caa a22 4500 378911244 CHVBK 20180305123542.0 cr unu---uuuuu 161128e20040101xx s 000 0 eng 10.1351/pac200476051007 doi (NATIONALLICENCE)gruyter-10.1351/pac200476051007 Hindered nucleoside analogs as antiflaviviridae agents [Elektronische Daten] [Stefano Manfredini, Angela Angusti, A. C. Veronese, Elisa Durini, S. Vertuani, F. Nalin, N. Solaroli, S. Pricl, Marco Ferrone, M. Mura, M. A. Piano, B. Poddesu, Alessandra Cadeddu, P. La Colla, Roberta Loddo] Flaviviridae are an important family of viruses, responsible for widely spread diseases such as dengue and West Nile fever and hepatitis C. Despite the severity of the related diseases, no effective antiviral treatments for infection are available. Following our discovery of adenosine-hindered analogs as potent antiflaviviridae agents, we have continued our investigation on guanosine and inosine derivatives, which were evaluated for activity against BVDV, YFV, DENV, and WNV viruses in cell-based assays. The present study allowed us to identify some newer features that led to improve the antiviral potency (down to the µM range) and to selectively inhibit BVDV and YFV viruses. The molecular modeling results were consistent with the hypothesis that test analogs act as RNA-dependent RNA polymerase (RdRp) inhibitors by interacting with a surface allosteric binding pocket. © 2013 Walter de Gruyter GmbH, Berlin/Boston Manfredini Stefano Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Angusti Angela Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Veronese A. C. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Durini Elisa Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Vertuani S. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Nalin F. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Solaroli N. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Pricl S. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Ferrone Marco Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Mura M. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Piano M. A. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Poddesu B. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Cadeddu Alessandra Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Colla P. La Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Loddo Roberta Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut Pure and Applied Chemistry De Gruyter 76/5(2004-01-01), 1007-1015 0033-4545 76:5<1007 2004 76 pac https://doi.org/10.1351/pac200476051007 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1351/pac200476051007 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Manfredini Stefano Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Angusti Angela Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Veronese A. C. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Durini Elisa Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Vertuani S. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Nalin F. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Solaroli N. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Pricl S. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Ferrone Marco Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Mura M. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Piano M. A. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Poddesu B. Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Cadeddu Alessandra Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Colla P. La Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 700 1- Loddo Roberta Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy; Division of Clinical Virology, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden; Computer-aided Systems Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; Department of Experimental Biology University of Cagliari, Cittadella Universitaria, S.P.Monserrato-Sestu Km 0.700, 09042, Monserrato, Cagliari, Italy aut NATIONALLICENCE 773 0- Pure and Applied Chemistry De Gruyter 76/5(2004-01-01), 1007-1015 0033-4545 76:5<1007 2004 76 pac CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter