Artemisinin-Derived Dimers Have Greatly Improved Anti-Cytomegalovirus Activity Compared to Artemisinin Monomers

Abstract

BackgroundArtesunate, an artemisinin-derived monomer, was reported to inhibit Cytomegalovirus (CMV) replication. We aimed to compare the in-vitro anti-CMV activity of several artemisinin-derived monomers and newly synthesized artemisinin dimers.MethodsFour artemisinin monomers and two novel artemisinin-derived dimers were tested for anti-CMV activity in human fibroblasts infected with luciferase-tagged highly–passaged laboratory adapted strain (Towne), and a clinical CMV isolate. Compounds were evaluated for CMV inhibition and cytotoxicity.ResultsArtemisinin dimers effectively inhibited CMV replication in human foreskin fibroblasts and human embryonic lung fibroblasts (EC50 for dimer sulfone carbamate and dimer primary alcohol 0.06±0.00 µM and 0.15±0.02 µM respectively, in human foreskin fibroblasts) with no cytotxicity at concentrations required for complete CMV inhibition. All four artemisinin monomers (artemisinin, artesunate, artemether and artefanilide) shared a similar degree of CMV inhibition amongst themselves (in µM concentrations) which was significantly less than the inhibition achieved with artemisinin dimers (P<0.0001). Similar to monomers, inhibition of CMV with artemisinin dimers appeared early in the virus life cycle as reflected by decreased expression of the immediate early (IE1) protein.ConclusionsArtemisinin dimers are potent and non-cytotoxic inhibitors of CMV replication. These compounds should be studied as potential therapeutic agents for the treatment of CMV infection in humans.

Artemisinin-Derived Dimer Diphenyl Phosphate Is an Irreversible Inhibitor of Human Cytomegalovirus Replication

“…Artemisinin derivatives were originally reported to inhibit CMV replication (7,17), and we have shown that artemisininderived dimers are highly potent inhibitors of CMV replication compared to their monomeric counterparts (2). We now report that AS and 838 have no activities against selected alpha-and gammaherpesviruses.…”

“…We recently reported on the highly potent anti-CMV activities of arteminisin-derived dimers (2). We also identified among a series of dimers the most potent anti-CMV compound, dimer diphenyl phosphate (molecular weight, 838).…”

In Vitro Combination of Anti-Cytomegalovirus Compounds Acting through Different Targets: Role of the Slope Parameter and Insights into Mechanisms of Action

“…The compounds used in this study and their mechanisms of action, when known, are listed in Table 1. Artemisinins (monomers and dimers), cardiac glycosides, and U0126 were reported to inhibit CMV replication and were therefore selected for this study (24)(25)(26)(27)(28)(29). The multikinase inhibitor sunitinib has not previously been reported to inhibit CMV replication, but other kinase inhibitors have been shown to inhibit CMV in vitro (30).…”

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Unfortunately, there is not yet a thorough evaluation of its efficacy but only sporadic reports of its in vivo anti CMV activity with contrasting results [57]. Interesting insights come from artemisinin-derived dimers, novel compounds with more potent in vitro anti-CMV effects [58,59] the efficacy of which remains to be addressed.…”