OU Researchers Investigate a Possible Drug Target against COVID-19

By Hannah Johns

It has been over a year since the first case of COVID-19 was documented in the United States, and over a year since Ohio University sent its entire student body home to transition to online classes for the next two semesters. Without a doubt, 2020 was a long and hard year for the countless frontline health care workers and scientists who worked tirelessly to save the lives of those who contracted COVID-19, as well as to develop safe and effective vaccines to protect the population. 

One of these diligent workers is Dr. Jennifer Hines, an Ohio University professor and researcher who studied a potential target for therapeutic drugs in treatment against COVID-19. She, along with graduate students and Honors Tutorial College (HTC) students, investigated a highly conserved noncoding RNA element that may be an important drug target: the stem-loop II motif. 

In her research, Hines focuses on targeting non-coding regulatory RNAs.  

“When the pandemic started and I had to shut down and go all online, I was looking for any RNA that was related to SARS-CoV-2,” Hines said, “and whether or not there was any structural information already out there because there are significant similarities between that genomic RNA and the virus that caused the SARS outbreak in the early 2000s.”

She looked for this in a protein data bank and found a three-dimensional structure that had been determined in the original SARS outbreak. The paper associated with the structure discussed that it was very highly conserved across many similar viruses. After learning this, she asked herself: “What does this sequence look like in SARS-CoV-2?”

Hines soon noticed that there was a very significant single nucleotide change. A single letter in the code was different. 

“This could result in a very different three-dimensional structure,” she explained. 

Image courtesy of the CDC

A change in the building blocks of DNA can result in genetic variation. The nucleotides cytosine, thymine, guanine and adenine are arranged in a unique order to make up the DNA of everything. If a cytosine replaces an adenine, for example, that could change the entire function of the gene and or the structure of a sequence. 

Think of a sequence as a sentence that tells scientists what genetic information is present in a DNA segment. If one part of that sentence is changed, it could change its entire meaning.

The graduate students working with Hines started research by examining the 3D structure from the early 2000s SARS and computationally changing it into the sequence that is in the SARS-CoV-2. They focused on answering a key research question: “How does the 3D structure change?”

Then, undergraduate HTC students learned how to use the Ohio Supercomputer Center (OSC) remotely, do computational work and use in silico modeling programs. The OSC provided priority, unbilled access to computational and storage resources for COVID-19 research. Emily Marino, one of the HTC students, described the research process.

“[We] began looking at if they can take all of these small-molecule drugs from databases—that are already approved by the FDA—and see how well the computer can predict that they would bind together to this piece of RNA, the SARS-CoV-2 model,” Marino said. 

The students learned how to dock small molecules to the RNA to look for potential therapeutic drugs. In showing them these processes and doing calculations as demonstrations for the students, Hines recalled that “it was clear that this was a very interesting change between these two viruses to really study in more detail.”

“[The research was] an interwoven team experience with undergrad and grad students doing computational and in-lab experiments and informing one another of results,” Hines said. “It was a very exciting group effort.” 

Hines complemented these computational studies with experimental studies in the lab, where they compared the two different sequences side by side, with experimental analyses to figure out how they were behaving in a 3D solution. 

“Developing the paper was very much like shining a spotlight on the significance of this single nucleotide change in this particular piece of RNA, but one of the challenges is that no one has figured out what this piece does,” Hines said. “But because it is so highly conserved in so many different similar viruses, it must have an important role. The challenge is, without knowing how it works, it is really hard to assay the impact of a drug.” 

However, Hines emphasized that the purpose of this paper was not to identify drugs that can be produced to cure the disease; that information is not yet known.

“Here is a target already highlighted by someone earlier, and now we have looked at targeting it with small molecules and we do see a structural difference,” she said. 

According to Hines, since RNA function is so closely tied to its structure, if one can disrupt the RNA structure, that could mean that it is probable to disrupt its function without even knowing its function. 

Hines’ work will be beneficial to other researchers who are seeking to understand this conserved part of the SARS-CoV-2 genome. 

Today, our understanding of COVID-19 has significantly increased. Experts have determined and implemented safety measures like masking and social distancing to reduce transmission. Vaccines have also been developed and authorized for emergency use to prevent COVID-19. 

Currently, the U.S. has three vaccines authorized and recommended for use. Vaccination of people globally is an important tool to help stop the pandemic. It is also important to continue vigilance to wear masks and stay away from large crowds. 

The light at the end of the tunnel, after this long painful year, is beginning to appear, but preventative measures are still critical. Wear a mask, social distance and get vaccinated to continue protecting the Athens community.

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