Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication
Language: 
English
Abstract: 

We previously reported that among a series of artemisinin-derived monomers and dimers, dimer diphenyl phosphate (838) was the most potent inhibitor of human cytomegalovirus (CMV) replication. Our continued investigation of a prototypic artemisinin monomer (artesunate [AS]) and dimer (838) now reveals that both compounds have specific activity against CMV but do not inhibit lytic replication of human herpesvirus 1 or 2 or Epstein-Barr virus. AS and 838 inhibited CMV replication during the first 24 h of the virus replication cycle, earlier than the time of ganciclovir (GCV) activities and prior to DNA synthesis. Neither compound inhibited virus entry. Quantification of DNA replication and virus yield revealed a similar level of inhibition by GCV, but AS and 838 had a 10-fold-higher inhibition of virus yield than of DNA replication, suggesting that artemisinins could inhibit CMV through multiple steps: a predominant early inhibition and possibly an additional step following DNA replication. During the strong early CMV inhibition, the transcription of immediate-early genes was not significantly downregulated, and viral protein expression was reduced only after 48 h. AS and GCV were reversible CMV inhibitors, but the inhibition of CMV replication by 838 was irreversible. Combinations of GCV and 838 as well as GCV and AS were highly synergistic. Finally, treatment with 838, but not AS, prior to CMV infection demonstrated strong anti-CMV activity. These findings illustrate the unique activities of dimer 838, including early and irreversible CMV inhibition, possibly by tight binding to its target.

Author(s): 
He, Ran
Park, Kyoungsook
Cai, Hongyi
Kapoor, Arun
Forman, Michael
Mott, Bryan
Posner, Gary H.
Arav-Boger, Ravit
Item Type: 
Journal Article
Publication Title: 
Antimicrobial Agents and Chemotherapy
Journal Abbreviation: 
Antimicrob. Agents Chemother.
Publication Date: 
7/12/2015
Publication Year: 
2012
Pages: 
3508-3515
Volume: 
56
Issue: 
7
ISSN: 
1098-6596
DOI: 
10.1128/AAC.00519-12
Library Catalog: 
PubMed
Extra: 
PMID: 22547612 PMCID: PMC3393438

Turabian/Chicago Citation

Ran He, Kyoungsook Park, Hongyi Cai, Arun Kapoor, Michael Forman, Bryan Mott, Gary H. Posner and Ravit Arav-Boger. 7/12/2015. "Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication." Antimicrobial Agents and Chemotherapy 56: 7: 3508-3515. 10.1128/AAC.00519-12.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/AAC.00519-12 | issn = 1098-6596 | volume = 56 | pages = 3508-3515 | last = He | first = Ran | coauthors = Park, Kyoungsook, Cai, Hongyi, Kapoor, Arun, Forman, Michael, Mott, Bryan, Posner, Gary H., Arav-Boger, Ravit | title = Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication | journal = Antimicrobial Agents and Chemotherapy | date = 7/12/2015 | pmid = | pmc = }} </ref>