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Development and Validation of a High-Throughput Screen for Inhibitors of SARS CoV and Its Application in Screening of a 100,000-Compound Library
1 Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, AL.
* To whom correspondence should be addressed. E-mail: jonsson{at}sri.org.
The authors have developed a high-throughput screen (HTS) that allows for the identification of potential inhibitors of the severe acute respiratory syndrome coronavirus (SARS CoV) from large compound libraries. The luminescent-based assay measures the inhibition of SARS CoV-induced cytopathic effect (CPE) in Vero E6 cells. The assay was validated in 96-well plates in a BSL3 containment facility. The assay is sensitive and robust, with Z values > 0.6, signal to background (S/B) > 16, and signal to noise (S/N) > 3. The assay was further validated with 2 different diversity sets of compounds against the SARS CoV. The "hit" rate for both libraries was approximately 0.01%. The validated HTS assay was then employed to screen a 100,000-compound library against SARS CoV. The hit rate for the library in a single-dose format was determined to be approximately 0.8%. Screening of the 3 libraries resulted in the identification of several novel compounds that effectively inhibited the CPE of SARS CoV in vitro--compounds which will serve as excellent lead candidates for further evaluation. At a 10-µM concentration, 3 compounds with selective indexes (SI50) of > 53 were discovered. Key Words: high-throughput screening, severe acute respiratory syndrome, coronavirus, cytopathic effect
First published on December 22, 2006, doi:10.1177/1087057106296688 This article has been cited by other articles:
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