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UCSF-led Team Wins $112M NIH Grant to Harness Omics Tools for Antiviral Target, Drug Development

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NEW YORK – Backed by $112 million in funding from the National Institutes of Health, a team led by researchers at the University of California, San Francisco's Quantitative Biosciences Institute (QBI) is applying a variety of omics tools to identify antiviral drug targets and agents against a wide range of pathogens.

The effort, which will be run by QBI's Coronavirus Research Group (QCRG), builds on work done throughout the COVID-19 pandemic by QBI researchers and their collaborators using protein-protein interaction studies to identify proteins that could potentially be targeted by anti-SARS-CoV-2 drugs.

The QCRG group is one of nine research teams receiving funding from the NIH's National Institute of Allergy and Infectious Diseases (NIAID) to establish Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern. The NIAID announced last week that it awarded roughly $577 million in funding to these nine AViDD groups. The QCRG received an initial award of $67.5 million to cover the first three years of research and is slated to receive a total of $112 million over five years, said Nevan Krogan, director of the QBI and principal investigator on the QCRG AViDD project.

In addition to the QBI team, the QCRG brings together 43 researchers from 14 institutions around the world, including Jennifer Doudna, professor of molecular and cell biology and chemistry at the University of California, Berkeley, and one of the developers of the CRISPR gene editing technology.

Krogan said the group is also collaborating with drugmaker Roche, which he noted brings its drug development expertise to the project.

"They have a lot greater capability to take [any drug candidate] through the pipeline, get it in people, get it into clinical trials, and ultimately get it approved so that we can use it," he said.

The QCRG will continue to focus on identifying drug targets for SARS-CoV-2 but will also explore targets in eight other virus families — Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, Hantaviridae, Arenaviridae, Nairoviridae, and Paramyxoviridae.

Krogan said the hope is that the researchers will identify targets that are shared across several viral families.

NIAID "wants pan-viral drugs," he said. "So we've used our tools in an integrated way to study not just the viral proteins of SARS-CoV-2 but for other coronaviruses as well as other virus families that they wanted us to target — other viruses that have the potential to become pandemic viruses."

Pandemic work by Krogan and his collaborators provides something of a starting point for the new project. In an April 2020 Nature study, the researchers detailed a workflow using an experimental setup for identifying virus-host protein interactions they had devised pre-pandemic.

In that work, they generated protein expression plasmids for almost all of the proteins predicted by the SARS-CoV-2 genome and transfected these plasmids into human HEK293T cells. Following expression of the proteins, they lysed the cells and pulled down the viral proteins using affinity purification. This was followed by mass spectrometry analysis to identify human proteins bound to the viral proteins.

They then explored what molecules might disrupt these interactions by looking for ligands of the human proteins using chemoinformatics and literature searches, identifying 69 agents targeting 63 of the human interactors. The researchers then performed viral assays to screen the identified compounds for effectiveness in countering SARS-CoV-2.

Krogan said that this protein-protein interaction work will be a key component of the QCRG's AViDD project but added that he and his team are looking to target other viral molecules, including RNA.

One difference between the group's original SARS-CoV-2 work and the AViDD project is that NIAID has instructed the researchers to target viral proteins, as opposed to host proteins, which were the primary focus of the original research.

Krogan said that the NIAID's focus on so-called "direct acting" agents that go after viral protein targets likely stemmed from a desire to limit side effects. He also suggested that it was informed by the success HIV drugs had in targeting viral proteins, noting that many in NIAID leadership had been active in this work.

That said, understanding viral-host protein interactions will still be important to identifying promising targets.

"Viral proteins can't exist by themselves," Krogan said. "They need human proteins in order to infect cells, so knowing what the repertoire of human proteins is will almost certainly be beneficial as we develop direct-acting antivirals. So that will definitely be a component of it."

In terms of the targets the group is currently exploring, Krogan said he and his colleagues were looking at proteases and polymerases as well as structural proteins like the envelope proteins E and M that exist in all or most viruses.

"And then we are looking at things that people haven't really looked at," he said. "For example, there's a region in a protease in SARS-CoV-2 called the macro domain, which is involved in modulating our immune response. That domain also exists in Chikungunya [virus] in a very different protein."

Krogan suggested that as novel as the research was the amount of funding being provided, noting that the grants were "four or five times larger than anything I've ever seen."

"I think it's incredibly exciting that the government and NIH are putting this much money into this science," he said. "The onus is on us to use the money in a way that helps people."

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