The anticytomegaloviral activity of raltitrexed is abrogated in quiescent mouse fibroblasts that overexpress thymidylate synthase

Cytomegalovirus (CMV) replication in non-proliferating cells requires the c oordinated expression of the host enzymes responsible for deoxyribonucleoti de synthesis. Thymidylate synthase (TS) is an essential cellular enzyme tha t catalyzes de novo synthesis of thymidylic acid (dTMP). In this report we show that murine CMV (MCMV) replication and DNA synthesis are inhibited in quiescent 3T6 fibroblasts by raltitrexed, a quinazoline-based folate analog that specifically inhibits TS. This antiviral activity was abrogated in LU 3-7 cells, a 3T6 derivative that overproduces TS by about 50-fold. These ob servations indicate that the anticytomegaloviral activity of raltitrexed is associated with TS inhibition and suggest that cellular TS activity is req uired for efficient CMV replication in quiescent cells. (C) 2001 Elsevier S cience B.V, All rights reserved.