Virtual screening of acyclovir derivatives as potential antiviral agents: design synthesis and biological evaluation of new acyclic nucleoside ProTides

摘要

Following our findings on the anti-HIV activity of acyclovir phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral (i.e. HIV) agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using adenylate/guanylate kinase, HIV RT, and human DNA polymerase. A total of thirty-nine new phosphate prodrugs were synthesised and evaluated against HIV-1 (in in vitro and in ex-vivo human tonsillar tissue system) and human herpesviruses. Several ProTide compounds showed good potency (low micromolar range) against HIV-1 while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for the selection of compounds showing different metabolic patterns.