Abstract
We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound.
Highlights
Infection with CMV, a member of the herpesvirus family, is common in humans
The virus establishes lifelong persistent infection, which usually remains asymptomatic. In immunocompromised hosts such as transplant recipients and patients with AIDS, CMV infection is associated with significant morbidity and mortality [2,3]
We previously reported on the anti-CMV activity of four artemisinin monomers and two artemisinin-derived dimers [13]
Summary
Infection with CMV, a member of the herpesvirus family, is common in humans. The virus establishes lifelong persistent infection, which usually remains asymptomatic. In immunocompromised hosts such as transplant recipients and patients with AIDS, CMV infection is associated with significant morbidity and mortality [2,3]. CMV is the most common congenitally-acquired infection causing mental retardation and deafness in congenitally-infected children [4]. The detection of CMV in immunocompetent individuals has been linked with outcomes of several syndromes including sepsis, pulmonary complications in patients in intensive care-units, and in a brain tumor, glioblastoma multiforme [5,6,7]. The direct role of CMV in these syndromes is unclear, virus replication may contribute to their natural history, and the role of anti-CMV therapy in these conditions is currently being investigated
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