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Coronavirus Biology and Pathogenesis
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Approaches to Vaccines and Drug Development
Blocking SARS Virus Fusion
Lessons in Interventions for SARS
Status of Drug Screening vs. SARS
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SARS in the Context of Emerging Infectious Threats SARS in the Context of Emerging Infectious Threats
Approaches to Vaccines and Drug Development
Status of Drug Screening vs. SARS

Catherine Laughlin, National Institute of Allergy and Infectious Diseases, Bethesda
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Highlights

Collaborative Screening of Drugs
• CDC, USAMRIID, and NIAID have are exploiting an existing collaboration to screen drugs against the SARS pathogen.
• FDA is following the screening to be prepared to act quickly on any potential drugs.
• To protect intellectual property of sponsors providing agents for testing, a single material transfer agreement / CRADA is being used.
• Jack Secrist at Southern Research Institute contacts sponsors, acquires compounds, puts compounds under code for testing, and returns data to sponsors.

Screening Assay
• An in vitro CPE-based assay is based on Neutral Red uptake, measuring living cells. • Capacity for testing is 400 compounds per week.
• Follow-up assays are more intensive for plaque or yield reduction.
• Testing is done on Vero E6 cells in 96-well plates, with four drugs and five dilutions per plate, covering 625 dilution-range concentrations from 1 to 100 micrograms per milliliter.
• Fifty percent inhibitory contentration is measured.
• The window of killing virus without killing cells is the selective index; ten or better is preferred but initial screening looks for anything over two.
• One hundred and twenty compounds have been screened; those with activity have been beta-interferon, rimantadine, and cysteine protease inhibitors.

Possible Viral Therapeutic Targets
• Cysteine protease inhibitors.
• RNA-dependent RNA polymerase.
• Helicase activity.
• Other targets in genome replication and transcription.
• Assemblyosome.
• N protein.
• Fusion between virus and host, or cell-to cell fusion.

Testing Priorities (beginning with highest)
• FDA-approved antiviral drugs.
• Antiviral drugs in clinical development for other indications.
• FDA-approved drugs for anything that also work against SARS.

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