Anthracene-based inhibitors of dengue virus NS2B-NS3 protease

Suzanne M. Tomlinson, Stanley Watowich

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Dengue virus (DENV) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (CDC, 2010), Australia (Hanna et al., 2009), Taiwan (Kuan et al., 2010) and France (La Ruche et al., 2010). DENV infection can cause significant disease, including dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and death. There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B-NS3 protease complex provides a strategic target for antiviral drug development since NS3 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the DENV protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (Tomlinson et al., 2009a). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four " second series" analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between ∼2- and 60-fold, resulting in selective low micromolar dengue protease inhibitors.

Original languageEnglish (US)
Pages (from-to)127-135
Number of pages9
JournalAntiviral Research
Volume89
Issue number2
DOIs
StatePublished - Feb 2011

Fingerprint

Dengue
Severe Dengue
Dengue Virus
Peptide Hydrolases
Antiviral Agents
Structure-Activity Relationship
Flavivirus
Structural Models
Virus Diseases
Centers for Disease Control and Prevention (U.S.)
Virus Replication
Protease Inhibitors
Culicidae
Taiwan
Developed Countries
Developing Countries
France
Disease Outbreaks
Vaccines
Cell Culture Techniques

Keywords

  • Dengue virus
  • Flavivirus
  • NS2B-NS3
  • Protease
  • Small-molecule inhibitor

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Anthracene-based inhibitors of dengue virus NS2B-NS3 protease. / Tomlinson, Suzanne M.; Watowich, Stanley.

In: Antiviral Research, Vol. 89, No. 2, 02.2011, p. 127-135.

Research output: Contribution to journalArticle

Tomlinson, Suzanne M. ; Watowich, Stanley. / Anthracene-based inhibitors of dengue virus NS2B-NS3 protease. In: Antiviral Research. 2011 ; Vol. 89, No. 2. pp. 127-135.
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