Desideri, F. Iacovelli, M. Falconi},
pubstate = {published},
tppubtype = {article}
}

@article{Gaziano2018,
title = {Antifungal activity of cardiospermum halicacabum L. (Sapindaceae) against trichophyton rubrum occurs through molecular interaction with fungal Hsp90},
author = {R Gaziano and E Campione and F Iacovelli and D Marino and F Pica and P Di Francesco and S Aquaro and F Menichini and M Falconi and L Bianchi},
doi = {10.2147/DDDT.S155610},
year = {2018},
date = {2018-07-12},
journal = {Drug Design, Development and Therapy},
volume = {12},
pages = {2185-2193},
abstract = {Introduction: Dermatophytosis is a superficial fungal infection limited to the stratum corneum of the epidermis, or to the hair and nails, and constitutes an important public health problem because of its high prevalence and associated morbidity. Dermatophyte fungi, especially 2 species, Trichophyton rubrum and Trichophyton mentagrophytes, are the predominant pathogens. Topical antifungal drugs, mainly azoles or allyamines, are currently used for the treatment of dermatophytoses, although in some cases, such as in nail and hair involvement, systemic treatment is required. However, therapeutic efficacy of current antifungal agents can be limited by their side effects, costs, and the emergence of drug resistance among fungi. Plant extracts represent a potential source of active antimicrobial agents, due to the presence of a variety of chemical bioactive compounds. In the present work, we evaluated in silico and in vitro the antifungal activity of an extract of the medicinal plant Cardiospermum halicacabum against T. rubrum suggesting a potential interaction with Hsp90 as playing an important role in both pathogenicity and drug susceptibility of T. rubrum. Methods: We investigated in vitro the effect of different concentrations of C. halicacabum (from 500 to 31.25 µg) against a clinical isolate of T. rubrum. Furthermore, using a computational assessment, the interaction between different C. halicacabum active compounds and the fungal Hsp90 was also investigated. Results: Our results indicate a clear-cut antifungal activity of the total plant extract at the highest concentrations (500 and 250 µg). Among all tested C. halicacabum compounds, the luteolin and rutin molecules have been identified in silico as the most important potential inhibitors of Hsp90. Based on these data, luteolin and rutin were also individually assessed for their antifungal activity. Results demonstrate that both substances display an antifungal effect, even if lower than that of the total plant extract. Conclusion: Our data indicate a strong fungistatic effect of C. halicacabum against T. rubrum, suggesting its potential therapeutic efficacy in the treatment of dermatophytoses. Additionally, C. halicacabum compounds, and particularly luteolin and rutin, are all possible Hsp90 interac-tors, explaining their fungistatic activity.},
keywords = {F. Iacovelli, M. Falconi},
pubstate = {published},
tppubtype = {article}
}

@article{Raniolo2018b,
title = { Entry, fate and degradation of DNA nanocages in mammalian cells: A matter of receptors},
author = {S Raniolo and G Vindigni and V Unida and A Ottaviani and E Romano and A Desideri and S Biocca},
year = {2018},
date = {2018-06-11},
journal = {Nanoscale},
volume = {10},
pages = {12078-12086},
abstract = {DNA has been used to build nanostructures with potential biomedical applications. However, their use is limited by the lack of information on the mechanism of entry, intracellular fate and degradation rate of nanostructures inside cells. We generated octahedral DNA nanocages functionalized with folic acid and investigated the cellular uptake mediated by two distinctive internalization pathways, using two cellular systems expressing the oxidized low-density lipoprotein receptor-1 (LOX-1) and the α isoform of the folate receptor (αFR), respectively. Here, we report that DNA nanocages are very efficiently and selectively internalized by both receptors with an efficiency at least 30 times higher than that observed in cells not expressing the receptors. When internalized by LOX-1, nanocages traffic to lysosomes within 4 hours and are rapidly degraded. When the uptake is mediated by αFR, DNA nanocages are highly stable (>48 hours) and accumulate inside cells in a time-dependent way. These data demonstrate that the selection of the cellular receptor is crucial for targeting specific sub-cellular compartments and for modulating the DNA nanocage intracellular half-life, indicating that vitamin-mediated uptake may constitute a protected pathway for intracellular drug delivery. },
keywords = {A. Desideri, S Biocca, S Raniolo},
pubstate = {published},
tppubtype = {article}
}