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

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 dis...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-03, Vol.19 (6), p.1636-1638
Main Authors: LEE, Chaewoon, JIN MOO LEE, LEE, Na-Ra, JIN, Bong-Suk, KYOUNG JIN JANG, KIM, Dong-Eun, JEONG, Yong-Joo, CHONG, Youhoon
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Binding Sites
Biological and medical sciences
Chemistry, Pharmaceutical - methods
DNA - chemistry
DNA Helicases - chemistry
Drug Design
Fluorescence Resonance Energy Transfer
Inhibitory Concentration 50
Ions
Keto Acids - chemistry
Medical sciences
Models, Chemical
Nucleoside-Triphosphatase - chemistry
Pharmacology. Drug treatments
Phosphates - chemistry
SARS coronavirus
SARS Virus - enzymology
Structure-Activity Relationship
Zinc - chemistry
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.02.010