A way to combat viruses by targeting host-cell proteins

Every two years, Bio-X provides seed funding to interdisciplinary projects that could lead to innovative improvements in human health. Since 2000, these Bio-X Interdisciplinary Initiatives Program seed grants have funded 141 research collaborations, connecting hundreds of faculty. The proof-of-concept projects have produced hundreds of scientific publications, dozens of patents and more than a tenfold return on research funds to Stanford. This is one of the research projects that has received a Bio-X grant.

Shirit Einav

When a virus infects a person, it hijacks the body's natural processes in order to fuel its rampage.

A pair of Stanford scientists aims to turn this strength into a weakness and develop what could become a broad-spectrum antiviral drug.

Most antiviral drugs are concocted to act against a specific viral protein. As such, they usually provide a "one drug/one bug" approach.

"Penicillin can kill many types of bacteria, but most antiviral drugs work only against one virus, and sometimes a single subtype of a virus," said Shirit Einav, MD, an assistant professor of medicine and of microbiology and immunology.

Additionally, targeting viral proteins is problematic; viruses can mutate quickly, and a single change in the viral sequence can render it fully resistant to the drug.

"With the exception of HIV, we still have very few antiviral drugs to offer patients with viral infections, and even those are often quite limited," Einav said. "No approved antiviral drugs or vaccines are available for emerging viruses, such as dengue, which pose major challenges to global health."

Viruses live within our cells and rely upon host cell machineries in order to replicate. Instead of targeting the virus directly, the solution, Einav said, may be to instead interfere with host cell proteins that are utilized by multiple viruses. "We treat diabetes and hypertension by targeting host proteins, so why not viral infections?" Einav said.

With support from Stanford's Bio-X Interdisciplinary Initiatives Program, Einav and Stephen Quake, PhD, professor of bioengineering and of applied physics, have developed a process of identifying human proteins that wide families of viruses depend on for their success.

The initial focus of the work has involved identifying host proteins that, if knocked out, could inhibit both hepatitis C virus and HIV. This requires combing through incredibly large libraries of thousands of proteins, and a careful understanding of their role in both the virus and the host.

To find the needle in the haystack, Einav and Quake have developed a sequential approach that integrates advanced proteomic technologies with genomic and molecular virology approaches. The researchers have developed a high-fidelity platform that uses microfluidic chips created by Quake to express small amounts of a wide variety of host and viral proteins, and screens for direct interactions between them. This innovative proteomic technology overcomes some important limitations of existing technologies, such as ability to study weak and transient protein interactions, and those involving membrane proteins.

Once the researchers discover a positive protein interaction between virus and host, they knock out the corresponding host gene in an infected cell to determine if the protein plays a vital role in the virus' life cycle. If it does, they then investigate whether other viruses require this protein.

Stephen Quake

In just a year, the researchers have shown that this approach can accurately identify host proteins or pathways that play critical roles in multiple infections by unrelated viruses. Based primarily on this work, the researchers are building a catalog of such overlapping host proteins that represent potential attractive targets for broad-spectrum antivirals.

The Einav lab has also produced proof-of-concept evidence that drugs that are already approved by the Food and Drug Administration for other indications, and target host proteins required by multiple viruses, could be repurposed as broad spectrum antivirals, with activity against hepatitis C virus, HIV, as well as the currently untreatable dengue and Ebola viruses.

"We have to make sure that the single targeted protein is absolutely crucial to multiple viruses," Einav said. "At the same time, we need to make sure that the drug that inhibits this host protein is safe. As long as viral replication is inhibited at a drug level that is not toxic and allows the host cell to function as close to normal as possible, this could work.

"This is just the beginning, but the more we look, the more we find.

"Bio-X has really made this possible for me," Einav said. "I'm a new assistant professor, and this is essentially defined as discovery-based research, which is very difficult to get funded by conventional funding mechanisms. Many funding agencies want you to catch, prepare and cook the fish, and they will provide you funding just before you take the first bite. So to get early-stage funding for high-risk but high-reward research like this is really quite remarkable."


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