A BSL-4 high-throughput screen identifies sulfonamide inhibitors of Nipah virus

Assay Drug Dev Technol. 2014 Apr;12(3):155-61. doi: 10.1089/adt.2013.567.

Abstract

Nipah virus is a biosafety level 4 (BSL-4) pathogen that causes severe respiratory illness and encephalitis in humans. To identify novel small molecules that target Nipah virus replication as potential therapeutics, Southern Research Institute and Galveston National Laboratory jointly developed an automated high-throughput screening platform that is capable of testing 10,000 compounds per day within BSL-4 biocontainment. Using this platform, we screened a 10,080-compound library using a cell-based, high-throughput screen for compounds that inhibited the virus-induced cytopathic effect. From this pilot effort, 23 compounds were identified with EC50 values ranging from 3.9 to 20.0 μM and selectivities >10. Three sulfonamide compounds with EC50 values <12 μM were further characterized for their point of intervention in the viral replication cycle and for broad antiviral efficacy. Development of HTS capability under BSL-4 containment changes the paradigm for drug discovery for highly pathogenic agents because this platform can be readily modified to identify prophylactic and postexposure therapeutic candidates against other BSL-4 pathogens, particularly Ebola, Marburg, and Lassa viruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / chemistry*
  • Chlorocebus aethiops
  • Containment of Biohazards / instrumentation
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / instrumentation*
  • Equipment Design
  • Equipment Failure Analysis
  • High-Throughput Screening Assays / instrumentation*
  • Nipah Virus / drug effects*
  • Nipah Virus / physiology*
  • Robotics / instrumentation
  • Sulfonamides / antagonists & inhibitors*
  • Vero Cells
  • Virus Replication / drug effects*
  • Virus Replication / physiology

Substances

  • Antiviral Agents
  • Sulfonamides