Aryl diketoacids (ADK) selectively inhibit duplex DNA-unwinding activity of SARS coronavirus NTPase/helicase

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1636-8. doi: 10.1016/j.bmcl.2009.02.010. Epub 2009 Feb 9.

Abstract

As anti-HCV aryl diketoacids (ADK) are good metal chelators, we anticipated that ADKs might serve as potential inhibitors of SARS CoV (SCV) NTPase/helicase (Hel) by mimicking the binding modes of the bismuth complexes which effectively competes for the Zn(2+) ion binding sites in SCV Hel thereby disrupting and inhibiting both the NTPase and helicase activities. Phosphate release assay and FRET-based assay of the ADK analogues showed that the ADKs selectively inhibit the duplex DNA-unwinding activity without significant impact on the helicase ATPase activity. Also, antiviral activities of the ADKs were shown dependent upon the substituent. Taken together, these results suggest that there might be ADK-specific binding site in the SCV Hel, which warrants further investigations with diverse ADKs to provide valuable insights into rational design of specific SCV Hel inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chemistry, Pharmaceutical / methods*
  • DNA / chemistry*
  • DNA Helicases / chemistry*
  • Drug Design
  • Fluorescence Resonance Energy Transfer
  • Inhibitory Concentration 50
  • Ions
  • Keto Acids / chemistry*
  • Models, Chemical
  • Nucleoside-Triphosphatase / chemistry*
  • Phosphates / chemistry
  • Severe acute respiratory syndrome-related coronavirus / enzymology*
  • Structure-Activity Relationship
  • Zinc / chemistry

Substances

  • Ions
  • Keto Acids
  • Phosphates
  • DNA
  • Nucleoside-Triphosphatase
  • DNA Helicases
  • Zinc