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Pure Appl. Chem. 76(5), 1007-1015, 2004

Pure and Applied Chemistry

Vol. 76, Issue 5

Hindered nucleoside analogs as antiflaviviridae agents

S. Manfredini, A. Angusti, A. C. Veronese, E. Durini, S. Vertuani, F. Nalin, N. Solaroli, S. Pricl, M. Ferrone, M. Mura, M. A. Piano, B. Poddesu, A. Cadeddu, P. La Colla, and R. 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 discov-
ery 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.

*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Kraków, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.

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