Slipping up for lack of interest
May 28 2020 11:21 PM
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SPOTLIGHT
SPOTLIGHT: Purdue University biochemistry graduate student Emma Lendy talks with Andy Mesecar, one of the leading scientists identifying protein targets for potential Covid-19 drug therapies, last month on campus at Purdue in West Lafayette, Indiana.

By Grace Wong

More than a decade ago, a centre was founded at Northwestern University as a rapid-response operation against infectious disease.
But its work was sporadic — a boom when epidemics like Mers hit, a bust when they were under control. Some promising drugs never made it out of the laboratory as funding waned.
Now, researchers with the Center for Structural Genomics of Infectious Diseases are rushing to find an effective treatment for Covid-19, making up for lost time against a disease that has already killed more than 352,000 people around the world, including over 100,000 in the United States.
And they hope they’ll be ready for whatever comes next.
“I think we’re making substantial strides,” said Karla Satchell, director of the centre who is a professor of microbiology-immunology at Northwestern’s Feinberg School of Medicine. “Drug discovery is a slow process, and our hope is that we can do something in time to help this round of the pandemic. But at the very least, we can do enough that this won’t happen again.”
One researcher funded through the centre is working on modifying a drug originally approved to treat hepatitis C. It isn’t on the market anymore because it was replaced by more efficient therapies, but it could be adjusted fairly quickly to disrupt how the coronavirus replicates itself.
Others at the centre, which co-ordinates research at eight universities, are reviewing past work on drugs that showed potential against the Sars epidemic in 2002 and the Mers outbreak in 2012. Both diseases are also caused by coronaviruses.
At some point, though, scientists at the centre and across the US will need to focus on future threats and break new ground.
“You can make a lot of movement fast, based on what you know,” Satchell said. “But at some point, you hit a wall where you have to discover new things.”
Andy Mesecar needs a weekend off.
An expert in biochemistry and gene therapy, he’s worked seven-day weeks for the last few months, racing to find a drug for patients with Covid-19 while teaching at Purdue University and submitting daily reports to the National Institutes of Health. The centre at Northwestern has funded his work since 2018.
Mesecar has a manuscript under review in a scientific journal on how a drug approved to treat hepatitis C could be modified to potentially treat Covid-19. His lab is one of the leading centres studying coronaviruses, and he and his team have dedicated nearly two decades to the research. But that was still not enough to rapidly create an effective therapy specific to Covid-19.
With a background in biochemistry and structural biology, Mesecar started out as an assistant professor at the University of Chicago, studying enzymes that could fight cancer. He got into infectious diseases after the anthrax attacks in the weeks after 9/11. Then, he pivoted to studying enzymes that could be used against Sars when it surfaced in November 2002.
“My training in structural biology allows me to work on any diseases that go around,” Mesecar said. “I can apply it to any disease and do so rapidly.”
The bulk of coronavirus research — both through the centre and across the country — began during the Sars epidemic and continued through the Mers outbreak less than 10 years later. At the time, hardly anything was known about coronaviruses, Satchell said, so researchers sprinted to learn its basic biochemistry and how it entered the body and replicated itself.
Remdesivir, the latest promise in treating Covid-19, was shown in animal studies to be effective against both Mers and Sars. But it was not approved for human trials until the Covid-19 pandemic hit, and is just now being distributed to some patients across the country after the US Food and Drug Administration authorised its emergency use.
During the basic science phase of drug discovery, scientists are looking for inhibitors to stop the virus. This is where Mesecar’s research lies.
When researchers identify the genetic sequence of a protein or enzyme that is essential to the virus’s replication, they then look for a compound that blocks it, called the inhibitor. The compounds are developed into a drug that not only lasts long enough in the body to kill the virus but is also nontoxic. Only then can it move to animal trials and, eventually, human trials.
When the NIH put out a call for grant proposals during the Sars outbreak, Mesecar was part of a group that focused on immunology and antibodies that could be used to treat the disease. They were given five years of funding. When the money ran out, he was faced with the question of how to continue his work. No-one was getting infected with Sars anymore, so the incentive for more research faded away and, with it, the money.
When Mers emerged in 2012, Mesecar’s team switched to this new coronavirus, publishing papers that shared their discovery of compounds that worked against it. He and his team were among the first to predict that the next coronavirus outbreak would come from bats, the suspected origin of Covid-19. “Everything we did was to predict the next outbreak,” he said. “What we wanted to do was to have compounds that could rapidly move toward the particular coronavirus strain that emerged.”
They worried their research would meet the same end as their Sars research — and they were right. Again, interest and funding declined.
To continue their work, they scoured for small amounts of funding that they could pool. But even three years ago, they didn’t have enough to support a single person fully. Around that time, the centre at Northwestern stepped in with money.
But the lull in funding had already done its damage, according to Satchell. No clinical trials of the compounds had been done by the time the pandemic hit.
“Nothing ever got out of the laboratory (for Sars),” she said. “There’s no treatment for Covid-19 that is specific to this virus and this infection, and the research tracking it really seems like it just ended. Most papers, they’ll have dates on them from 2003, 2004, 2005 and 2009, and then the literature just goes blank. It picks up again around 2014 with regards to Mers.”
It’s ultimately up to the NIH to determine which basic science research should go forward. Should it continue funding research for a disease such as Sars with no known cases anymore, or allocate money to something else, like studying drug-resistant bacteria that still kills thousands of people?
And with new viruses surfacing all the time, how does NIH ensure there is enough money for what is needed most? “You get stretched,” Mesecar said.
As the coronavirus spread at an alarming rate, the NIH was allocated $1.78 billion for research on the novel coronavirus, including $1.5 billion to the National Institute of Allergy and Infectious Diseases, which is funding the work at the Center for Structural Genomics of Infectious Diseases.
Drug therapies for Ebola, influenza, yellow fever and other viruses are now being reviewed for their potential against Covid-19, according to the NIAID. Investments are being made on more rapid testing of vaccines and antibody-based therapies.
“It is also important to note that Sars-CoV-2 emerged in 2019,” the agency said in a statement. “While NIAID supports the development of broad-spectrum therapeutics to be prepared for such an event, it is difficult to understand whether a drug is effective against a certain virus until that virus emerges.”
But Satchell, Mesecar and others point to earlier warnings. In 2015, the World Health Organization said coronaviruses were one of the top emerging health threats and likely to cause major epidemics. And in 2017, a paper was published in PLOS Pathogens by experts studying coronaviruses in horseshoe bats in China who emphasised the need for “preparedness for future emergence of Sars-like diseases.”
Mesecar said researchers could have studied the effects of certain compounds on animals so they could be more quickly developed when new viruses appeared. This was the key to Remdesivir reaching patients now. “We’re not as far behind as we could be because of the love and ingenuity of scientists who want to pursue and learn about it,” he said.
The coronavirus field is undergoing a rapid change, with many new researchers and much more money. Half the supplemental funding the centre got from NIAID went to Mesecar’s drug discovery unit — which “was not particularly well-funded and short-staffed,” Satchell said — and the other half went to other labs that are a part of the centre.
Satchell and others hope some of these people will want to stay in the field to prepare for the next public health threat. She’s seen this effect during the tuberculosis crisis, anthrax attacks and Sars, and she believes the Covid-19 pandemic will yield similar results.
“Let’s go for a good drug. Not a vaccine but a universal vaccine,” Satchell said. “Let’s understand a little more about immunology; let’s understand how this virus engages the immune system in the host response.” — Chicago Tribune/TNS



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