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New Virtual Screening Strategy Identifies Existing Lymphoma Drug (Pralatrexate) That Inhibits SARS-CoV-2 Virus Replication; Drug Targets Viral RNA-Dependent RNA Polymerase (RdRP); Viral Inhibition Is Stronger Than That Achieved by Remdesivir

A novel computational drug screening strategy, combined with lab experiments, suggest that pralatrexate, a chemotherapy medication originally developed to treat lymphoma, could potentially be repurposed to treat COVID-19. Haiping Zhang, PhD, of the Shenzhen Institutes of Advanced Technology in Shenzhen, China, and colleagues presented these findings in the open-access journal PLOS Computational Biology in an article published on December 31, 2020. The article is titled “A Novel Virtual Screening Procedure Identifies Pralatrexate As Inhibitor of SARS-CoV-2 Rdrp and It Reduces Viral Replication in Vitro.” With the COVID-19 pandemic causing illness and death worldwide, better treatments are urgently needed. One shortcut could be to repurpose existing drugs that were originally developed to treat other conditions. Computational methods can help identify such drugs by simulating how different drugs would interact with SARS-CoV-2, the virus that causes COVID -19. To aid virtual screening of existing drugs, Dr. Zhang and colleagues combined multiple computational techniques that simulate drug-virus interactions from different, complementary perspectives. They used this hybrid approach to screen 1,906 existing drugs for their potential ability to inhibit replication of SARS-CoV-2 by targeting a viral protein called RNA-dependent RNA polymerase (RdRP). The novel screening approach identified four promising drugs, which were then tested against SARS-CoV-2 in lab experiments. Two of the drugs, pralatrexate and azithromycin, successfully inhibited replication of the virus. Further lab experiments showed that pralatrexate more strongly inhibited viral replication than did remdesivir, a drug that is currently used to treat some COVID -19 patients.

These findings suggest that pralatrexate could potentially be repurposed to treat COVID -19. However, this chemotherapy drug can prompt significant side effects and is used for people with terminal lymphoma, so immediate use for COVID -19 patients is not guaranteed. Still, the findings support the use of the new screening strategy to identify drugs that could be repurposed.

"We have demonstrated the value of our novel hybrid approach that combines deep-learning technologies with more traditional simulations of molecular dynamics," Dr. Zhang says. He and his colleagues are now developing additional computational methods for generating novel molecular structures that could be developed into new drugs to treat COVID -19.

IMAGE

Colorized scanning electron micrograph of an apoptotic cell (pink) heavily infected with SARS-CoV-2 virus particles (green), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. (Credit: National Institute of Allergy and Infectious Diseases/NIH, 2020 (CC0).

[Press release] [PLOS Computational Biology article]