Yuk-Ching Tse-Dinh, director of the FIU Biomolecular Sciences Institute, and associate director Prem Chapagain have teamed up with researchers from the Texas Medical Branch (UTMB) of Galveston and the National Cancer Institute. The team is looking for potential treatment leads, hoping to reduce the spread of the virus in at least one of those infected individuals. There are no evidence-based treatments at present or for any other.
Last month, UTMB’s Dr. Mariano García-Blanco, in his discovery at BioRxiv, reported that enzymes rely on topoisomerase III-ß (TOP3B) as a host factor. Generally, topiosomerases aid in DNA replication within human cells. But when some viruses, including dengue, zika, and top3B latch on, they use enzymes to help collect new copies of the virus, transforming infected cells into virus factories.
On this discovery, García-Blanco helped Topo-Dinh, an internationally known specialist in topoisomerase, who could begin screening a drug that could block enzymes and high numbers in a person’s body May prevent multiplication.
“We approached FIU as a place where the best blockers could come in,” said Garcia-Blanco.
Tse-Dinh is starting with drugs already approved by the Food and Drug Administration as it looks for a treatment that can be tested quickly on patients.
“We’re targeting a host factor, something already in the human cell that is hijacking the virus,” Ts-Dinh said. “If the cell’s TOP3B is not working, the virus will not do so well.”
Researchers believe that antiviral drugs can be combined with the ToNMB inhibitor to give the virus a double whammy and improve its chances of recovering for those who are seriously ill.
“Our researchers are focused on real, concrete solutions to the biggest challenges of our time,” said Mike Heithaus, dean of FIU’s College of Arts, Sciences and Education. “This effort, if successful, is beyond the current epidemic. This may provide a new approach to treat other viruses and even emerging ones. ”
But with thousands of FDA-approved drugs, knowing where to start is a real challenge. The place where Chapagain comes.
“A lot of researchers have drawn attention from their own projects because it is suddenly hitting us like a hammer,” said Chapagain.
Using artificial intelligence and molecular modeling, physicists were able to quickly identify top drug candidates that could possibly serve as TOP3B inhibitors. Tse-Dinh and Ph.D. Students Ahmed Cedek and Tumpa Dasgupta are testing drugs that are related to the pure version of TOP3B and the associated topoisomes. Tse-Dinh is referring to drugs that potentially show Garcia-Blanco’s team now testing them, including living cell cultures and viruses.
Companion, which includes Dr. from the National Cancer Institute. Also included are Yves Pomiere, hyper-focused, working long hours in his labs across the country and simultaneously attempting to block TOP3B.
Garcia-Blanco separated his social team into two small groups to increase social distances and to ensure that one of those groups also had to quarantine.
Meanwhile Chappagne is working remotely at his home, refining his modeling and continuing to search for other potential drug candidates.
“We really feel the urgency,” Tse-Dinh said. “But we have to work with a scientific basis.”
Topoisomerase III is required for efficient replication of positive-sense RNA viruses.
Based on a genome-scale loss-of-function screen, we found that topoisomerase III-ome (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 signaling.
Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SAR3-CoV-2. While there are no drugs that specifically inhibit this topiosomerase, we believe that TOP3B is an attractive anti-viral target.