THE
WINDING
PATH
of COVID-19 Research

By Brian Wallheimer

THE
WINDING
PATH

of COVID-19 Research

By Brian Wallheimer

In March 2003, the World Health Organization and the U.S. Centers for Disease Control and Prevention sent out alerts about a novel virus that caused an illness called severe acute respiratory syndrome, or SARS. It seemed to spread easily and kill at a high rate. By July, the virus would be contained, but not before 774 people, about 10 percent of patients, had died.

A decade later, a similar virus would cause the Middle East respiratory syndrome, or MERS. This much more deadly virus claimed 858 lives, more than one-third of those infected, and still shows up sporadically in more than two dozen countries.

SARS and MERS are caused by coronaviruses, and while these viruses captured attention, coronaviruses themselves aren’t new to scientists and health professionals. For decades, we’ve known that other common types of coronaviruses cause runny noses, sore throats and other cold-like symptoms.

Past research, present purpose

person with test tube illustration

SARS and MERS made scientists around the world take note. Among them was Andrew Mesecar, professor and department head of the Department of Biochemistry and deputy director of the Purdue Center for Cancer Research. For over 15 years, he’s collaborated with Arun Ghosh, Ian P. Rothwell Distinguished Professor in the Department of Chemistry, to create small molecules that could be used to develop drugs to fight these viruses.

They made significant progress, developing and testing hundreds of molecules that held promise as protease inhibitors, which bind to critical enzymes in viruses and disrupt their ability to replicate.

“These proteases do two things: they help the virus live and replicate, and one of them also serves as a ‘cloaking device’ to hide the virus from our own immune systems,” Mesecar says. “We were trying to tear down the cloaking device, exposing the virus to our immune systems.”

Their work was promising, but SARS was contained quickly and MERS only infects a few people each year. As the global threat subsided, funding and interest dried up, and Mesecar and Ghosh essentially shelved their small molecules.

In early 2020, as news of a new viral illness was making headlines, Mesecar saw the similarities to SARS and MERS. The SARS-CoV-2 virus, as it was named, is responsible for the COVID-19 pandemic that has claimed millions of lives.

“I’m like, ‘Here we go again. I wonder what this one’s going to be.’ Two or three days later they realize it’s a coronavirus,” Mesecar says. “I got word that the genome was released on a Friday night and woke up early, downloaded it and compared it against SARS and MERS. When I saw the high similarity to SARS, I knew this was going to be bad.

“I was thinking bad like maybe 10,000 cases and 100 percent mortality in the first wave, and then it might go away with proper controls like quarantine,” Mesecar adds. “But I had no idea the potential for a pandemic on this scale at the time.”

Mesecar and Ghosh started pulling out the small molecules that had shown promise against SARS and MERS. Ghosh’s lab quickly pivoted to COVID-19 research and worked to synthesize a few hundred more molecules, sharing them with Mesecar for initial efficacy tests against the proteases.

“People are dying. We know this virus very well. We think we can make a contribution,” Ghosh says. “We believe we are in the right place at the right time with the right know-how to make a difference.”

Mesecar all but lived in his lab and office for the first three months, subsisting on cans of tuna and macaroni and ramen he would buy in bulk so he could devote more time to his work. He gathered Ghosh’s molecules, measuring the activity of the compounds and then crystallizing the molecules stuck to the proteases, a process that allows researchers to see where the drugs would bind to virus enzymes, as well as other properties of the molecule. If the molecule seemed promising from there, it was sent to other collaborators who tested the efficacy of the molecules on live virus.

Person at desk with snack illustration

While the most significant global efforts to fight the virus have focused on vaccines, Mesecar and Ghosh believe there will still be a need for drugs that can kill the virus in infected patients. They have filed three provisional patents on promising molecules, and Mesecar was awarded a patent in 2018 for his broad-spectrum coronavirus inhibitors.

“We are marching forward on antivirals. We need the Tamiflu of coronaviruses. We need a pill form that will kill the virus,” Mesecar says. “Having that in addition to a vaccine is what’s going to keep this at bay for those who can’t or won’t get a vaccine, or others who contract new variants of the virus."

To that end, Mesecar has shifted much of his lab work — and even classroom work — to identifying new targets for antiviral drugs. When in-person classes and labs were canceled last spring, Mesecar offered an undergraduate drug discovery class some hands-on experience of a different sort. He asked students to review all the potential drug targets for coronaviruses identified in the literature and write white papers on their findings.

“I was really surprised on a couple of the targets. Reading what they came up with, there are a few new targets I’m interested in understanding better,” Mesecar says.

Gaby Fernandez, a senior biology major in that class, dug into NSP-13, from a class of enzymes called helicases, which unwind DNA, an essential step for virus replication. She scoured clinical trials, review papers and any other mentions of the protein.

“We narrowed down what we currently know to help decide whether there is enough research to look for viable drug targets,” Fernandez says. “I loved working on this. It made me feel like I was contributing something potentially important during this global pandemic, and it gave me insights about how drug discovery and delivery play out.”

Practical testing

cow illustrationAs the pandemic came into focus in the early months of 2020, many Purdue scientists shuttered their labs temporarily unless they had a direct tie to COVID-19 or other essential research. Some, like Mohit Verma, assistant professor of agricultural and biological engineering, saw an opportunity.

Verma has been developing a rapid test for bovine respiratory disease (BRD). As one of the most prevalent and costly illnesses in the beef and dairy industries, the disease causes about half of feedlot deaths in North America and costs producers as much as $900 million per year.

By the time a producer suspects BRD, orders a test and waits several days for the results, it may be too late. Often, the disease spreads rapidly to other animals.

The technology Verma’s lab designed is similar to a pregnancy test. Livestock producers get a nasal swab from an animal, apply it to a paper strip that is warmed to speed up chemical reactions and get a result within 60 minutes.

Even before the pandemic, Verma had considered this technology could have an application outside a farm setting. When the U.S. Department of Defense’s Defense Advanced Research Projects Agency called for proposals in 2019 for rapid biosensors that could be used in a pandemic, Verma expressed interest.

“I had this paper-based platform that I thought could fit well, and I was looking for partners,” Verma says. “I had started working with Raytheon BBN Technologies, which has a lot of algorithmic designs to identify DNA and RNA sequences in February, right when the pandemic started to grow.”

Verma’s lab quickly became all hands on deck as he pulled every available graduate student and lab technician into the project. Needing even more researchers over the summer, he brought on Molecular Agriculture Summer Institute (MASI) students, whose program had been canceled due to the pandemic.

Those students jumped in to conduct a slew of experiments to quickly improve the technology. Andres Dextre, a junior agricultural and biological engineering major, learned to test new chemical formulations on the paper strips to decrease the time it takes to get results and weed out false positives.

“After the MASI program got canceled, I was disappointed. I had made my peace that the summer was going to be a loss,” Dextre says. “It was definitely exciting to get into something like this. You can see the impact this pandemic is having on everyone, and the idea of working on something that can help people feels important.”

The tests Verma’s team is developing haven’t been used to detect virus during the pandemic so far. However, as new strains arise, it’s likely that inexpensive, simple and rapid tests will be needed on a wide scale. For instance, the technology could be used to screen airline passengers before boarding planes or employees before they come to work.

“We’re interested in serving companies or organizations that will need to test people often and quickly to ensure safe workplaces and other environments,” Verma said. “You need something scalable and cheap and something that gives confidence. We think we have that.”

Boosting drug efficiency

Years before the COVID-19 pandemic hit, Yuan Yao, professor of food science, made a fortuitous decision. He and his collaborators had developed a nanoparticle able to solubilize drugs with tough crystalline structures, making them easier to dissolve and more efficient as a treatment. When they looked for a drug to use for proof of concept, they decided to pick a tough one: niclosamide.

hands holding corn illustration

“This is a drug often used to treat tapeworms, and it may have potential as a cancer therapeutic,” Yao says. “We also know that niclosamide has potential to be used as a broad-spectrum antiviral drug and could be used to treat COVID-19. Fortunately, we have a drug-enabling agent that can make niclosamide much more effective than it could ever be on its own.”

Yao was originally interested in niclosamide for treating cancer; good results would be evidence that his nanoparticle was highly effective. While published studies have also shown that niclosamide has potential to be more effective than chloroquine, remdesivir, and lopinavir as a COVID-19 therapeutic, niclosamide’s structure keeps the human body from absorbing much of it. This drug is poorly water-soluble, so when taken orally, it can’t easily be dissolved and absorbed by patients. OHPP (octenylsuccinate hydroxypropyl phytoglycogen), the highly functional nanoparticle Yao and his collaborators prepared from a carbohydrate extracted from corn, can improve niclosamide solubility by 5,000 times, substantially increase its bioavailability, and largely reduce the progression of infection in mice.

Yao in the lab illustration

“Patients need a drug that can be taken in pill form and be effective,” Yao says. “Our nanoparticle gives niclosamide the properties it needs to meet those requirements. If this virus continues to produce new variants or other viruses appear, we may need drugs like this to care for patients who contract it.”

Yao and his collaborators have received funding to begin pre-clinical trials for the OHPP-formulated niclosamide. Pilot viability studies have indicated the formulation’s outstanding oral bioavailability and demonstrate a prolonged release of niclosamide that hasn’t been achieved with other technologies.

the takeaway covid
  • When outbreaks of the coronaviruses, SARS and MERS occurred, Andrew Mesecar, professor and head of the Department of Biochemistry, and his colleague Arun Gosh, professor in the Department of Chemistry, researched small molecules that could be used to develop drug treatments. They returned to that work after receiving the SARS-CoV-2 genome.
  • These small molecules hold promise as protease inhibitors, which bind to enzymes in viruses and disrupt ability to replicate.
  • Mesecar asked students in his undergraduate drug discovery class to review literature and submit papers on potential drug targets for coronaviruses - "hands-on" experience in a virtual class environment.
  • Mohit Verma, assistant professor of agricultural and biological engineering, developed a rapid test for bovine respiratory disease using paper test strips to deliver results in 60 minutes. He had begun testing that paper-based platform to detect human viruses and accelerated the work during the pandemic.
  • Rapid tests like Verma's could potentially be used to screen airline passengers or employees.
  • Years before the pandemic, Yuan Yao, professor of food science, had developed a plant-based nanoparticle, OHPP, that made it easier to dissolve drugs with tough crystalline structures.
  • One of those drugs, niclosamide, has shown potential to be effective as a COVID-19 therapeutic. OHPP helps improve its solubility by about 5,000 times, which provides better bioavailability and efficacy. Yao and his collaborators have received funding for pre-clinical trials of OHPP-formulated niclosamide.

“Publications by other groups showed niclosamide’s antiviral effects against SARS-CoV, MERS-CoV, Zika, hepatitis C virus, influenza A and dengue. Our patented technology could be crucial to translating lab findings into practical therapeutics for patients,” Yao says. “I’m glad that OHPP, which originated from corn, is enabling a promising drug.”

Pivoting fast for the future

College of Agriculture scientists nimbly revived earlier work and adapted current work to address COVID-19, with goals to save lives and improve long-term recovery for patients and the economy. Their research offers hope in the face of a deadly pandemic that might be a harbinger for future generations.

Category Feature, Spring 2021

In March 2003, the World Health Organization and the U.S. Centers for Disease Control and Prevention sent out alerts about a novel virus that caused an illness called severe acute respiratory syndrome, or SARS. It seemed to spread easily and kill at a high rate. By July, the virus would be contained, but not before 774 people, about 10 percent of patients, had died.

A decade later, a similar virus would cause the Middle East respiratory syndrome, or MERS. This much more deadly virus claimed 858 lives, more than one-third of those infected, and still shows up sporadically in more than two dozen countries.

SARS and MERS are caused by coronaviruses, and while these viruses captured attention, coronaviruses themselves aren’t new to scientists and health professionals. For decades, we’ve known that other common types of coronaviruses cause runny noses, sore throats and other cold-like symptoms.

Past research, present purpose

person with test tube illustration

SARS and MERS made scientists around the world take note. Among them was Andrew Mesecar, professor and department head of the Department of Biochemistry and deputy director of the Purdue Center for Cancer Research. For over 15 years, he’s collaborated with Arun Ghosh, Ian P. Rothwell Distinguished Professor in the Department of Chemistry, to create small molecules that could be used to develop drugs to fight these viruses.

They made significant progress, developing and testing hundreds of molecules that held promise as protease inhibitors, which bind to critical enzymes in viruses and disrupt their ability to replicate.

“These proteases do two things: they help the virus live and replicate, and one of them also serves as a ‘cloaking device’ to hide the virus from our own immune systems,” Mesecar says. “We were trying to tear down the cloaking device, exposing the virus to our immune systems.”

Their work was promising, but SARS was contained quickly and MERS only infects a few people each year. As the global threat subsided, funding and interest dried up, and Mesecar and Ghosh essentially shelved their small molecules.

In early 2020, as news of a new viral illness was making headlines, Mesecar saw the similarities to SARS and MERS. The SARS-CoV-2 virus, as it was named, is responsible for the COVID-19 pandemic that has claimed millions of lives.

“I’m like, ‘Here we go again. I wonder what this one’s going to be.’ Two or three days later they realize it’s a coronavirus,” Mesecar says. “I got word that the genome was released on a Friday night and woke up early, downloaded it and compared it against SARS and MERS. When I saw the high similarity to SARS, I knew this was going to be bad.

“I was thinking bad like maybe 10,000 cases and 100 percent mortality in the first wave, and then it might go away with proper controls like quarantine,” Mesecar adds. “But I had no idea the potential for a pandemic on this scale at the time.”

Mesecar and Ghosh started pulling out the small molecules that had shown promise against SARS and MERS. Ghosh’s lab quickly pivoted to COVID-19 research and worked to synthesize a few hundred more molecules, sharing them with Mesecar for initial efficacy tests against the proteases.

“People are dying. We know this virus very well. We think we can make a contribution,” Ghosh says. “We believe we are in the right place at the right time with the right know-how to make a difference.”

Mesecar all but lived in his lab and office for the first three months, subsisting on cans of tuna and macaroni and ramen he would buy in bulk so he could devote more time to his work. He gathered Ghosh’s molecules, measuring the activity of the compounds and then crystallizing the molecules stuck to the proteases, a process that allows researchers to see where the drugs would bind to virus enzymes, as well as other properties of the molecule. If the molecule seemed promising from there, it was sent to other collaborators who tested the efficacy of the molecules on live virus.

Person at desk with snack illustration

While the most significant global efforts to fight the virus have focused on vaccines, Mesecar and Ghosh believe there will still be a need for drugs that can kill the virus in infected patients. They have filed three provisional patents on promising molecules, and Mesecar was awarded a patent in 2018 for his broad-spectrum coronavirus inhibitors.

“We are marching forward on antivirals. We need the Tamiflu of coronaviruses. We need a pill form that will kill the virus,” Mesecar says. “Having that in addition to a vaccine is what’s going to keep this at bay for those who can’t or won’t get a vaccine, or others who contract new variants of the virus."

To that end, Mesecar has shifted much of his lab work — and even classroom work — to identifying new targets for antiviral drugs. When in-person classes and labs were canceled last spring, Mesecar offered an undergraduate drug discovery class some hands-on experience of a different sort. He asked students to review all the potential drug targets for coronaviruses identified in the literature and write white papers on their findings.

“I was really surprised on a couple of the targets. Reading what they came up with, there are a few new targets I’m interested in understanding better,” Mesecar says.

Gaby Fernandez, a senior biology major in that class, dug into NSP-13, from a class of enzymes called helicases, which unwind DNA, an essential step for virus replication. She scoured clinical trials, review papers and any other mentions of the protein.

“We narrowed down what we currently know to help decide whether there is enough research to look for viable drug targets,” Fernandez says. “I loved working on this. It made me feel like I was contributing something potentially important during this global pandemic, and it gave me insights about how drug discovery and delivery play out.”

Practical testing

cow illustration

As the pandemic came into focus in the early months of 2020, many Purdue scientists shuttered their labs temporarily unless they had a direct tie to COVID-19 or other essential research. Some, like Mohit Verma, assistant professor of agricultural and biological engineering, saw an opportunity.

Verma has been developing a rapid test for bovine respiratory disease (BRD). As one of the most prevalent and costly illnesses in the beef and dairy industries, the disease causes about half of feedlot deaths in North America and costs producers as much as $900 million per year.

By the time a producer suspects BRD, orders a test and waits several days for the results, it may be too late. Often, the disease spreads rapidly to other animals.

The technology Verma’s lab designed is similar to a pregnancy test. Livestock producers get a nasal swab from an animal, apply it to a paper strip that is warmed to speed up chemical reactions and get a result within 60 minutes.

Even before the pandemic, Verma had considered this technology could have an application outside a farm setting. When the U.S. Department of Defense’s Defense Advanced Research Projects Agency called for proposals in 2019 for rapid biosensors that could be used in a pandemic, Verma expressed interest.

“I had this paper-based platform that I thought could fit well, and I was looking for partners,” Verma says. “I had started working with Raytheon BBN Technologies, which has a lot of algorithmic designs to identify DNA and RNA sequences in February, right when the pandemic started to grow.”

Verma’s lab quickly became all hands on deck as he pulled every available graduate student and lab technician into the project. Needing even more researchers over the summer, he brought on Molecular Agriculture Summer Institute (MASI) students, whose program had been canceled due to the pandemic.

Those students jumped in to conduct a slew of experiments to quickly improve the technology. Andres Dextre, a junior agricultural and biological engineering major, learned to test new chemical formulations on the paper strips to decrease the time it takes to get results and weed out false positives.

“After the MASI program got canceled, I was disappointed. I had made my peace that the summer was going to be a loss,” Dextre says. “It was definitely exciting to get into something like this. You can see the impact this pandemic is having on everyone, and the idea of working on something that can help people feels important.”

The tests Verma’s team is developing haven’t been used to detect virus during the pandemic so far. However, as new strains arise, it’s likely that inexpensive, simple and rapid tests will be needed on a wide scale. For instance, the technology could be used to screen airline passengers before boarding planes or employees before they come to work.

“We’re interested in serving companies or organizations that will need to test people often and quickly to ensure safe workplaces and other environments,” Verma said. “You need something scalable and cheap and something that gives confidence. We think we have that.”

Boosting drug efficiency

Years before the COVID-19 pandemic hit, Yuan Yao, professor of food science, made a fortuitous decision. He and his collaborators had developed a nanoparticle able to solubilize drugs with tough crystalline structures, making them easier to dissolve and more efficient as a treatment. When they looked for a drug to use for proof of concept, they decided to pick a tough one: niclosamide.

hands holding corn illustration

“This is a drug often used to treat tapeworms, and it may have potential as a cancer therapeutic,” Yao says. “We also know that niclosamide has potential to be used as a broad-spectrum antiviral drug and could be used to treat COVID-19. Fortunately, we have a drug-enabling agent that can make niclosamide much more effective than it could ever be on its own.”

Yao was originally interested in niclosamide for treating cancer; good results would be evidence that his nanoparticle was highly effective. While published studies have also shown that niclosamide has potential to be more effective than chloroquine, remdesivir, and lopinavir as a COVID-19 therapeutic, niclosamide’s structure keeps the human body from absorbing much of it. This drug is poorly water-soluble, so when taken orally, it can’t easily be dissolved and absorbed by patients. OHPP (octenylsuccinate hydroxypropyl phytoglycogen), the highly functional nanoparticle Yao and his collaborators prepared from a carbohydrate extracted from corn, can improve niclosamide solubility by 5,000 times, substantially increase its bioavailability, and largely reduce the progression of infection in mice.

Yao in the lab illustration

“Patients need a drug that can be taken in pill form and be effective,” Yao says. “Our nanoparticle gives niclosamide the properties it needs to meet those requirements. If this virus continues to produce new variants or other viruses appear, we may need drugs like this to care for patients who contract it.”

Yao and his collaborators have received funding to begin pre-clinical trials for the OHPP-formulated niclosamide. Pilot viability studies have indicated the formulation’s outstanding oral bioavailability and demonstrate a prolonged release of niclosamide that hasn’t been achieved with other technologies.

“Publications by other groups showed niclosamide’s antiviral effects against SARS-CoV, MERS-CoV, Zika, hepatitis C virus, influenza A and dengue. Our patented technology could be crucial to translating lab findings into practical therapeutics for patients,” Yao says. “I’m glad that OHPP, which originated from corn, is enabling a promising drug.”

the takeaway covid
  • When  outbreaks of the  coronaviruses SARS and MERS  occurred,  Andrew  Mesecar, professor and  head  of  the  Department of Biochemistry,  and his  colleague Arun Gosh, professor in  the Department of Chemistry,  researched small molecules that could be used to develop drug treatments. They  returned to that work  after receiving the SARS-CoV-2 genome.
  • These small molecules  hold promise as protease inhibitors, which bind to enzymes in viruses and disrupt  their ability to replicate.
  • Mesecar  asked students in his undergraduate drug discovery class to review  literature and submit papers on potential drug targets for coronaviruses — “hands-on” experience in a virtual class environment.
  • Mohit Verma, assistant professor of  agricultural and biological engineering,  developed  a rapid test for bovine respiratory disease  using paper test  strips to  deliver  results in  60 minutes. He  had begun  testing  that paper-based platform  to detect  human viruses and accelerated  the  work during the  pandemic.
  • Rapid tests  like Verma’s could potentially be used to screen airline passengers or  employees.
  • Years before the pandemic, Yuan Yao, professor of food science, had developed a plant-based nanoparticle, OHPP, that made it easier to dissolve drugs with tough crystalline structures.
  • One of those drugs, niclosamide, has shown potential to be effective as a COVID-19 therapeutic. OHPP helps improve its solubility by about 5,000 times, which provides better bioavailability and efficacy. Yao and his collaborators have received funding for pre-clinical trials of OHPP-formulated niclosamide.

Pivoting fast for the future

College of Agriculture scientists nimbly revived earlier work and adapted current work to address COVID-19, with goals to save lives and improve long-term recovery for patients and the economy. Their research offers hope in the face of a deadly pandemic that might be a harbinger for future generations.

Category Feature, Spring 2021

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