The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65

Journal article
(Original article)


Publication Details

Author(s): 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
Journal: Antiviral Research
Publication year: 2015
Volume: 124
Pages range: 101-109
ISSN: 1872-9096
Language: English


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.



FAU Authors / FAU Editors

Einsiedel, Jürgen Dr.
Lehrstuhl für Pharmazeutische Chemie
Fröhlich, Tony
Lehrstuhl für Organische Chemie I
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Milbradt, Jens PD Dr.
Sonderforschungsbereich 796 (mit integriertem Graduiertenkolleg) Steuerungsmechanismen mikrobieller Effektoren in Wirtszellen
Niemann, Ina
Professur für Virologie
Reiter, Christoph
Lehrstuhl für Organische Chemie I
Stamminger, Thomas Prof. Dr.
Professur für Virologie
Tsogoeva, Svetlana Prof. Dr.
Professur für Organische Chemie
Vogel, Nicolas Dr.
Lehrstuhl für Biochemie und Molekulare Medizin


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


External institutions with authors

Evotec AG
Johannes Gutenberg-Universität Mainz


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.

BibTeX: 

Last updated on 2019-18-07 at 07:22

Share link