Hindered nucleoside analogs as antiflaviviridae agents

Manfredini, Stefano; Angusti, Angela; Veronese, A. C.; Durini, Elisa; Vertuani, S.; Nalin, F.; Solaroli, N.; Pricl, S.; Ferrone, Marco; Mura, M.; Piano, M. A.; Poddesu, B.; Cadeddu, Alessandra; Colla, P. La; Loddo, Roberta

doi:10.1351/pac200476051007

Pure Appl. Chem., 2004, Vol. 76, No. 5, pp. 1007-1015

http://dx.doi.org/10.1351/pac200476051007

Hindered nucleoside analogs as antiflaviviridae agents

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 and Roberta Loddo

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

Abstract: 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.