Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics

An international team of researchers led by CoVaRR-Net Pillar 10 Lead Dr. François Jean (Professor of Virology, Department of Microbiology and Immunology, University of British Columbia) investigated a catalogue of more than 350 compounds derived from natural sources including plants, fungi, and marine sponges in a bid to identify new antiviral drugs to treat COVID-19 variants such as omicron. “This interdisciplinary research team is unraveling the important possibilities of biodiversity and natural resources and discovering nature-based solutions for global health challenges such as COVID-19,” said senior author Dr. Jean.

By incubating human lung cells in vitro with these natural products and then infecting the cells with SARS-CoV-2, they identified 26 compounds that completely reduced viral infection. Three were effective in the cells—at nanomolar doses (alotaketal C, bafilomycin D, and holyrine A).  “The advantage of these three compounds is that they are targeting the cells, rather than the virus, blocking the virus from replicating and helping the cell to recover,” said co-first author Dr. Jimena Pérez-Vargas, a research associate in Dr. Jean’s lab. “Human cells evolve more slowly than viruses, so these compounds could work against future variants and other viruses such as influenza if they use the same mechanisms.”

The three most effective compounds were found in Canada: alotaketal C from a sea sponge collected in Howe Sound, B.C., bafilomycin D from marine bacteria collected in Barkley Sound, B.C., and holyrine A from marine bacteria collected in Newfoundland waters.

Further testing showed the three compounds were effective against the Delta variant and several Omicron variants, and they are about as safe for human cells as current COVID-19 treatments. Many of these treatments are no longer effective against currently circulating Omicron variants because the virus is evolving. This highlights the need for new antivirals, said Dr. Jean.

The researchers explored how effective the compound bafilomycin D was when used in combination with a COVID-19 antiviral, the molecule N-0385. They found bafilomycin D and N-0385 worked synergistically against the Omicron subvariant BA.2. This suggests a promising starting point for developing multidrug treatments of Omicron variants that are efficacious in treating COVID-19 and other viruses.

The researchers plan to test the compounds in animal models within the next six months. “Our research is also paving the way for large-scale testing of natural product medicines that can block infection associated with other respiratory viruses of great concern in Canada and around the world, such as influenza A and RSV,” said Dr. Jean.

Funding for this study was provided by the Rapid Research Funding program of the Canadian Institutes of Health Research (CIHR), the COVID-19 Rapid Response Funding Initiative of Genome British Columbia, and CoVaRR-Net.

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