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    Artesunate-derived monomeric, dimeric and trimeric experimental drugs - Their unique mechanistic basis and pronounced antiherpesviral activity (2018)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Hahn, Friedrich
    Fröhlich, Tony
    Frank, Theresa
    Bertzbach, Luca D (WE 5)
    Kohrt, Stephan
    Kaufer, Benedikt B (WE 5)
    Stamminger, Thomas
    Tsogoeva, Svetlana B
    Marschall, Manfred
    Quelle
    Antiviral research
    Bandzählung: 152
    Seiten: 104 – 110
    ISSN: 0166-3542
    Sprache
    Englisch
    Verweise
    DOI: 10.1016/j.antiviral.2018.02.013
    Pubmed: 29458133
    Kontakt
    Institut für Virologie

    Robert-von-Ostertag-Str. 7-13
    14163 Berlin
    +49 30 838 51833
    virologie@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC50 values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC50 of 0.03 ± 0.00 μM, which even exceled the antiviral potency of TF27 (EC50 0.04 ± 0.01 μM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 μM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.