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Related Concept Videos

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Inhibitors of Viral Protein Synthesis

Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
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Identification of iNOS inhibitors using InteraX.

Philip R Mallinder1, Alan V Wallace, Gary Allenby

  • 1Department of Molecular Biology, AstraZeneca R&D Charnwood, Loughborough, UK. philip.mallinder@astrazeneca.com

Journal of Biomolecular Screening
|February 13, 2009
PubMed
Summary

A new high-throughput screening assay identified novel inhibitors of inducible nitric oxide synthase (iNOS) dimerization. This assay also revealed compounds that inhibit already formed iNOS dimers, offering new therapeutic avenues.

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Area of Science:

  • Biochemistry
  • Enzymology
  • Drug Discovery

Background:

  • Inducible nitric oxide synthase (iNOS) functions as a homodimer.
  • Identifying iNOS dimerization inhibitors is crucial for therapeutic development.
  • Existing assays may not capture all inhibition mechanisms.

Purpose of the Study:

  • To develop a high-throughput screening (HTS) assay for identifying inhibitors of iNOS dimerization.
  • To characterize the assay's performance with known iNOS inhibitors.
  • To discover novel compounds that inhibit iNOS dimerization or activity.

Main Methods:

  • Utilized the InteraX enzyme complementation technology with chimeric beta-galactosidase and iNOS oxygenase domains.
  • Screened approximately 800,000 compounds in a 384-well format.
  • Performed IC50 and cytotoxicity assays for hit confirmation and characterization.

Main Results:

  • The assay successfully identified compounds that decrease beta-galactosidase activity, indicating iNOS dimerization inhibition.
  • Surprisingly, the assay also detected compounds increasing activity, similar to known inhibitors of dimeric iNOS.
  • 182 novel compounds were identified as potential arginine-competitive inhibitors of dimeric iNOS after rigorous screening and validation.

Conclusions:

  • The developed iNOS InteraX assay is effective for HTS of iNOS dimerization inhibitors.
  • The assay's ability to detect different inhibition profiles broadens its utility.
  • This study identified promising novel compounds for targeting iNOS, potentially for inflammatory diseases.