Repurposing Cancer and Seizure Medications to Aid Fight Against COVID-19

02/22/2021

Tipiracil and parampanel bound to SARS-CoV-2 proteins. Left: Structure of SARS-CoV-2 hexamer with the bound tipiracil in surface representation. Tipiracil atoms shown in color spheres (carbon, chlorine, nitrogen, and oxygen colored white, green, blue, and red, respectively). [Kim, Y., et al. 2021. “Tipiracil Binds to Uridine Site and Inhibits Nsp15 Endoribonuclease NendoU from SARS-CoV-2,” Communications Biology 4, 193. DOI:10.1038/s42003-021-01735-9. Reprinted under a Creative Commons License (CC BY 4.0).] Right: Perampanel docked with the SARS-CoV-2 main protease (Mpro). [Reprinted under a Creative Commons license (CC BY-NC-ND 4.0) from C-H Zhang, et al. 2021. DOI: 10.1021/acscentsci.1c00039]]

Two teams of researchers used resources at the Structural Biology Center at Argonne National Laboratory’s (ANL) Advanced Photon Source to investigate two drugs that may be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.

In research led by Andrzej Joachimiak of ANL and the University of Chicago, along with ANL protein crystallographer Youngchang Kim and University of Chicago structural biologist Natalia Maltseva and colleagues, the team found that tipiracil, a drug used to treat colorectal cancer, can inhibit the action of one of the main proteins that comprise SARS-CoV-2. They used high-powered X-ray beams to study one of the virus’s proteins, called Nsp15.

In a separate study, scientists from Yale University used the Structural Biology Center resource to study the structure of perampanel, an anti-seizure medication, as a starting point for SARS-CoV-2 inhibitor design. Modifying perampanel to create new configurations of the drug gave researchers new molecules that were effective against the virus. The new molecules would be used along with remdesivir, a current therapeutic agent for COVID-19.

References

Zhang, Chun-Hui, et al. Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations, ACS Central Sci. 7 (3), 467-475 (2021). DOI: 10.1021/acscentsci.1c00039

Youngchang Kim, Jacek Wower, Natalia Maltseva, Changsoo Chang, Robert Jedrzejczak, Mateusz Wilamowski, Soowon Kang, Vlad Nicolaescu, Glenn Randall, Karolina Michalska, and Andrzej Joachimiak. 2021. Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2, Communications Biology 4 (193). DOI: 10.1038/s42003-021-01735-9