The thymidylate synthase inhibitor ZD1694 potently inhibits murine and human cytomegalovirus replication in quiescent fibroblasts

Tomudex (ZD1694) is a quinazoline-based folate analog and a powerful inhibi tor of cellular thymidylate synthase and is approved in Europe for use in o ncology. Here the first evidence of its activity against murine and human c ytomegalovirus (MCMV and HCMV) is reported. ZD1694 irreversibly inhibited t he replication and DNA synthesis of both viruses in quiescent fibroblasts. The corresponding 50% effective concentrations were 0.006 and 0.002 mu M re spectively, whereas the 50% cytotoxic concentration was >10 mu M for both m urine and human quiescent fibroblasts. A similar antiviral effect was obser ved against two ganciclovir-resistant HCMV strains isolated from AIDS patie nts. Taken as a whole these results demonstrate that cellular thymidylate s ynthase plays an essential role in viral replication and that ZD1693 merits further investigation as anticytomegaloviral agent. (C) 2000 Published by Elsevier Science B.V.