2015
|
Crespan E; Hübscher U; Maga G Expansion of CAG triplet repeats by human DNA polymerases λ and β in vitro, is regulated by flap endonuclease 1 and DNA ligase 1. Journal Article In: DNA Repair, vol. 29, pp. 101-111, 2015. @article{%a1:%Y_361,
title = {Expansion of CAG triplet repeats by human DNA polymerases λ and β in vitro, is regulated by flap endonuclease 1 and DNA ligase 1.},
author = {Crespan E and Hübscher U and Maga G},
url = {https://www.sciencedirect.com/science/article/pii/S1568786415000178?via%3Dihub},
doi = {10.1016/j.dnarep.2015.01.005},
year = {2015},
date = {2015-05-29},
journal = {DNA Repair},
volume = {29},
pages = {101-111},
abstract = {Huntington's disease (HD) is a neurological genetic disorder caused by the expansion of the CAG trinucleotide repeats (TNR) in the N-terminal region of coding sequence of the Huntingtin's (HTT) gene. This results in the addition of a poly-glutamine tract within the Huntingtin protein, resulting in its pathological form. The mechanism by which TRN expansion takes place is not yet fully understood. We have recently shown that DNA polymerase (Pol) beta can promote the microhomology-mediated end joining andtriplet expansion of a substrate mimicking a double strand break in the TNR region of the HTT gene. Here we show that TNRexpansion is dependent on the structure of the DNA substrate, as well as on the two essential Pol beta co-factors: flap endonuclease1 (Fen1) and DNA ligase 1 (Lig1). We found that Fen1 significantly stimulated TNR expansion by Pol beta, but not by the related enzyme Pol lambda, and subsequent ligation of the DNA products by Lig1. Interestingly, the deletion of N-terminal domains of Pol lambda, resulted in an enzyme which displayed properties more similar to Pol beta, suggesting a possible evolutionary mechanism. These results may suggest a novel mechanism for somatic TNR expansion in HD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Huntington's disease (HD) is a neurological genetic disorder caused by the expansion of the CAG trinucleotide repeats (TNR) in the N-terminal region of coding sequence of the Huntingtin's (HTT) gene. This results in the addition of a poly-glutamine tract within the Huntingtin protein, resulting in its pathological form. The mechanism by which TRN expansion takes place is not yet fully understood. We have recently shown that DNA polymerase (Pol) beta can promote the microhomology-mediated end joining andtriplet expansion of a substrate mimicking a double strand break in the TNR region of the HTT gene. Here we show that TNRexpansion is dependent on the structure of the DNA substrate, as well as on the two essential Pol beta co-factors: flap endonuclease1 (Fen1) and DNA ligase 1 (Lig1). We found that Fen1 significantly stimulated TNR expansion by Pol beta, but not by the related enzyme Pol lambda, and subsequent ligation of the DNA products by Lig1. Interestingly, the deletion of N-terminal domains of Pol lambda, resulted in an enzyme which displayed properties more similar to Pol beta, suggesting a possible evolutionary mechanism. These results may suggest a novel mechanism for somatic TNR expansion in HD. |
Spallarossa A; Caneva C; Caviglia M; Alfei S; Butini S; Campiani G; Gemma S; Brindisi M; Zisterer DM; Bright SA; Williams CD; Crespan E; Maga G; Sanna G; Delogu I; Collu G; Loddo R Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents. Journal Article In: European Journal of Medicinal Chemistry, vol. 102, pp. 648-660, 2015. @article{%a1:%Y_418,
title = {Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents.},
author = {Spallarossa A and Caneva C and Caviglia M and Alfei S and Butini S and Campiani G and Gemma S and Brindisi M and Zisterer DM and Bright SA and Williams CD and Crespan E and Maga G and Sanna G and Delogu I and Collu G and Loddo R},
url = {https://www.sciencedirect.com/science/article/pii/S0223523415301938?via%3Dihub},
doi = {10.1016/j.ejmech.2015.08.009},
year = {2015},
date = {2015-03-12},
urldate = {2017-03-03},
journal = {European Journal of Medicinal Chemistry},
volume = {102},
pages = {648-660},
abstract = {A new series of indole-based analogues were recently identified as potential anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b. Copyright 2015 Elsevier Masson SAS. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A new series of indole-based analogues were recently identified as potential anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b. Copyright 2015 Elsevier Masson SAS. All rights reserved. |
Tintori C; Fallacara AL; Radi M; Zamperini C; Dreassi E; Crespan E; Maga G; Schenone S; Musumeci F; Brullo C; Richters A; Gasparrini F; Angelucci A; Festuccia C; Delle Monache S; Rauh D; Botta M Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma. Journal Article In: Journal of Medicinal Chemistry, vol. 58, no. 1, pp. 347-361, 2015. @article{%a1:%Y_348,
title = {Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma.},
author = {Tintori C and Fallacara AL and Radi M and Zamperini C and Dreassi E and Crespan E and Maga G and Schenone S and Musumeci F and Brullo C and Richters A and Gasparrini F and Angelucci A and Festuccia C and {Delle Monache S} and Rauh D and Botta M},
url = {https://pubs.acs.org/doi/10.1021/jm5013159},
doi = {10.1021/jm5013159},
year = {2015},
date = {2015-02-12},
journal = {Journal of Medicinal Chemistry},
volume = {58},
number = {1},
pages = {347-361},
abstract = {c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells. |
Vincetti P; Caporuscio F; Kaptein S; Gioiello A; Mancino V; Suzuki Y; Yamamoto N; Crespan E; Lossani A; Maga G; Rastelli G; Castagnolo D; Neyts J; Leyssen P; Costantino G; Radi M Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases. Journal Article In: Journal of Medicinal Chemistry, vol. 58, no. 12, 2015. @article{%a1:%Y_353,
title = {Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases.},
author = {Vincetti P and Caporuscio F and Kaptein S and Gioiello A and Mancino V and Suzuki Y and Yamamoto N and Crespan E and Lossani A and Maga G and Rastelli G and Castagnolo D and Neyts J and Leyssen P and Costantino G and Radi M},
url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00108},
doi = {10.1021/acs.jmedchem.5b00108},
year = {2015},
date = {2015-02-12},
journal = {Journal of Medicinal Chemistry},
volume = {58},
number = {12},
abstract = {This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concentrations with no significant toxicity to the host cell. Among the identified antivirals, compound 16i proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concentrations with no significant toxicity to the host cell. Among the identified antivirals, compound 16i proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn. |
2014
|
Maga G AIDS: la verità negata Book Il Pensiero Scientifico Editore, 2014, ISBN: 978-8849004809, (Vincitore del primo premio categoria saggi del Premio Letterario Nazionale Fanz Kafka - 2014). @book{CNRPRODOTTI303054,
title = {AIDS: la verità negata},
author = {Maga G},
url = {http://www.pensiero.it/ecomm/pc/viewPrd.asp?idproduct=651},
isbn = {978-8849004809},
year = {2014},
date = {2014-01-01},
publisher = {Il Pensiero Scientifico Editore},
series = {Informa},
abstract = {Ancora oggi esiste una corrente di opinione, tutt’altro che secondaria e sempre vitale, che afferma che l’AIDS non esiste e che l’HIV è un innocuo parassita. Ma negare l’AIDS significa sottovalutare la pericolosità dell’infezione da HIV e indurre i pazienti a rifiutare terapie in grado di salvare loro la vita. Quando l’opinione errata di alcuni compromette la salute e la sicurezza di altri, è necessario correggerla. Giovanni Maga dimostra, con un linguaggio comprensibile a tutti e attraverso la narrazione appassionata di tante storie di pazienti, medici e ricercatori, che respingere la relazione tra HIV e AIDS è un errore dalle drammatiche conseguenze. Documentando, inoltre, gli straordinari progressi fatti nel combattere questa malattia, il libro vuole essere un invito all’ottimismo e alla speranza. La difficoltà nell’accettare l’AIDS e, di conseguenza, la disponibilità a credere che non esista nascono spesso dalla disperazione di chi vive la sieropositività come una condanna senza appello. Ma la scienza arriverà inevitabilmente a sconfiggere l’HIV e questo libro ci spiega come e perché.},
note = {Vincitore del primo premio categoria saggi del Premio Letterario Nazionale Fanz Kafka - 2014},
keywords = {},
pubstate = {published},
tppubtype = {book}
}
Ancora oggi esiste una corrente di opinione, tutt’altro che secondaria e sempre vitale, che afferma che l’AIDS non esiste e che l’HIV è un innocuo parassita. Ma negare l’AIDS significa sottovalutare la pericolosità dell’infezione da HIV e indurre i pazienti a rifiutare terapie in grado di salvare loro la vita. Quando l’opinione errata di alcuni compromette la salute e la sicurezza di altri, è necessario correggerla. Giovanni Maga dimostra, con un linguaggio comprensibile a tutti e attraverso la narrazione appassionata di tante storie di pazienti, medici e ricercatori, che respingere la relazione tra HIV e AIDS è un errore dalle drammatiche conseguenze. Documentando, inoltre, gli straordinari progressi fatti nel combattere questa malattia, il libro vuole essere un invito all’ottimismo e alla speranza. La difficoltà nell’accettare l’AIDS e, di conseguenza, la disponibilità a credere che non esista nascono spesso dalla disperazione di chi vive la sieropositività come una condanna senza appello. Ma la scienza arriverà inevitabilmente a sconfiggere l’HIV e questo libro ci spiega come e perché. |
