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

Autoren

Corina Hutterer
Ina Niemann
Jens Milbradt
Tony Fröhlich
Christoph Reiter
Onat Kadioglu
Hanife Bahsi
Isabel Zeitträger
Sabrina Wagner
Jürgen Einsiedel
Peter Gmeiner
Nico Vogel
Sebastian Wandinger
Klaus Godl
Thomas Stamminger
Thomas Efferth
Svetlana B Tsogoeva
Manfred Marschall

DOI

10.1016/j.antiviral.2015.10.003

ISSN

0166-3542

Zeitschrift

Antiviral Research

Sprache

en

Paginierung

101 - 109

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.antiviral.2015.10.003

Datum der Datenerfassung

2020

Titel

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

Ausgabe der Zeitschrift

124

Data source: Crossref

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.

Addresses

Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.

Autoren

Corina Hutterer
Ina Niemann
Jens Milbradt
Tony Fröhlich
Christoph Reiter
Onat Kadioglu
Hanife Bahsi
Isabel Zeitträger
Sabrina Wagner
Jürgen Einsiedel
Peter Gmeiner
Nico Vogel
Sebastian Wandinger
Klaus Godl
Thomas Stamminger
Thomas Efferth
Thomas Efferth
Svetlana B Tsogoeva
Manfred Marschall

DOI

10.1016/j.antiviral.2015.10.003

eISSN

1872-9096

Externe Identifier

PubMed Identifier: 26546752

Funding acknowledgements

Wilhelm Sander-Stiftung: 2011.085.1/2
Deutsche Forschungsgemeinschaft: SFB796/C3
Deutsche Forschungsgemeinschaft: I1/M.M.-C.H
Deutsche Forschungsgemeinschaft: MA 1289/7-1
Bayerische Forschungsstiftung:

Open access

false

ISSN

0166-3542

Zeitschrift

Antiviral research

Schlüsselwörter

Humans
Herpesviridae
Cytomegalovirus
Artemisinins
NF-kappa B
Antiviral Agents
Drug Resistance, Viral
Signal Transduction
Up-Regulation
Mutation
Cyclic AMP Response Element-Binding Protein
Transcription Factor RelA
Transcriptional Activation
HEK293 Cells
Artesunate

Sprache

eng

Medium

Print-Electronic

Online publication date

2015

Paginierung

101 - 109

Datum der Veröffentlichung

2015

Status

Published

Datum der Datenerfassung

2015

Titel

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

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

124

Data source: Europe PubMed Central

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.

Date of acceptance

2015

Autoren

Corina Hutterer
Ina Niemann
Jens Milbradt
Tony Fröhlich
Christoph Reiter
Onat Kadioglu
Hanife Bahsi
Isabel Zeitträger
Sabrina Wagner
Jürgen Einsiedel
Peter Gmeiner
Nico Vogel
Sebastian Wandinger
Klaus Godl
Thomas Stamminger
Thomas Efferth
Svetlana B Tsogoeva
Manfred Marschall

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26546752

DOI

10.1016/j.antiviral.2015.10.003

eISSN

1872-9096

Zeitschrift

Antiviral Res

Schlüsselwörter

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
Antiviral Agents
Artemisinins
Artesunate
Cyclic AMP Response Element-Binding Protein
Cytomegalovirus
Drug Resistance, Viral
HEK293 Cells
Herpesviridae
Humans
Mutation
NF-kappa B
Signal Transduction
Transcription Factor RelA
Transcriptional Activation
Up-Regulation

Sprache

eng

Country

Netherlands

Paginierung

101 - 109

PII

S0166-3542(15)30008-5

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

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

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

124

Data source: PubMed

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

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