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Antiviral Res. 2015 Dec;124:101-9. doi: 10.1016/j.antiviral.2015.10.003. Epub 2015 Nov 4.

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

Author information

1
Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
2
Institute of Organic Chemistry I, FAU, Erlangen, Germany.
3
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
4
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, FAU, Erlangen, Germany.
5
Institute for Biochemistry, Biochemistry and Molecular Medicine, Emil Fischer Center, FAU, Erlangen, Germany.
6
Evotec Munic AG, Martinsried, Germany.
7
Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: manfred.marschall@viro.med.uni-erlangen.de.

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.

KEYWORDS:

Artesunate and chemical derivatives; Binding of artesunate to NF-κB RelA/p65; Broad antiviral activity; Human cytomegalovirus; Increase of antiviral efficacy; Interference with NF-κB signaling pathways

PMID:
26546752
DOI:
10.1016/j.antiviral.2015.10.003
[Indexed for MEDLINE]

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