Artemisinin-derived dimers have greatly improved anti-cytomegalovirus activity compared to artemisinin monomers.
BACKGROUND
Artesunate, 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.


METHODS
Four 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.


RESULTS
Artemisinin dimers effectively inhibited CMV replication in human foreskin fibroblasts and human embryonic lung fibroblasts (EC(50) for dimer sulfone carbamate and dimer primary alcohol 0.06+/-0.00 microM and 0.15+/-0.02 microM 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 microM 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.


CONCLUSIONS
Artemisinin 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.
Arav-Boger
Ravit
R
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. boger@jhmi.edu
He
Ran
R
Chiou
Chuang-Jiun
CJ
Liu
Jianyong
J
Woodard
Lauren
L
Rosenthal
Andrew
A
Jones-Brando
Lorraine
L
Forman
Michael
M
Posner
Gary
G
D000890:Anti-Infective Agents; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D055503:Protein Multimerization; D014779:Virus Replication / Q000187:drug effects
D000890:Anti-Infective Agents; D037621:Artemisinins