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.
• 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.
• 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.