29 June 2020

Drug-target dragnet

Lucio Frydman is part of a global team of science detectives leaving no stone unturned in their hunt for a weakness in the virus that causes COVID-19. Lucio Frydman is part of a global team of science detectives leaving no stone unturned in their hunt for a weakness in the virus that causes COVID-19. Illustration by Caroline McNiel, photo by Stephen Bilenky

Inside the virus that causes COVID-19 are thousands of potential drug targets. As part of a global team, Lucio Frydman is on a needle-in-a-haystack hunt for the best candidates.

By KRISTEN COYNE

We've all seen the classic whodunit stories where every character remains a suspect until the very end, at which point a detective finally puts the pieces together to solve the mystery.

Today, scientists across the globe are grappling with a real and very serious mystery: Where are the weak links in SARS-CoV-2, the virus that causes COVID-19, and how can science exploit those vulnerabilities to destroy it?

COMBATTING COVID

This series focuses on MagLab scientists who are leveraging their expertise and high-field magnets in the fight against COVID-19.

All of the 29 proteins comprising the SARS-CoV-2 are suspects — suspected as possible candidates for drug targets. So is all the RNA genome that the virus uses to build these proteins in its host cell as it seeks to replicate itself.

The SARS-CoV-2 genetic information rests in about 30,000 RNA fragments called nucleotides. That's a lot of suspects. A mystery of that scale and gravity needs more than a detective: It needs a whole army of them.

Luckily, such an army exists. Called the COVID19-NMR project, it is made up of dozens of scientists from around the world using nuclear magnetic resonance (NMR) high-field magnets to deconstruct SARS-CoV-2. Lucio Frydman, chief scientist for chemistry and biology at the National High Magnetic Field Laboratory and a professor of chemistry at Israel's Weizmann Institute of Science, is one of them. But being a COVID detective is the last thing that Frydman expected to be doing.

 

Working on Frydman’s COVID research are Weizmann Institute scientists Sabine Akabayov (left) and Tali Scherf (right), and Ph.D. student Mihajlo Novakovic (middle).

Working on Frydman’s COVID research are Weizmann Institute scientists Sabine Akabayov (left) and Tali Scherf (right), and Ph.D. student Mihajlo Novakovic (middle).
Photo credit: Rahamim Guliamov

 

"If you had told me six months ago that I'd be running NMR spectra on viral RNAs, I would have laughed," he said recently from his office outside Tel Aviv, "because it was really very far away from our activities and our interests."

But Frydman, an international expert in NMR technique development, got "very annoyed" when the pandemic sidelined him and began looking for ways to make himself useful. When he heard about the NMR project, he knew he had something to contribute.

Headquartered at Goethe University in Frankfurt, Germany, the project's mission is to use NMR to examine the proteins and RNA fragments that make up the virus. NMR uses magnets and radio waves to find out how atoms that make up these structures are connected, and how those relationships define their dynamic function. By monitoring SARS-CoV-2 constituents in their native environment, this technique, which yields amazing detail when coupled with high magnetic fields, could help scientists identify Achilles’ heels in those structures vulnerable to the right drug.

Given the high stakes, this is definitely not science as usual. The teams are working quickly and openly sharing results as they resolve one protein and RNA fragment after another. Frydman's team is already drafting their first publication.

"It's only science, I think, and rational action that will save the day."

— Lucio Frydman

"There are people focusing on the interactions between the drugs and the proteins, and people focusing on interactions between the drugs and the RNAs, because we don't know what will work," Frydman explained. "So we're trying everything against everyone."

The project is taking the divide-and-conquer approach, and Frydman's team is tackling a number of the viral RNA fragments. They are running a battery of NMR tests using a powerful 1,000-megahertz NMR magnet at the Weizmann Institute that produces high-resolution data on the fragments' structures. In addition to standard NMR measurements, Frydman's team is developing new multidimensional NMR techniques that will benefit not just this project, he said, but hopefully the field as a whole.

Moving swiftly, the researchers are almost done characterizing their fragments and are poised to start testing them against various drugs.

Although Frydman's NMR and magnetic resonance imaging (MRI) work is internationally recognized, he's a bit outside his comfort zone in applied structural biology, he said. But that makes anything he can do to help solve the COVID mystery all the more fulfilling.

"It's nice to have a chance to do something that could make even a little contribution to defeating this problem," he said. "In the end, it's only science, I think, and rational action that will save the day.

"In that sense," he added, "it was not such a bad choice of profession after all."


The National High Magnetic Field Laboratory is the world’s largest and highest-powered magnet facility. Located at Florida State University, the University of Florida and Los Alamos National Laboratory, the interdisciplinary National MagLab hosts scientists from around the world to perform basic research in high magnetic fields, advancing our understanding of materials, energy and life. The lab is funded by the National Science Foundation (DMR-1644779) and the state of Florida. For more information, visit us online at nationalmaglab.org or follow us on Facebook, Twitter, Instagram and Pinterest at NationalMagLab.