The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65
Hutterer C, Niemann I, Milbradt J, Fröhlich T, Reiter C, Kadioglu O, Bahsi H, Zeitträger I, Wagner S, Einsiedel J, Gmeiner P, Vogel N, Wandinger S, Godl K, Stamminger T, Efferth T, Tsogoeva S, Marschall M (2015)
Publication Language: English
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2015
Journal
Book Volume: 124
Pages Range: 101-109
DOI: 10.1016/j.antiviral.2015.10.003
Abstract
Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of standard antiviral therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy is based on the exploitation of cell-directed signaling inhibitors. The broad antiinfective drug artesunate (ART) offers additional therapeutic options such as oral bioavailability and low levels of toxic side-effects. Here, novel ART-derived compounds including dimers and trimers were synthesized showing further improvements over the parental drug. Antiviral activity and mechanistic aspects were determined leading to the following statements: (i) ART exerts antiviral activity towards human and animal herpesviruses, (ii) no induction of ART-resistant HCMV mutants occurred in vitro, (iii) chemically modified derivatives of ART showed strongly enhanced anti-HCMV efficacy, (iv) NF-κB reporter constructs, upregulated during HCMV replication, could be partially blocked by ART treatment, (v) ART activity analyzed in stable reporter cell clones indicated an inhibition of stimulated NF-κB but not CREB pathway, (vi) solid-phase immobilized ART was able to bind to NF-κB RelA/p65, and (vii) peptides within NF-κB RelA/p65 represent candidates of ART binding as analyzed by in silico docking and mass spectrometry. These novel findings open new prospects for the future medical use of ART and ART-related drug candidates.
Authors with CRIS profile
Ina Niemann
Professur für Virologie
Jens Milbradt
Tony Fröhlich Lehrstuhl für Organische Chemie I Christoph Reiter Lehrstuhl für Organische Chemie I Jürgen Einsiedel Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie Nicolas Vogel Lehrstuhl für Biochemie und Molekulare Medizin Thomas Stamminger Professur für Virologie Svetlana Tsogoeva Professur für Organische Chemie Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie
Tony Fröhlich Lehrstuhl für Organische Chemie I Christoph Reiter Lehrstuhl für Organische Chemie I Jürgen Einsiedel Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie Nicolas Vogel Lehrstuhl für Biochemie und Molekulare Medizin Thomas Stamminger Professur für Virologie Svetlana Tsogoeva Professur für Organische Chemie Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie
Additional Organisation(s)
Involved external institutions
Germany (DE)How to cite
APA:
Hutterer, C., Niemann, I., Milbradt, J., Fröhlich, T., Reiter, C., Kadioglu, O.,... Marschall, M. (2015). The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65. Antiviral Research, 124, 101-109. https://dx.doi.org/10.1016/j.antiviral.2015.10.003
MLA:
Hutterer, Corina, et al. "The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65." Antiviral Research 124 (2015): 101-109.
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