Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses

Lieve Naesens, Chad E. Stephens, Graciela Andrei, Arianna Loregian, Leen De Bolle, Robert Snoeck, J. Walter Sowell, Erik De Clercq

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure. The benzene-fused derivative 2H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred ≥95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalAntiviral Research
Volume72
Issue number1
DOIs
StatePublished - Oct 1 2006

Fingerprint

Human Herpesvirus 6
Benzene Derivatives
Cytomegalovirus
Human Activities
Foscarnet
Antiviral Agents
Viral DNA
Catalytic Domain
Human Herpesvirus 7
Thiazines
Thiophenes
Ganciclovir
Enzyme Assays
DNA-Directed DNA Polymerase
Viruses
Gene Expression
Polymerase Chain Reaction
DNA
Genes
Proteins

Keywords

  • Antiviral
  • Arylsulfone derivative
  • Betaherpesvirus
  • Cytomegalovirus
  • Human herpesvirus 6

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses. / Naesens, Lieve; Stephens, Chad E.; Andrei, Graciela; Loregian, Arianna; De Bolle, Leen; Snoeck, Robert; Sowell, J. Walter; De Clercq, Erik.

In: Antiviral Research, Vol. 72, No. 1, 01.10.2006, p. 60-67.

Research output: Contribution to journalArticle

Naesens, L, Stephens, CE, Andrei, G, Loregian, A, De Bolle, L, Snoeck, R, Sowell, JW & De Clercq, E 2006, 'Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses', Antiviral Research, vol. 72, no. 1, pp. 60-67. https://doi.org/10.1016/j.antiviral.2006.03.013
Naesens, Lieve ; Stephens, Chad E. ; Andrei, Graciela ; Loregian, Arianna ; De Bolle, Leen ; Snoeck, Robert ; Sowell, J. Walter ; De Clercq, Erik. / Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses. In: Antiviral Research. 2006 ; Vol. 72, No. 1. pp. 60-67.
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AB - Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure. The benzene-fused derivative 2H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred ≥95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.

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