|Chaitan Khosla, professor of chemistry, biochemistry and chemical engineering at Stanford|
Viruses have long tripped up drug development efforts thanks to their ability to take refuge within human cells. So instead of targeting a specific virus with a specific drug, Stanford scientists have used an abandoned GlaxoSmithKline ($GSK) drug to boost human cells' ability to defend themselves against viruses in vitro.
The [email protected] center is funded by an NIAID grant and aims to develop antiviral strategies using a "one drug, multiple bugs" approach rather than the traditional "one drug, one bug" concept. The team was aware of a GSK drug, GSK983, a tetrahydrocarbazole, that seemed to be what they were seeking, but was shelved, the university said in a statement Monday.
They pitted the drug against dengue virus and Venezuelan equine encephalitis virus (VEEV). While it enabled human cells in a lab dish to fend off the viruses, it didn't work quite perfectly and also caused the cells to stop dividing after 24 hours of treatment.
Michael Bassik, a senior author and professor of genetics at Stanford, used shRNA and CRISPR-Cas9 screens to pinpoint how GSK983 works. It blocks a protein that is essential for producing the building blocks of RNA, which some viruses use as their genetic material. "Most of the really nasty viruses use RNA," said Chaitan Khosla, a senior author of the paper, in the statement. Without the ability to produce RNA components, the viruses were unable to make more of themselves. But it was a double-edged sword: cells need to produce DNA to replicate, and DNA and RNA have some common building blocks. When they ran out of these shared components, they stopped dividing.
The drug also left a back door for viruses: cells need RNA too, and can either produce it or import components from the bloodstream. While RNA production was blocked, the cells could still pick up RNA ingredients from the blood, thus making it available to the viruses hiding within them.
Khosla warned that the drug has proved effective only in a lab dish and on certain viruses. His team is going full speed ahead, already testing it in combination with a drug that will block the import pathway, and planning animal studies to test safety and determine which viruses the treatment would be most effective against. To tackle toxicity, they tried feeding the cells components that can be used to build DNA but not RNA. The cells kept dividing normally while successfully fending off dengue and VEEV.