Repurposing Proven Remedies

When will there be a vaccine for COVID-19? The world is waiting anxiously, believing that a vaccine will enable us to fully resume our normal lives.

But, according to Suresh Kuchipudi, clinical professor of veterinary and biomedical sciences and associate director of the Animal Diagnostic Lab, a vaccine alone is unlikely to be the panacea we've been waiting for.

"We are not certain about the ability of COVID-19 vaccines in development to prevent infection in all age-groups, especially in the elderly, who are most susceptible and are at significantly increased risk of morbidity and mortality," he said.

Meanwhile, the global death toll continues to rise. What other options do we have to protect ourselves?

"We need multiple approaches to inhibit virus replication and to treat the downstream adverse effects of virus infection to save lives," said Kuchipudi. "Repurposed drugs that are already widely available can bypass part of the early cost and time needed to validate and authorize new drugs and help save lives now."

Kuchipudi is among several researchers in the College of Agricultural Sciences who are examining preexisting therapeutics and supplements that are already approved by the Food and Drug Administration (FDA) to see if they will work against COVID-19. Drawing on years of related expertise, these scientists were able to rapidly transition their research programs to address a global threat.

A Diabetes Drug with Antiviral Properties

In early 2020, when news of a novel coronavirus outbreak in China first hit the United States, Kuchipudi was writing a paper about another deadly virus, Zika. The paper, published in the journal Frontiers in Microbiology on April 7, described his investigation of a group of compounds--called iminosugars, or sugar molecules with a nitrogen atom in place of an oxygen atom--that are known to have broad-spectrum efficacy against a range of viruses. Kuchipudi's research confirmed that iminosugars significantly inhibited Zika virus replication in human brain and monkey kidney cells in the lab.

"SARS-CoV-2, the virus that causes COVID-19, spreads by entering our cells, hijacking their machinery, and replicating itself," said Kuchipudi. "Iminosugars have previously been shown to block two coronaviruses--SARS-CoV and HCoV-NL-63--from entering human cells and replicating. It made sense that these compounds would work in the same way on SARS-CoV-2."

Kuchipudi and his team investigated two iminosugars that are FDA approved for type 2 diabetes treatment, namely acarbose and miglitol. The team demonstrated that these two compounds significantly inhibit SARS-CoV-2 in monkey kidney and human liver cells. In April, Kuchipudi filed a provisional patent with the U.S. Patent and Trademark Office to investigate the ability of acarbose to prevent COVID-19 in older adults.

"Our experiments so far have shown that treating cells with 10 micromoles of acarbose resulted in 75 percent inhibition of SARS-CoV-2 replication," said Kuchipudi, who is conducting the work in Penn State's Eva J. Pell ABSL3 Laboratory for Advanced Biological Research, a high-security biocontainment facility. "These results strongly suggest that acarbose and miglitol may be an effective therapeutic option against SARS-CoV-2."

The next steps involve evaluating these compounds in animal models. If these studies show success, the team hopes to move on to clinical trials, which will comprise a randomized, double-blind, placebo-controlled trial.

"Eighty percent of deaths associated with COVID-19 are among adults ages 65 years and older, with the highest percentage of severe outcomes among people ages 85 years and older," said Kuchipudi.

"Older adults, particularly those with underlying health conditions, such as hypertension, diabetes, and cardiovascular disease, are at higher risk for severe COVID-19-associated illness and death than younger people," said Kuchipudi. "Given the high risk of transmission from asymptomatic carriers of SARS-CoV-2, the reported 20 to 30 percent false negative rates for laboratory-confirmed COVID-19, and the potential lack of access to testing due to a shortage of supplies, our hope is that previously FDA-approved therapeutics can be used as primary prophylaxis in older adults to reduce the dangerous effects of infection, along with their application as a postexposure treatment."

Vitamins and Minerals

While acarbose works directly on SARS-CoV-2 to inhibit its ability to replicate and spread, other treatment options may target the body's reaction to the virus.

"When SARS-CoV-2 enters the lungs, it triggers immune cells to attack the virus, which ultimately results in localized inflammation," said Sandeep Prabhu, professor and head of the Department of Veterinary and Biomedical Sciences. "In many people, however, SARS-CoV-2 causes their immune systems to overreact and produce cytokine storms, which can result in hyperinflammation that can seriously harm or kill the patient. My research over the last two decades has shown that selenium and other antioxidants can help tone down the inflammation, while actively supporting the resolution phase of inflammation."

In 2008, Prabhu and his colleagues began an investigation on the demonstrated relationship between selenium deficiency and HIV/AIDS severity. They wanted to understand the molecular mechanisms at play. "We wanted to look more closely at the nuts and bolts of how selenium was actually regulating the virus," said Prabhu. "And we discovered that a protein was interfering with the virus's genetic machinery."

Today, many HIV/AIDS patients take a daily supplement of selenium, a mineral that can also be found in some nuts (especially Brazil nuts), fish, beef, poultry, and grains.

Prabhu said that although SARS-CoV-2 is a different kind of virus from HIV, the similarities between the two indicate that selenium supplementation might work in the same way on COVID-19. Indeed, in Wuhan where the coronavirus pandemic started, some evidence points to a correlation between selenium deficiency and COVID-19 severity, said project collaborator Girish Kirimanjeswara, associate professor of veterinary and biomedical sciences and scientific director of the Pell Lab.

Prabhu and Kirimanjeswara plan to study the effects of supplementing different doses and types of selenium, both organic and inorganic, on SARS-CoV-2, first in monkey cells and then in human lung epithelial cells. If successful, they will replicate the experiment in knock-in mice that have been engineered to express the human protein ACE2, which is a receptor for SARS-CoV-2 in humans, so they become susceptible to the virus.

Another over-the-counter supplement, vitamin D, may also reduce the severity of COVID-19.

"There has been a lot of interest in using vitamin D to treat respiratory infections associated with COVID-19," said Margherita Cantorna, Distinguished Professor of Molecular Immunology who studies the role of vitamin D in the immune system. "The problem is that we don't know very much about how it works in the lungs."

According to Cantorna, several research groups claim to have found a link between low vitamin D status and COVID-19 severity, but the scientific evidence is limited. "This is problematic because, not only can such claims give people false hope, but they also could cause harm," she said. "There is this idea that vitamin D is completely harmless, which is not really correct. Too much vitamin D can cause calcium to build up and lead to kidney stones or other serious side effects."

In a new project, Cantorna--in collaboration with Kirimanjeswara and Troy Sutton, assistant professor of veterinary and biomedical sciences who studies influenza and COVID-19 transmission and vaccine development--aims to determine whether vitamin D deficiency really does influence the severity of COVID-19 infection in the lungs. The team plans to use animal models to examine fundamental questions about how vitamin D is involved in the immune system. In addition, they will experiment with a variety of vitamin D supplementation interventions; for example, given early versus late during the course of an infection.

"The timing of treatment can be very important," said Cantorna. "A patient's inflammatory response triggered by an infection is important for helping to clear the infection, so you may not want to introduce anything that can reduce this response early in an infection. These kinds of questions we just don't have answers to. We need more information. That's why we're doing this research."

No End in Sight

Like influenza, many scientists predict that COVID-19 is here to stay. A vaccine will help to control outbreaks, but it will not entirely eliminate the disease. Therapies that reduce the severity of symptoms can give people's immune systems a chance to overcome the virus.

"Successfully managing SARS-CoV-2 will require the implementation of several strategies simultaneously," said Kuchipudi. "Vaccines and therapeutics are urgently needed, but continuing to practice good hygiene and social distancing will also be key."

By Sara LaJuenesse

Drugs in Wastewater

Fever, sore throat, diarrhea, cough. People with COVID-19 suffer from a variety of ailments, and many turn to over-the-counter pain relievers, fever reducers, and antidiarrheals, among other drugs, to manage their symptoms. Could this increased use of medications have unintended consequences?

Heather Preisendanz, associate professor of agricultural and biological engineering, believes it can. "We know that pharmaceuticals can persist through wastewater treatment plants and end up in streams where they can impact aquatic ecosystems," she said. "If COVID-19 cases become prevalent in our community, we may see higher concentrations of pharmaceuticals in our waterways."

With support from a COVID-19 seed grant from the college's Institute for Sustainable Agricultural, Food, and Environmental Science, Preisendanz has begun monitoring local wastewater for the presence of pharmaceuticals that could be related to COVID-19.

"Much of the wastewater that is generated in State College is discharged directly to Spring Creek after it has been treated," she said, noting that Spring Creek is a high-quality cold-water fishery. "An increased load of pharmaceuticals in our streams demonstrates the ripple effects that COVID-19 could have on our lives for years to come. It is important to study these effects so we can pursue solutions that protect our health and environment."

--Sara LaJeunesse