title: The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-κB) pathway by targeting RelA/p65.
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.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Hutterer
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Niemann
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
authors.affiliation: Institute of Organic Chemistry I, FAU, Erlangen, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Institute of Organic Chemistry I, FAU, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reiter
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Onat
authors.initials: O
authors.lastname: Kadioglu
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Hanife
authors.initials: H
authors.lastname: Bahsi
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zeitträger
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, FAU, Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, FAU, Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Institute for Biochemistry, Biochemistry and Molecular Medicine, Emil Fischer Center, FAU, Erlangen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Vogel
authors.affiliation: Evotec Munic AG, Martinsried, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wandinger
authors.affiliation: Evotec Munic AG, Martinsried, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Godl
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Institute of Organic Chemistry I, FAU, Erlangen, Germany.
authors.forename: Svetlana B
authors.initials: SB
authors.lastname: Tsogoeva
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: manfred.marschall@viro.med.uni-erlangen.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D000077332:Artesunate; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D024882:Drug Resistance, Viral; D057809:HEK293 Cells; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D000998:Antiviral Agents; D037621:Artemisinins; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000077332:Artesunate
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