Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses

Autoren

Thomas Efferth
Manfred Marschall
Xin Wang
Shu-Mei Huong
Ilona Hauber
Armin Olbrich
Martina Kronschnabl
Thomas Stamminger
Eng-Shang Huang

DOI

10.1007/s00109-001-0300-8

eISSN

1432-1440

ISSN

0946-2716

Ausgabe der Veröffentlichung

4

Zeitschrift

Journal of Molecular Medicine

Sprache

en

Online publication date

2001

Paginierung

233 - 242

Datum der Veröffentlichung

2002

Status

Published

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1007/s00109-001-0300-8

Datum der Datenerfassung

2019

Titel

Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses

Ausgabe der Zeitschrift

80

Data source: Crossref

Abstract

Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 microM and 6.9+/-0.2 microM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunate-sensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades.

Addresses

Virtual Campus Rhineland-Palatinate, P.O. Box 4380, 55033 Mainz, Germany. efferth@vcrp.de

Autoren

Thomas Efferth
Thomas Efferth
Manfred Marschall
Xin Wang
Shu-Mei Huong
Ilona Hauber
Armin Olbrich
Martina Kronschnabl
Thomas Stamminger
Eng-Shang Huang

DOI

10.1007/s00109-001-0300-8

eISSN

1432-1440

Externe Identifier

PubMed Identifier: 11976732

Funding acknowledgements

NIAID NIH HHS: AIO47438
NCI NIH HHS: CA19014

Open access

false

ISSN

0946-2716

Ausgabe der Veröffentlichung

4

Zeitschrift

Journal of molecular medicine (Berlin, Germany)

Schlüsselwörter

Cells, Cultured
Humans
Simplexvirus
Cytomegalovirus
Sesquiterpenes
Artemisinins
Ganciclovir
Ribosomal Protein S6 Kinases
NF-kappa B
Luminescent Proteins
Green Fluorescent Proteins
Proto-Oncogene Proteins
DNA, Viral
Protein Kinase Inhibitors
Antiviral Agents
Microbial Sensitivity Tests
Drug Resistance, Viral
Virus Replication
Sp1 Transcription Factor
Proto-Oncogene Proteins c-akt
Viral Plaque Assay
Artesunate
Protein Serine-Threonine Kinases

Sprache

eng

Medium

Print-Electronic

Online publication date

2001

Paginierung

233 - 242

Datum der Veröffentlichung

2002

Status

Published

Datum der Datenerfassung

2002

Titel

Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses.

Sub types

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

Ausgabe der Zeitschrift

80

Data source: Europe PubMed Central

Abstract

Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 microM and 6.9+/-0.2 microM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunate-sensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades.

Date of acceptance

2001

Autoren

Thomas Efferth
Manfred Marschall
Xin Wang
Shu-Mei Huong
Ilona Hauber
Armin Olbrich
Martina Kronschnabl
Thomas Stamminger
Eng-Shang Huang

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/11976732

DOI

10.1007/s00109-001-0300-8

Funding acknowledgements

NIAID NIH HHS: AIO47438
NCI NIH HHS: CA19014

ISSN

0946-2716

Ausgabe der Veröffentlichung

4

Zeitschrift

J Mol Med (Berl)

Schlüsselwörter

Antiviral Agents
Artemisinins
Artesunate
Cells, Cultured
Cytomegalovirus
DNA, Viral
Drug Resistance, Viral
Ganciclovir
Green Fluorescent Proteins
Humans
Luminescent Proteins
Microbial Sensitivity Tests
NF-kappa B
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases
Sesquiterpenes
Simplexvirus
Sp1 Transcription Factor
Viral Plaque Assay
Virus Replication

Sprache

eng

Country

Germany

Paginierung

233 - 242

Datum der Veröffentlichung

2002

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2002

Titel

Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses.

Sub types

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

Ausgabe der Zeitschrift

80

Data source: PubMed

Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses

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