ATLANTA—Compounds targeting enzymes that control key processes such as fatty acid metabolism and functions related to cell membranes that are required to efficiently produce infectious viruses are potent inhibitors of SARS-CoV-2, the virus that causes COVID-19, according to a study led by the Institute for Biomedical Sciences at Georgia State University.
SARS-CoV-2, an enveloped RNA virus, is responsible for the most significant pandemic in the last century. The severity of SARS-CoV-2 has prompted urgent efforts to understand the life cycle of the virus and identify potential therapeutic targets. Using compounds known to target specifc factors in the host may reveal key pathways and processes involved in SARS-CoV-2 replication.
The study tested small molecule inhibitors that target fatty acid metabolism and VPS34, an enzyme involved in biological pathways related to cell membranes, for anti-SARS-CoV-2 activity. These targets were chosen because coronaviruses rely on host cell membranes to enter cells, establish specialized structures in a cell known as replication organelles and promote assembly of new virus particles.
The researchers found compounds targeting VPS34 are powerful inhibitors of SARS-CoV-2 replication and blocking fatty acid metabolism resulted in significantly impaired SARS-CoV-2 replication in human airway epithelial cells. The findings are published in the journal Cell Reports.
The project is a collaboration among university and industry scientists from Georgia State, Axion BioSystems Inc., and Synthego Corporation, the genome engineering company whose platforms were used to deliver cell pools lacking a key gene that confirmed the role of fatty acid synthesis in viral replication.
“These studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 replication and identify promising avenues for the development of novel countermeasures against SARS-CoV-2,” said Dr. Christopher Basler, corresponding author of the study, professor and director of the Center for Microbial Pathogenesis in the Institute for Biomedical Sciences at Georgia State and a Georgia Research Alliance Eminent Scholar in Microbial Pathogenesis.
The study revealed that VPS34 inhibited an early step in the SARS-CoV-2 replication cycle. It’s also possible that VPS34 facilitates membrane availability for the formation of replication organelles during the SARS-CoV-2 growth cycle. The researchers also discovered specific fatty acid and lipid metabolism pathways are critical for SARS-CoV-2 replication.
The data provide novel insights that may serve as the basis for potentially repurposing and developing therapeutics targeting these pathways for the treatment of COVID-19.
Co-authors of the study include Caroline G. Williams (first author), Alexander S. Jureka, Jesus A. Silvas (at Texas Biomedical Research Institute) and Basler; Anthony M. Nicolini and Stacie A. Chvatal of Axion BioSystems Inc. in Atlanta; and Jared Carlson-Stevermer, Jennifer Oki and Kevin Holden of Synthego Corporation in Redwood City, Calif.
The study was supported by grants from the National Institutes of Health, a Fast Grant for COVID-19 from the Emergent Ventures program at the Mercatus Center of George Mason University and the Augusta University–Georgia State University Seed Grant program.
To read the study, visit https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00906-2.
Caroline G. Williams
Ph.D. Student in Dr. Christopher Basler's lab
Institute for Biomedical Sciences