In 1947, amid the “Golden Age” of antibiotic research that yielded many of the medicines we use against bacteria today, the soil of Venezuela provided a scientific prize. Researchers at a drug company on the wane discovered chloramphenicol, a molecule that could combat a wide array of bacteria from different families. It was among the first FDA-approved broad-spectrum antibiotics and was used against typhus or meningitis. Now, chloramphenicol's side effects make it a last-resort drug, but similarly versatile treatments, referred to as broad-spectrum, remain invaluable weapons against a host of bacterial infections.
Soon after that discovery, scientists began to find ways to target another type of pathogen: viruses. The FDA approved its first antiviral (IDU, for a type of herpes) in 1963, and today we have drugs that are hyper-focused on a particular virus (like many HIV-1 treatments), some medicines that work on multiple viruses within the same family (like Tamiflu, which is approved for both major types of influenza), but precious few that stretch across viral families. The promise of antiviral drugs with a truly expansive range has remained elusive.
“That’s a very challenging biological question,” says Kara Carter, the president of the International Society of Antiviral Research, when asked whether a panacea for all viruses would be feasible. If a scientist is searching for a treatment targeting the virus itself, “There’s really no common mechanism across all of them.” Instead, researchers hope to expand the existing roster of broad-spectrum antivirals and find more medicines that work on all viruses of a certain family, and ideally, across more than one family.
This reality makes the search for treatments for SARS-CoV-2, the virus that causes COVID-19, all the more challenging. Currently, no broad-spectrum antiviral is approved for the treatment of all coronaviruses, of which a new strain has driven the current pandemic. Scientists are rushing to find a solution.
“If you have an antiviral that works against multiple respiratory viruses [from different families], that would be super useful,” says Andrea Pruijssers, an assistant professor of research at Vanderbilt University Medical Center. “That’s like shooting for the moon, but we’re doing it anyway.” Pruijssers researches coronavirus antivirals, including the broad-spectrum drug remdesivir, which recently became the first medication to receive FDA authorization for emergency use for COVID-19.
Why Broad-Spectrum Antivirals Are So Hard to Make
Viruses are more slippery targets than bacteria. They’re often a hundred times smaller and consist only of bare-bones cellular machinery. Their tiny footprint creates a conundrum for researchers: There are simply fewer targets at which to aim antivirals, especially for drugs that would shoot for the rare viral components that remain common across diverse types of viruses. Hepatitis C, for example, is caused by HCV viruses from Flaviviridae, a family that also includes the virus behind yellow fever. Some Hepatitis C treatments are so targeted that they combat only some of the six main types of HCV, and certainly not yellow fever. Scientists call this virus-pinpointing model the “one drug, one bug” approach.
An antiviral’s mechanism can’t be too generic, either. “The broader you go, the more likely you are to pick off something in the host cell,” says Amesh Adalja, a senior scholar at the Johns Hopkins University Center for Health Security. For instance, a broad-spectrum antiviral called ribavirin, which fights both Hepatitis C and respiratory syncytial virus, can cause birth defects and destroy blood cells. To deal directly with the microorganisms at the root of the disease, “you want it to be very exquisitely targeted to the virus and not affect the host,” Adalja says. (Broad-spectrum treatments called host-acting or host-directed antivirals are an exception to this rule, aiming for the host instead of the virus, but can come with the possibility of serious side effects.)
On top of the biological challenge of finding new broad-spectrum antiviral drugs lies an economic one. Pharmaceutical companies have little financial incentive to develop broad-spectrum drugs against emerging diseases since they have no guarantee they’ll recoup the costs of research. “Big pharma is rarely interested in developing a drug against an unknown that might emerge in the future, and so consequently, the entire global response to new emerging outbreaks of viral disease is reactive rather than proactive,” says microbiologist Ralph Baric, who has been investigating coronaviruses and warning of their emerging-disease potential for decades. While federal funds have bankrolled research in this area, Congress has historically been more apt to spend money on already-here crises like Ebola than on preparedness measures.
“We don’t really have a drug on the shelf for all SARS-like viruses, or all Ebola-like viruses, or all flu-like viruses,” Baric says. So when a virus like Ebola or SARS-CoV-2 (the novel coronavirus) jumps into humans, clinicians have few treatments to work with, and scientists must start the lengthy process of testing and developing drugs from scratch. Broad-spectrum antivirals are not miracle drugs, but they would be a helpful addition to a toolbox that is currently sparse. In a paper published last year, Adalja and another Johns Hopkins colleague called the scarcity of broad-spectrum antivirals “a major chasm in preparedness for infectious disease emergencies.”
The Rise of Remdesivir
To fill that void, for the past seven years, Baric’s lab has partnered with the Vanderbilt lab where Pruijssers and her colleagues work. Together, they’ve tested some 200,000 drugs against bat coronaviruses and identified at least two dozen that showed promise. That tally includes remdesivir, so far the only antiviral to have significantly reduced recovery times (though not mortality) for COVID-19 patients in a clinical trial.
Remdesivir’s potential first drew public attention in October 2015 during an Ebola outbreak in West Africa that claimed more than 11,000 lives. The U.S. Army Medical Research Institute of Infectious Diseases announced that, in partnership with the biopharmaceutical company Gilead Sciences, it had found the first small-molecule drug that protected infected rhesus monkeys from the deadly effects of Ebola. GS-5734 (remdesivir’s original name) was a fine-tuned version of a compound from Gilead’s libraries that was concocted to treat other viruses. A CDC screen of 1,000 possibilities had established its broad-spectrum activity. In cells in the lab, it hampered not only Ebola viruses but also several others, including the coronavirus that caused MERS.
Remdesivir subdues a virus by interfering with replication—the way a virus copies itself. It’s a common strategy among broad-spectrum antivirals because the enzymes involved tend to be conserved across many types of viruses. For example, the genetic sequences of coronaviruses’ RNA polymerases are at least 70 percent identical. By contrast, the genetic code behind the “spike” that helps coronaviruses invade host cells varies more widely, Baric says.
First, the body converts remdesivir into an imposter. It becomes what’s called a nucleoside analog—a genetic doppelganger that resembles adenosine, one of the four “letters” of the RNA alphabet that make up the genomes of ebolaviruses and coronaviruses. When the virus replicates, it weaves this analog into the new strand of genetic material. However, the analog's molecular makeup differs from real adenosine just enough to grind the copying process to a halt. “If the virus can’t make copies of itself, the body’s immune system can take over and fight off the infection,” USAMRIID researcher Travis Warren explained in the 2015 announcement.
As COVID-19 swept the globe, researchers conducted an international trial of remdesivir as a treatment option. This April, the National Institutes of Health announced preliminary results: The drug reduced recovery time by 31 percent—from 15 days to 11—for severely ill COVID-19 patients, although it hadn’t significantly affected the death rate. NIAID director Anthony Fauci framed the early results as a reason for optimism and a starting point for finding a better course of treatment. Experts also expect the drug to have a stronger effect when administered to patients who are at an earlier stage in their illness or who have more moderate cases of COVID-19.
EIDD-2801, another treatment option that becomes a nucleoside analog in the body, also has demonstrated broad-spectrum antiviral potential, as well as an ability to defend cells from SARS-CoV-2. It seeds the replicating coronavirus with mutations that prove lethal as the virus copies more and more of its genome. EIDD-2801, which can be administered as a pill rather than intravenously, isn’t as far along in clinical trials as remdesivir. However, it appears that both can somewhat evade coronaviruses’ proofreading mechanism, which (unusually for a virus) checks the copied genome’s accuracy and can root out other nucleoside analogs. Both have beaten back the novel coronavirus in lab-grown versions of the airway cells SARS-CoV-2 batters. Pruijssers says both treatments are at least ten times more potent than other buzzed-about drugs, like hydroxychloroquine or camostat. Remdesivir and EIDD-2801 have also passed the laboratory safety screenings that check that they mess with only the virus’ RNA and not that of the host cell, a step that derails many nucleoside analogs, as well as more advanced safety tests.
What Comes Next
Remdesivir and EIDD-2801 “aren’t the only drugs that we are chasing,” Baric says, though he declined to go into more detail on ongoing research. The bulk of coronavirus drug research, in Pruijssers’ estimation, is predominantly focused on treatments that will work on the novel coronavirus—the crisis at hand—but not necessarily other viruses.
That eventual best treatment for COVID-19 may not be remdesivir, EIDD-2801 or any single antiviral at all. That’s because stopping the virus is only part of the equation. Clinicians also must address the numerous and perplexing symptoms of the disease, and in severe cases, they must deal with the vehement immune response to the virus. Broad-spectrum antivirals could be invaluable in the short-term, especially because remdesivir and other repurposed drugs have already had their safety in humans assessed. Baric and Pruijssers both suggest that such antivirals could be especially useful when combined with other treatments.
For example, when remdesivir reached rigorous clinical trials in the Democratic Republic of the Congo as a treatment for Ebola—admittedly, a very different disease—it didn’t become the recommended treatment. Although the drug reduced Ebola’s mortality rate to 50 percent, it turned out that two antibody-based treatments worked better at preventing deaths.
Right now, people shouldn’t expect one versatile uber-drug that routinely quashes diverse viruses affecting different organ systems. “I would emphasize that it’s not going to be one broad-spectrum antiviral that works for all future pandemics we might have,” says Jassi Pannu, who researched pandemic preparedness policy for Oxford University’s Future of Humanity Institute and is now an incoming internal medicine resident at Stanford University Hospital. “The most likely scenario is we’re going to have a suite of these drugs and a lot of them will never be used…but the goal is that you have, at least, an array of them [to try out].”
Last year, Adalja wrote that developing more broad-spectrum antivirals that work reliably within (or ideally, across) families will be “difficult” but “not impossible.” He suggested increased screening of new drugs to see whether they work against more than just the virus they were designed for, the same way scientists uncovered the versatility of remdesivir. Such research needs funding, and on the federal level, more money may soon be available. “The NIH is really starting to push the concept of one drug, many bugs,” Baric says, noting that the institute helped to establish the antiviral development center that sponsors his research. “They want to move, certainly the academic side of the antiviral drug development community, toward broad-based inhibitors.”
But, Pannu warns, we’ve been here before. The early success of remdesivir suggests that broad-spectrum antivirals will get their moment in the scientific limelight. After a pandemic passes, though, the surge in interest about a multipurpose treatment wanes. This time around, doctors confronted with a new disease had no clinically proven treatments to offer COVID-19 patients. Next time could be different—if research budgets prioritize accordingly.
#Nature | https://sciencespies.com/nature/remdesivir-works-against-many-viruses-why-arent-there-more-drugs-like-it/
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