UCSFled team uncovers virus’ weakness, potential treatment
A global team of scientists led by UCSF has discovered a range of existing drugs and experimental compounds that block the new coronavirus in lab tests, revealing some of the virus’ key weaknesses for the first time. Their findings point to possible treatments for COVID19, according to a paper released Thursday in the journal Nature.
“We’ve found something about this virus that I hope can help people,” said Nevan Krogan, a molecular biologist who directs the Quantitative Biosciences Institute at UCSF, where 22 labs have worked on the project along with teams at the Icahn School of Medicine at Mount Sinai in New York and the Institut Pasteur in Paris.
The research grew from a unique system developed by the biosciences institute to understand how viruses wreak havoc on the body.
Scientists first created a detailed map of how the coro
navirus manipulates human proteins to infect cells and replicate like mad. They then used the map to find existing drugs and experimental compounds that act on those key proteins. Finally, in the lab, they tested 47 of those drug candidates against the virus, to see if the drugs interfered with infection.
According to the new paper, the tests identified two main classes of drugs and compounds that blocked the virus in different ways. Five of the drugs that showed an antiviral effect are already approved by the Food and Drug Administration to fight mental illness, malaria, menopause, coughs and allergies.
None of the five is approved to treat COVID19, and some have dangerous side effects. The paper cautions that people with the disease should not take the drugs outside of controlled studies.
One is hydroxychloroquine, a malaria treatment championed by President Trump, who has promoted it as a COVID19 cure against the advice of health experts. Hydroxychloroquine can be toxic to the heart, and a recent study of coronavirus patients at Veterans Health Administration medical centers found a higher death rate in patients who received the drug.
The other four approved drugs that showed antiviral effects in the lab tests were haloperidol, often sold as Haldol, a widely available drug to treat schizophrenia; cloperastine, a cough suppressant that has been around since the 1970s; clemastine, an antihistamine; and progesterone, a natural hormone that is also available as a medication.
The rest of the drug candidates flagged in the Nature paper are experimental compounds. Most have been studied previously as potential weapons against cancer.
Many other research groups are also searching for COVID19 treatments. Some are developing drugs that attack the virus’ own molecular machinery. One such candidate is remdesivir, owned by Foster City’s Gilead Sciences, which announced promising results Wednesday from a trial of remdesivir in COVID19 patients.
The USCFled group took a different approach, focusing instead on the human proteins that the virus needs to survive. Instead of designing a drug from scratch, they relied on libraries of existing drugs and compounds to speed the search.
Krogan directed the study, working closely with UCSF chemists Kevan Shokat and Brian Shoichet, as well as Adolfo GarcíaSastre, director of the Global Health and Emerging Pathogens Institute at Mount Sinai, and Marco Vignuzzi, a virologist at the Institut Pasteur.
Krogan said he expects that human clinical trials will start soon to determine if some of the drug candidates identified in the paper are safe and effective for COVID19 patients. Depending on how those trials go, new treatments could be available in months, he said: “Hopefully, by the end of the year.”
One compound, known as PB28, was 20 times more potent than hydroxychloroquine against the virus in one test. It also did not bind as strongly to proteins that affect the heart, suggesting that it may be less toxic.
The researchers also studied an ingredient in popular cough medicines like Nyquil, dextromethorphan, and found a surprising effect: When added to infected cells in lab tests, the infection grew.
“If I had the virus right now, I wouldn’t be taking Nyquil,” said Krogan, who is also an investigator with the Gladstone Institutes.
Beyond simply testing drug candidates, the researchers have also shed light on how they work, making it easier to design improved versions. One class of drugs targets a pair of human proteins known as Sigma R1 and R2.
Another group of drugs interferes with the virus’ ability to create proteins once it’s inside a cell.
“You have a mechanism of action,” said GarcíaSastre. “And so you can make a better drug, sooner.”
“From a scientific point of view, that’s huge,” Krogan said. “And we’re digging into this deep. This is a way to manipulate the virus.”