In vitro inhibition of human cytomegalovirus replication by calcium trinatrium diethylenetriaminepentaacetic acid

Desferrioxamine (DFO) has been shown to inhibit human cytomegalovirus (CMV)) replication in vitro. in the present study, we compared antiviral effects of DFO in human foreskin fibroblast (HFF) cells against several CMV strains with those of other chelators that interact with iron and other ions from different pools. DFO, a hydrophilic chelator, that may chelate both intracellular and extracellular ions inhibited production of CMV late antigen at 50% effective concentrations (EC(50)s) ranging from 6.2 to 8.9 mu M. EC(50)s for calcium trinatrium diethylenetriaminepentaacetic acid (CaDTPA) ranged from 6.1 to 9.9 mu M. EC(50)s for 2,2'-bipyridine (BPD), a hydrophobic chelator, which diffuses into cell membranes ranged from 65 to 72 mu M. Concentrations which inhibited BrdU incorporation into cellular DNA by 50% (IC(50)s) ranged from 5.2 to 12.0 mu M (DFO), from 65 to 89 mu M (BPD), and from 139 to 249 mu M (CaDTPA). CaDTPA was the only chelator which completely inhibited production of infectious virus in HFF and vascular endothelial cells at concentrations which had no significant effects on cellular DNA synthesis and growth. Addition of stoichiometric amounts of Fe3+ in the culture medium of HFF cells completely eliminated antiviral effects of DFO while antiviral effects of CaDTPA and BPD were only moderately affected. Fe2+ and Cu2+ were stronger inhibitors of CADTPA than Fe3+; however, Mn2+ and Zn2+ completely suppressed antiviral effects of CaDTPA. The results show that CaDTPA is a novel nontoxic inhibitor of CMV replication. The antiviral activity of CaDTPA is suppressed by metal ions with a decreasing potency order of Mn2+/Zn2+ > Fe2+ > Cu2+ > Fe3+.