Dipyridamole is an effective inhibitor of cardiovirus growth in cell culture. The effects of
dipyridamole on mengovirus replication in vivo and in vitro were examined in the hope the
drug could be used as an experimental analog of the poliovirus inhibitor
guanidine.
Guanidine selectively inhibits poliovirus
RNA synthesis but not
RNA translation, and as such, has been a valuable research tool. Although
guanidine does not inhibit
cardiovirus infection, a compound with similar discriminatory characteristics would be experimentally useful for parallel work with these viruses. We found that mengovirus plaque formation in HeLa or L cells was inhibited nearly 100% by the presence of 80 muM
dipyridamole. The inhibitory effect was reversible and targeted an early step in the replication cycle. Studies with
luciferase-expressing mengovirus replicons showed that
viral protein synthesis was unaffected by
dipyridamole, and rather,
RNA synthesis was the step targeted by the
drug. This assessment was confirmed by direct analyses of viral translation and
RNA synthesis activities in a Krebs-2-derived in vitro system that supported complete, infectious cardiovirus replication. In Krebs extracts,
dipyridamole specifically inhibited
viral RNA synthesis to more than 95%, with no concomitant effect on
viral protein translation or
polyprotein processing. The observed inhibition reversibly affected an early step in both minus-strand and plus-strand
RNA synthesis, although inhibition of plus-strand synthesis was more profound than that of minus-strand synthesis. We conclude that
dipyridamole is a potent experimental tool that readily distinguishes between cardiovirus translation and RNA replication functions.