As the coronavirus outbreak in China continues to spread, having infected over 24,000 people so far, scientists around the world are racing to find a treatment. Most of the people infected with the new coronavirus, dubbed 2019-nCov, have not received a treatment specific to that virus — because there isn’t one.
In fact, none of the handful of coronaviruses known to infect humans has an approved treatment, and people who are infected typically receive care mainly to help relieve symptoms, according to the U.S. Centers for Disease Control and Prevention (CDC). However, a handful of repurposed drugs, from drugs targeting Ebola to HIV, have already shown promise, according to new findings.
Repurposing antivirals
Until recently, there were very few effective antivirals, said Stephen Morse, a professor at Columbia University’s Mailman School of Public Health. That was especially true for RNA viruses — like 2019-nCov and HIV — which use RNA, rather than DNA, as their genetic material, Morse said.
That’s changing.
“In recent years, perhaps encouraged by the successful development of HIV anti-virals, which proved it might be feasible to do more, our armamentarium has greatly expanded,” Morse said. Even so, developing brand-new drugs requires a huge investment of both time and resources, he added. So “while you’re waiting for the new miracle drug, it’s worthwhile looking for existing drugs that could be repurposed” to treat new viruses, Morse told Live Science.
That’s exactly the route doctors took to treat a 35-year-old man in Washington state, the first U.S. patient to have been infected with the new coronavirus. When his symptoms worsened, the man was given an unapproved antiviral drug called remdesivir that was originally developed to treat Ebola, according to a case report published Jan. 31 in The New England Journal of Medicine.
Doctors gave this drug to the patient by making a “compassionate use” request to the Food and Drug Administration (FDA), which allows experimental drugs to be given to people outside of clinical trials, usually in emergency situations. The patient, who was recently released from the hospital, didn’t seem to experience any side effects of the drug.
In animal models, scientists have found that remdesivir can knock down similar coronaviruses, such as the ones that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). Despite its use in an emergency situation, the drug “has not been demonstrated to be safe or effective for any use,” Gilead Sciences, the biopharmaceutical company that is developing the drug, said in a statement.
Viral battles in the lab
Recently, a group of researchers tested a number of antivirals in the lab for their effectiveness against the new coronavirus. They found that remdesivir stopped the virus from replicating in a lab dish. Similarly, the group found that chloroquine — an approved and widely used anti-malarial and autoimmune disease drug — was also effective in stopping the virus from spreading in human cells in the lab, the researchers reported in a short letter published Feb. 4 in the journal Cell Research. What’s more, both drugs were effective at low concentrations, and neither drug was highly toxic to human cells.
“These findings were encouraging but not entirely surprising” because of the previous testing in Ebola patients, cell cultures and animal models, said Fanxiu Zhu, a professor in the Department of Biological Science at Florida State University who was not part of the study. Both drugs “maybe are worthy of trial in this unprecedented and devastating situation,” Zhu told Live Science.
Though researchers expected the drugs to work, this group effectively proved they did, at least in the lab, in a short time frame, Morse said. Chloroquine “seems to need a higher concentration than remdesivir, but it’s within the feasible range, and if it really works as well as the published in vitro results, it would be quite promising,” he said.
Despite those results, testing antivirals in lab dishes “is the beginning, not the end of the process,” Morse said. If it works in the lab, or even in animal models, “that’s no guarantee it will work in a human patient.” Gilead Sciences is now working with health officials in China to establish clinical trials to test the effect of remdesivir on patients infected with the new coronavirus, according to their statement.
“I think that there’s a lot of hope with remdesivir having some effect, and I think we’ll only find that out from clinical trials,” said Dr. Amesh Adalja, an infectious-disease specialist and a senior scholar at the Johns Hopkins Center for Health Security in Baltimore.
The molecular standoff
But viruses aren’t as easy as bacteria to treat. That’s because viruses are very diverse, with unique characteristics that can’t be targeted with a broad-spectrum drug like a general antibiotic, Adalja said. Also, viruses use human cellular machinery to create proteins that help it replicate, so targeting the viruses while not damaging human cells can prove challenging, he added.
When a virus infects the body, it first finds a cell and latches onto a protein on the cell’s surface called a receptor. The virus then enters the cell via a vesicle called an “endosome.” From inside this vesicle, it releases its RNA into the cell’s cytoplasm and two things happen: the virus hijacks the human cell’s machinery to produce the viral proteins needed for replication and it uses its own viral enzyme to copy its RNA. Finally, the viral proteins and RNA assemble into a structure that lets the virus leave the cell and move on to infecting the next cell.
Antivirals target various points in this process of viral replication, said Carol Shoshkes Reiss, a professor of biology and neural science at New York University. Chloroquine blocks the virus’s ability to acidify endosomes and release its RNA into the cell, which is a critical step for most viruses to begin their infection. Remdesivir, in contrast, acts like a nucleotide — the building blocks for RNA — and squishes itself into the copied RNA sequence, creating a “typo” and rendering it useless, Reiss said.
When a similar coronavirus caused a SARS outbreak in 2003, some evidence suggested that another class of drugs called “protease inhibitors” approved to treat HIV could also be effective against the SARS coronavirus, Adalja said. Based on previous studies that showed possible benefit of these drugs in treating both SARS and MERS, two of them are now being tested for their ability to treat 2019-nCov in a clinical trial in China, according to an article published in the journal JAMA. These are drugs that target yet another point in viral replication: They block the ability of protein called the “protease” to cut a very long nonfunctional protein into smaller proteins that are needed for the virus to replicate.
The Chinese government previously suggested that people infected with the coronavirus should take two lopinavir/ritonavir pills (the protease inhibitors that are currently being tested for use with the novel coronavirus in the Chinese clinical trial) and inhale an interferon (nebulized alpha-interferon) twice a day. Interferon alphas are already approved to treat diseases such as multiple sclerosis and hepatitis C.
These drugs induce interferons, proteins that human cells naturally release as an alarm to other cells that there is an infection in the body. Interferons are very useful because they aren’t specific to a single virus but respond to all viruses and all stages of viral replication, Reiss said.
And once researchers identify the specific protein on the outside of human cells that the new coronavirus uses to gain entry, “then they’ll be able to find small molecules that can block the binding of the virus into cells,” Reiss said. In other words, they might create completely new types of drugs rather than repurpose older ones. “But these will take time to find,” Reiss said.
Current research is underway in laboratories to do just that. For example, in a collaboration between the U.S. Department of Health and Human Services and Regeneron Pharmaceuticals, scientists are working to identify antibodies that will stop the coronavirus from entering cells, according to a statement. Still others are looking to develop a vaccine: Researchers at the U.S. National Institutes of Health are in the early stages of developing a vaccine and plan to launch a clinical trial within the next three months, according to a statement.
Cocktail of drugs
Instead of finding a single drug to treat the coronavirus, “I would suggest a cocktail of drugs that target different stages of replication,” Reiss said. “This virus is probably going to be like a number of other viruses, and it will undergo mutation and selection, so if you use only one antiviral drug, you are going to ultimately select for resistance.”
What’s more, the treatment will be most effective when given to a patient early on, perhaps even before symptoms develop, she said. “Taken very early in the course of exposure, the antiviral drugs could have a real impact,” she said. After someone is already in the hospital in respiratory distress and a high fever, “it is much harder to treat the infection, people are more likely to treat the disease.”
Treating the disease means lessening the symptoms by providing respiratory support, lowering the fever and making sure people are hydrated, among other things. The vast majority of coronavirus patients today are receiving this type of treatment.
Though several potential antivirals might one day be used to treat the new coronavirus, it will likely take a couple of years for such drugs to be tested and approved. Once they are approved, there will probably be discussion around whether these antivirals should be given to patients to prevent disease or given to patients with relatively uncomplicated cases, similar to the debate around the best use for Tamiflu, Morse said.
“A good antiviral, given early enough, could be lifesaving in severe infections with this coronavirus,” he said. “It’s probably most valuable in severe cases, and we may want to save it for those.”
Sourse: www.livescience.com
