Identification and characterization of nonsubstrate based inhibitors of the essential dengue and West Nile virus proteases

Vannakambadi K. Ganesh, Nik Muller, Ken Judge, Chi Hao Luan, Radhakrishnan Padmanabhan, Krishna H M Murthy

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Using the structure of the dengue serine protease complexed with a protein inhibitor as a template, five inhibitory compounds were identified and characterized against Dengue and West Nile viral proteases. The 72 known members of the flavivirus genus include lethal human pathogens such as Yellow Fever, West Nile, and Dengue viruses. There is at present no known chemotherapy for any flavivirus and no effective vaccines for most. A common genomic organization and molecular mechanisms of replication in hosts are shared by flaviviruses with a viral serine protease playing a pivotal role in processing the viral polyprotein into component polypeptides, an obligatory step in viral replication. Using the structure of the dengue serine protease complexed with a protein inhibitor as a template, we have identified five compounds, which inhibit the enzyme. We also describe parallel inhibitory activity of these compounds against the West Nile virus Protease. A few of the compounds appear to provide a template for design of more potent and specific inhibitors of the dengue and West Nile virus proteases. Sequence similarities among flaviviral proteases suggests that such compounds might also possibly inhibit other flaviviral proteases.

Original languageEnglish (US)
Pages (from-to)257-264
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number1
DOIs
StatePublished - Jan 3 2005

Keywords

  • Dengue
  • Drug design
  • Flavivirus
  • Inhibitor
  • Protease
  • West Nile

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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