Project finds dozens of drugs that could block entry or replication of the COVID-19 virus in human cells.
UCSF project could combat this pandemic — and the next one
If our cells could fend off the new coronavirus, it doesn’t matter how awful it is. The virus dies. End of story.
That simple fact is behind an ambitious drug-hunting project led by UC San Francisco molecular biologist Nevan Krogan.
On Thursday, Krogan’s team of 120 international scientists announced the discovery of dozens of existing drugs that, if repurposed, could block entry or replication of the COVID-19 virus in human cells. The research is published in the most recent issue of the journal Nature.
The strategy is very different from the approach used to create antiviral drugs like remdesivir, which attack the virus’s internal machinery.
That effort is focusing on the virus. Krogan’s team is focusing, instead, on us.
Can the drugs help lock and bolt the cellular door to its entry? Or starve or chase it out? That’s what they hope to learn.
“The virus itself cannot live by itself. It cannot replicate by itself. It needs our cells, our genes, our proteins in order to live,” Krogan said at a Thursday news briefing. “So it’d be very advantageous to understand the human genes and proteins that the virus needs.”
The concept, he said, is “targeting the human counterparts and vulnerabilities required for viral infection in a human cell.”
Already, there are several promising candidates. They are now slated for further investigation, and perhaps human trials.
The scientists also discovered something far more disconcerting: a popular over-the-counter cold medicine that actually helps the virus. The studies are just in a lab, not in people. But dextromethorphan, used in cough syrup, tablets and capsules, caused the coronavirus to multiply.
“Obviously, if you have COVID-19, you’re coughing and you’re reaching on the shelf for the cough syrup,” said Krogan, director of the Quantitative Biosciences Institute at UCSF and a
senior investigator at Gladstone Institutes. “It actually appears to be ‘pro viral’ in the laboratory … it actually makes the virus grow better.
“We’re not necessarily recommending that everybody stop taking dextromethorphan for sure,” he said. But “if I had COVID-19, I would think twice about using some of these cough syrups until more information was available to us.”
Normally, Krogan’s lab studies how disease genes interact with proteins in the human body.
But the news of a community-acquired COVID-19 in a woman hospitalized at Mountain View’s El Camino Hospital alarmed him. It told him that the virus could be widespread.
He realigned the focus of his lab. According to a report in the Proceedings of the National Academy of Sciences, he came up with a schedule of lab shifts to work around the clock while maintaining at least 6 feet of space among colleagues. Although a mass spectrometer broke down and the group failed to synthesize three viral proteins, the last pieces of data — revealing which host proteins interacted with viral proteins — came in just as the lab shut down to comply with the state’s shelterin-place orders.
In just a few weeks, Krogan and his collaborators purified 26 of the virus’s 29 proteins and identified more than 300 proteins in our cells that the virus uses to enter, infect and multiply.
They started sorting through chemical libraries of existing drugs that could be candidates for treatment.
Of 69 potential drugs, many are already in the development pipeline or in clinical trials for other diseases. Nearly 25 already are approved by the U. S. Food and Drug Administration. Repurposing existing medicine is faster than developing a new drug from scratch.
Moreover, repurposed drugs already have been through safety trials, proving that medicine won’t cause death. Some are already in production; if they are effective against COVID-19, it would just mean scaling up manufacturing to meet the demand.
There are therapeutic advantages to this human-focused approach, he said. Unlike antiviral drugs that attack the virus, drugs that target the human cells are less likely to induce viral resistance.
“The problem with developing a drug against the virus … it mutates quickly; you can get resistance,” he said. “If you target a human protein that virus needs, you don’t have to worry so much.”
It also would offer hope for the next coronavirus that comes our way, he added.
“Many different viruses target similar human genes and proteins,” he said, “so if we can come up with a therapy here, a treatment that works for COVID-19, it potentially could work for COVID-22, COVID-24 and other viruses as well.”