title: The unique antiviral activity of artesunate is broadly effective against human cytomegaloviruses including therapy-resistant mutants.
abstract: Current therapy options to treat infections with human cytomegalovirus face severe limitations leading to a continued search for novel drug candidates. Here, we describe novel characteristics of the strong antiviral potency of the drug artesunate. In vitro virus replication systems were applied to analyze a number of laboratory and clinically relevant strains of human cytomegalovirus. An inhibitory block at a very early stage of infection was demonstrated. Time-of-addition experiments indicated that the antiviral efficacy could be optimized when artesunate was applied as fractional doses consecutively added post-infection. Artesunate showed a clearly higher anti-cytomegaloviral activity than its parental drug artemisinin (approximately 10-fold) or other artesunate-related compounds. Mean IC(50) values of artesunate for a variety of standard therapy-resistant virus mutants were within a 2-fold range compared to wild-type virus. Furthermore, a synergistic effect was identified when artesunate was combined with the mechanistically distinct antiviral compound maribavir. These findings point to unique antiviral properties of artesunate which may offer an advantage over standard antiviral therapy particularly in cases of drug resistance.
authors.affiliation: Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Sunwen
authors.initials: S
authors.lastname: Chou
authors.forename: Gail
authors.initials: G
authors.lastname: Marousek
authors.forename: Sabrina
authors.initials: S
authors.lastname: Auerochs
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D012263:Ribonucleosides / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D037621:Artemisinins; D000077332:Artesunate; D001562:Benzimidazoles; D012263:Ribonucleosides; C031327:artemisinin; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole