A new antiviral drug shown to be effective both in vivo in mice and in vitro in human cell lines appears to treat more than 10 deadly viruses that currently have no commercial medication. The extensive pool contains devastating ailments such as Zika virus, dengue fever, Ebola, yellow fever, Japanese encephalitis and even COVID-19.
Made from the extract of a Chinese plant, the drug's multifaceted uses were identified by a group of researchers initially focused on finding treatment routes for HIV. It contains a small molecule called 6-deoxyglucose-diphyllin, or DGP, and rather than target the viruses themselves, which continuously mutate — the usual limiting factor for virus medications — it targets the body.
The inventor behind the drug has applied to patent the molecule's use as medication against a broad spectrum of viruses, and the application was published by the World Intellectual Property Organization on March 4. Foundational research for the medication was published by the team in September 2019 in The Lancet.
The revelatory molecule, DGP, was initially sent to Felipe Diaz-Griffero, a professor at Albert Einstein College of Medicine in New York and the inventor of the final drug, by a colleague who believed it could target the HIV capsid he was examining. But upon testing it, something strange happened.
"It didn't target the capsid of HIV," Diaz-Griffero told The Academic Times. "So we decided, just by chance, to see whether this drug blocks Zika. And when we did that, we found that the virus was actually limited by this drug — and very potently."
As it turns out, Diaz-Griffero's lab was also working on Zika virus treatments as a separate project, and his shock at this outcome led him to continue testing the drug on several other elusive diseases.
"We started testing dengue, West Nile, tick-borne encephalitis virus," he said. "Then we tested Ebola virus. They were all inhibited by this drug."
The drug even inhibited COVID-19 — the original strain as well as the U.K., South Africa and Brazil variants. These viruses are just the tip of the iceberg, according to Diaz-Griffero's patent application, which states that the invention's mechanism means that it can tackle many other diseases that lack dedicated medication, too.
The exciting discovery adds to the growing number of upcoming epidemiology advances, particularly a recent promising development regarding a vaccine against malaria.
Diaz-Griffero loosely compares his discovery with the way antibiotics work, noting that it isn't quite the same because while it could be effective against a slew of viruses, it won't be for all of them.
"An antibiotic inhibits protein synthesis of all bacteria, so it doesn't matter which bacteria you're infected with. In viruses, this concept doesn't exist," he said. "It's almost like we found an antibiotic for viruses."
Due to its versatility, the drug has already received interest from U.S. Department of Defense officials who hope to have it on hand to guard against future biological attacks. Diaz-Griffero also plans to publish a paper concerning ongoing tests in which the drug is converted to an intra-nasal spray to treat COVID-19. The pandemic has killed 2.8 million people around the world.
"One of the issues with this pandemic that we are having right now is that this is the third one that has occurred in the last 20 years," he said. "This is going to continuously happen, so we need to have drugs like this one, drugs that can have a wide range of viruses."
Several viruses targeted by the invention can have devastating impacts if untreated.
In 2016, the World Health Organization declared Zika virus a Public Health Emergency of International Concern, with more than 3,000 infants born with debilitating defects. Dengue fever's worldwide case count has increased from 2.4 million in 2010 to 4.2 million in 2019. And another Ebola outbreak, in Guinea, was officially declared in February, with 13 deaths reported in Africa.
The necessary human trials to begin the process of making the drug available to the public will begin in about two years, the researchers say.
James E. Crowe Jr., director of the Vanderbilt Vaccine Center and a professor in the department of pathology, microbiology and immunology at Vanderbilt University, urged researchers to test the drug very rigorously.
"Whether or not these particular compounds are safe and effective against such diverse viruses in vivo will need to be tested more broadly, to determine the level of promise for human use," Crowe told The Academic Times.
But he said the innovative molecule appears to have footing, adding, "This finding suggests an important common step in the virus lifecycle that is vulnerable to inhibition by drugs."
However, Nikko Quevada, lead scientific advisor and patent agent at the patent research firm Parola Analytics, has reservations regarding DGP.
"The success of a compound as drug depends on so many factors, such as potential side effects," he told The Academic Times. "Even if a drug is effective, it won't be commercially successful if it has severe side effects."
Quevada also stressed that for a patent application, "Often, you need only results from in vitro or animal model tests, and these tests are not conclusive. But patents on drugs — even based only on these preliminary tests — are allowed because the more conclusive evidence, clinical trials, require as long as 10 years."
Diaz-Griffero intends to conduct extensive toxicity and safety testing prior to the human clinical trials, although he noted that the drug was considered completely non-toxic in all mouse studies, so far.
According to the 2019 paper, those studies were conducted on mice that were genetically altered, referred to as knockout mice, to be susceptible to infection of the diseases tested.
The mechanism of the new antiviral agent is at the crux of its groundbreaking nature. Citing Remdesivir, which is being used for COVID-19, Diaz-Griffero relayed that typical virus medications don't always work very well because viruses have so much genetic variability that it's nearly impossible for one drug to target every single type, even if it can attack up to 99%.
"Usually with viruses, like RNA viruses, the problem is escape," he explained. "They change and escape. In this case, if you target the host, [the host] won't change."
DGP, which Diaz-Griffero says hasn't yet been used commercially, circumvents this issue in a unique way. It temporarily alters a body's cell that has been infiltrated by a virus in a way that prevents the virus from infecting the cell without needing to attack the virus at all.
Dhruv H. Patel, an infectious disease specialist and critical care physician in New York, told The Academic Times that the drug is seemingly quite effective based on the mice studies. But he noted a potential caveat: The testing was, thus far, only done in an ideal setting.
"It is an interesting discovery, which shows good results in controlled lab settings," he said. "As a clinician, I am always skeptical about experiments in controlled settings and its true impact in the real world."
Patel pointed out that in the experiments, DGP and Zika virus were injected in mice around the same time.
"They do not provide data on an established Zika virus infection, and hence its true real world applicability is difficult to deduce," he said.
But if the newfound molecule is still effective after being run through the crucial tests that experts — including the inventor himself — are recommending, it could be revolutionary.
Viruses enter the cell through its built-in transport chain; they pass the cell membrane, then push into a vesicle. Vesicles can be thought of as train cars, and the one the virus enters is called an endosome. However, endosomes are always headed to their next station, the lysosome. That complicates things for the virus.
"The lysosome is almost like a really bad place for the virus. Everything gets destroyed there," Diaz-Griffero said. "And if the virus is trapped [in the endosome] for too long, it's completely destroyed because it goes directly to the lysosome, where everything is digested."
This is bad news for the virus, but terrific for the inventor. The drug prevents the virus from leaving the vesicle before reaching the lysosome, forcing its death. It does this by impeding the virus' exit route.
"To get out of the vesicle, the pH of that vesicle has to be acidic," Diaz-Griffero said. "This drug, what it does is it changes this acidic pH; it makes it neutral. So the virus cannot enter the cell."
When the virus, inside the endosome and traveling toward the center of the cell, is ready to begin infection, it will find itself trapped and unable to ever leave. Upon inevitably reaching the endpoint lysosome, it will die.
The application for the patent, "Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus and COVID-19," was filed Aug. 28, 2020, to the World Intellectual Property Organization. It was published March 4, 2021 with the application number WO 2021/041852 A1. The earliest priority date is Aug. 30, 2019. The inventor of the pending patent is Felipe Diaz-Griffero, Albert Einstein College of Medicine. The applicant listed is Albert Einstein College of Medicine.
Parola Analytics provided technical research for this story.