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Researchers to revisit drug trials for major viruses

Stanford scientists have relaunched research on a previously shelved category of drugs, known as broad-spectrum antiviral drugs, in the hope that it will reveal information about new strategies to fight both difficult-to-combat viruses such as dengue and ebola, along with cancer.

This research, published in Nature Chemical Biology, was headed by the two senior authors of the paper, assistant professor of genetics Michael Bassik and professor of chemistry Chaitan Khosla.

The project itself is part of a larger initiative headed by associate professor of medicine Jeffrey Glenn. Glenn started the U19 Center for Excellence in Translational Research, which aims to identify new strategies to fight viruses. One technique is to develop drugs that target the host cell rather than the virus itself.

“Viruses are very good at mutating and changing their activities, and so often you get resistant viruses that come up very quickly,” Bassik said. “This new class of drugs…that target the host cell processes are much more likely to be applied to a wide range of viruses, and the viruses [are] much less likely to be able to mutate around that activity.”

The drug was originally a product of GlaxoSmithKline, a British pharmaceutical company. The company had performed a chemical screen to identify compounds that blocked viral replication, and one in particular, GSK983, proved very successful. After further studies, however, the company decided to halt research.

“They probably spent, without exaggeration, hundreds of millions of dollars researching this drug,” Bassik said. “But then they stopped working on it, and we still don’t know why that is.”

To study how the mechanisms behind the drug’s function, these researchers used two screening techniques: shRNA and CRISPR-Cas9. Both work by reducing or deleting expression of individual genes and assessing the resulting activity of the drug. shRNA reduces expression by up to 90 percent, while CRISPR-Cas9 effectively stops all expression. Using both techniques allows researchers to study which genes interact with the drug.

The researchers discovered that the drug operated by inhibiting the activity of dihydroorotate dehydrogenase (DHODH), a protein that appears early on in the pathway the cell uses to synthesize pyrimidines, which are simple building blocks of nucleic acids such as DNA and RNA. The virus, unable to use the cell’s hijacked nucleotide synthesis mechanisms to replicate itself, dies. However, the main problem with this drug is that cells can also gather the building blocks for nucleic acids from the blood.

Future research aims to halt the cell’s absorption of these building blocks from the blood, thus preventing both pathways from building RNA needed for viral replication.

“The idea is to block the two pathways together,” said Ayse Okesli, a postdoctoral research fellow in chemistry. “[to inhibit] uptake from the blood, in addition to synthesis from scratch. And then, hopefully, we will have a good strategy to go forward to work in humans.”

Okesli also comments on the applicability of this research to tackle other problems. One such problem is cancer research which, likewise, relies on DNA/RNA synthesis in order to propagate.

“It’s pretty real” said Okesli. “Academic projects don’t always apply to life this easily. This is a cool project that has a potential to change many people’s lives in the future.”

Correction: A previous version of this article spelled Ayse Okesli’s last name as “Okelsi.” Additionally, references to protein synthesis were changed to nucleotide synthesis and a clarification was added to distinguish shRNA and CRISPR-Cas9. The Daily regrets these errors. 

Contact Aulden Foltz at [email protected]

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