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TThe more researchers know how the coronavirus attacks, invades and hijacks human cells, the more effective the search for drugs to combat it. That was the idea that my colleagues and I hoped would be true when we started building a coronavirus map two months ago. The map shows all the coronavirus proteins and all the proteins found in the human body with which those viral proteins could interact.
In theory, any intersection on the map between viral and human proteins is a place where drugs could fight the coronavirus. But instead of trying to develop new drugs to work on these interaction points, we turned to the more than 2,000 unique drugs already approved by the FDA for human use. We believed that somewhere on this long list there would be some drugs or compounds that interact with the same human proteins as the coronavirus.
We were right
Our multidisciplinary team of researchers at the University of California, San Francisco, called QCRG, identified 69 existing drugs and compounds with potential to treat COVID-19. A month ago, we started shipping boxes of these drugs to the Institut Pasteur in Paris and Mount Sinai in New York to see if they really fight the coronavirus.
In the past four weeks, we have tested 47 of these drugs and compounds in the laboratory against live coronavirus. I am pleased to report that we identified some strong treatment leads and identified two separate mechanisms for how these medications affect SARS-CoV-2 infection. Our findings were published on April 30 in the journal Nature.
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The testing process
The map we developed and the FDA drug catalog we analyzed showed that there were potential interactions between the virus, human cells, and existing drugs or compounds. But we didn’t know if the drugs we identified would make a person more resistant to the virus, more susceptible, or if they would do anything.
To find those answers, we needed three things: medications, live viruses, and the cells to test them on. It would be optimal to test the drugs on infected human cells. However, scientists still don’t know which human cells work best to study the coronavirus in the laboratory. Instead, we use African green monkey cells, which are frequently used in place of human cells to test antiviral drugs. They can easily become infected with the coronavirus and respond to drugs very closely to the way that human cells do.
Institute for Quantitative Biosciences
After infecting these monkey cells with live viruses, our partners in Paris and New York added half of the drugs we identified and kept the other half as controls. They then measured the amount of virus in the samples and the number of cells that were alive. If the drug samples had a lower virus count and more live cells compared to the control, that would suggest that the drugs interrupt viral replication. The teams were also looking to see how toxic the drugs were to the cells.
After ranking the results of hundreds of experiments with 47 of the predicted drugs, it appears that our interaction predictions were correct. In fact, some of the drugs work to fight the coronavirus, while others make the cells more susceptible to infection.
It is incredibly important to remember that these are preliminary findings and have not been tested on people. No one should go out and buy these drugs.
But the results are interesting for two reasons. Not only do we find individual medications that seem promising to fight the coronavirus or that can make people more susceptible to it; We know, at the cellular level, why this happens.
We identified two groups of drugs that affect the virus and do so in two different ways, one of which has never been described.
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Interrupting the translation
At a basic level, viruses spread by entering a cell, hijacking some of the cell’s machinery, and using it to make more copies of the virus. These new viruses then infect other cells. One step in this process involves the cell making new viral proteins from the viral RNA. This is called translation.
As we scanned the map, we noted that various viral proteins interacted with human proteins involved in translation, and a number of drugs interacted with these proteins. After testing them, we found two compounds that interrupt the translation of the virus.
The two compounds are called ternatin-4 and zotatifine. Both are currently used to treat multiple myeloma and appear to fight COVID-19 by binding to and inhibiting the proteins in the cell that are needed for translation.
Plitidepsin is a molecule similar to ternatin-4 and is currently in a clinical trial to treat COVID-19. The second drug, zotatifin, hits a different protein involved in translation. We are working with the CEO of the company that produces it to take it to clinical trials as soon as possible.
Sigma receivers
The second group of drugs that we identify works in a completely different way.
Cellular receptors are found both inside and on the surface of all cells. They act as specialized switches. When a specific molecule binds to a specific receptor, it tells a cell to do a specific task. Viruses often use receptors to infect cells.
Our original map identified two promising MV cell receptors for pharmacological treatments, SigmaR1 and SigmaR2. The tests confirmed our suspicions.
We identify seven drugs or molecules that interact with these receptors. Two antipsychotics, haloperidol and melperone, which are used to treat schizophrenia, showed antiviral activity against SARS-CoV-2. Two powerful antihistamines, clemastine and chloperastine, also showed antiviral activity, as did compound PB28 and the female hormone progesterone.
Remember, all of these interactions so far have only been observed in monkey cells in Petri dishes.
At this time we do not know exactly how viral proteins manipulate the SigmaR1 and SigmaR2 receptors. We believe that the virus uses these receptors to help make copies of itself, so decreasing their activity probably inhibits replication and reduces infection.
Interestingly, a seventh compound, an ingredient commonly found in cough suppressants, called dextromethorphan, does the opposite: its presence helps the virus. When our partners tested the cells infected with this compound, the virus was able to replicate more easily and more cells died.
This is a potentially very important finding, but, and I can’t emphasize this enough, more testing is needed to determine if someone with COVID-19 should avoid cough syrup with this ingredient.
All of these findings, while exciting, must undergo clinical trials before the FDA or anyone else concludes whether to take or stop taking any of these medications in response to COVID-19. Neither people nor policy makers nor the media should panic and jump to conclusions.
Another interesting thing to note is that hydroxychloroquine, the controversial drug that has shown mixed results in the treatment of COVID-19, also binds to SigmaR1 and SigmaR2 receptors. But based on our experiments in both labs, we don’t believe that hydroxychloroquine binds them efficiently.
Researchers have long known that hydroxychloroquine easily binds to receptors in the heart and can cause damage. Due to these differences in binding trends, we do not believe that hydroxychloroquine is a reliable treatment. Ongoing clinical trials will soon clarify these unknowns.
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Treatment sooner rather than later
Our idea was that by better understanding how the coronavirus and human bodies interact, we could find treatments among the thousands of drugs and compounds that already exist.
Our idea worked. Not only did we find multiple drugs that could fight SARS-CoV-2, we learned how and why.
But that’s not the only thing to be excited about. These same proteins that SARS-CoV-2 uses to infect and replicate in human cells and that are the target of these drugs are also hijacked by the related SARS-1 and MERS coronaviruses. So if any of these drugs work, they will probably be effective against COVID-22, COVID-24, or any future iterations of COVID that may emerge.
Will these promising clues have any effect?
The next step is to test these drugs in human trials. We have already started this process, and through these trials, researchers will examine important factors such as dose, toxicity, and possible beneficial or harmful interactions within the context of COVID-19.
Nevan Krogan, professor and director of the Institute for Quantitative Biosciences and principal investigator of the Gladstone Institutes, University of California, San Francisco.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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