Many organisms have evolved antiviral substances to fend off infection by viruses, so a potential treasure trove of new treatments for COVID-19 may lie in nature’s library. A recent study published in Antiviral Research by an international team of 21 scientists investigated more than 350 compounds extracted from plants, fungi, and marine sponges to isolate potential precursors to antiviral drugs potentially effective against COVID-19 variants like omicron. The consortium, led by a team at the University of British Columbia with collaborators at other universities in Canada plus the US, Italy, Brazil, and Thailand, identified 26 compounds that reduce viral infection in cells, three of which are effective in small doses.
Screening the natural-sourced compounds for antiviral efficacy involved bathing infected human lung cells in solutions. Co-lead author on the paper, Dr. Jimena Pérez-Vargas, research associate in the department of microbiology and immunology, explains that “In the beginning we start with one single concentration of the compound to see if we can see some effect.” If an effect was detected, the team then differed concentrations to test dosage effects. They also examined toxicity – “to make sure there is good [viral] inhibition, but without toxicity to the cells,” says Pérez-Vargas. Antiviral efficacy of these compounds was examined against a version of SARS-CoV-2 that causes infected cells to glow fluorescent green. This technique, in combination with software to automate cell counting, allowed efficient screening of thousands of compounds.
About one out of five compounds screened (73/373) of showed potential antiviral properties, explains co-lead author, UBC molecular virologist François Jean. “This is a success rate of 20%, which is pretty impressive,” he says. The most efficacious three molecules came from Canadian marine organisms. Alotaketal C is from a British Columbian sea sponge collected in Howe Sound. Bafilomycin D comes from a marine bacteria collected in Barkley Sound, B.C. And holyrine A is from marine bacteria collected off Newfoundland.
The advantage of the compounds newly identified as antivirals is that they target host cells, rather than the virus itself, blocking the virus from replicating and thus helping cells to recover.
For bafilomycin D, the researchers also tested its effectiveness in combination with the recently discovered COVID-19 antiviral molecule N-0385, finding that together, they produce a promising synergistic defence against omicron subvariant BA.2.
As for alotaketal C, it appears to work against the virus by targeting a host protein, explains Jean. With this molecule previously studied, chemists have already determined how to synthesize it, so the next step is to see if alotaketal C can be tweaked into an even more effective antiviral. Synthesis makes it possible to scale up production to eventually support clinical trials.
Why might sponges be a good source of antivirals? Jean speculates that filtering vast quantities of ocean water likely creates strong evolutionary pressure for antiviral properties in their body chemistry. “These organisms are amazing and we are just in the first steps to discover how tremendous they are,” sea sponge expert Camille Victoria Leal said on LinkedIn in response to the new research. Leal, a molecular biologist at the Universidade Federal do Rio de Janeiro, Brazil, works on the metagenomics of Atlantic and Antarctic sponges.
Immunotherapy expert Bruce Lyday, who is Chief Executive Officer at Coronavax LLC, said of the UBC-led research, “it looks like they’ve got some encouraging results.” He cautioned, however, that there’s a long road between identifying antiviral chemicals in the lab and drug development. “In the lab, you control the conditions in a cellular monoculture. In a person, it’s a whole ’nother ballgame,” he says, due to living bodies having thousands of different cell types.
Jean stressed that the intention is not to harvest these compounds directly from natural sources, which could threaten wild populations, but rather to synthesize the useful compounds in the lab. The next phase of the planned research is to test the most promising of these compounds in animal models. Jean says they will continue their testing against incoming new viral variants, and are looking for partners in industry.
With use early after infection, the currently approved antivirals remdesivir and paxlovid/nirmatrelvir are effective at preventing hospitalization and mortality due to COVID-19. However, over time, SARS-CoV-2 may develop resistance to these monotherapies, so a search for alternatives, like these candidate compounds, is valuable.
When it comes to emerging diseases, “biodiversity may the solution,” Jean says, so we need to conserve it wisely.