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, Krak�w, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.
