A group of B.C. scientists has isolated three naturally occurring compounds that prevent COVID-19 infections in human cells. The discovery, say researchers, could pave the way for the development of powerful anti-viral drugs and form a first line of defence against future pandemics.
The study, published this month in the journal Antiviral Research, analyzed the contents of a biological library containing roughly 350 natural specimens known as special metabolites. The natural occurring compounds are used by species to communicate and defend themselves across a variety of ecosystems, from the tropical reefs of Thailand, Brazil and Indonesia, to more northern climes in Italy and Canada.
“For 40 years, we have been collecting these organisms from all over the world,” said Raymond Andersen, a professor in the University of British Columbia’s Departments of Chemistry and Earth, Ocean and Atmospheric Sciences.
“About half of the drugs in clinical use are produced by these special metabolites.”
Back in a secure laboratory at the University of British Columbia, some members of the team of more than 40 researchers bathed human lung cells in solutions made from the compounds. They then added an engineered strain of the SARS-CoV-2 virus that glows a fluorescent green when it infects a cell.
Peering through a powerful microscope, the researches saw most human cells in their samples gave off a green glow. The more powerful the glow, the more infected the cell. But in the a handful of cases, the glowing was significantly muted — the compound appeared to be stifling infection.
Of the hundreds of samples from around the world, three of the compounds — all from Canada — killed 50 per cent of a viral infection, found the study.
“That’s sort of the sweet spot for drug development. You want them to be potent.” Andersen said.
All three of the potent compounds came from Canadian seas: alotaketal C from a sponge-dwelling bacteria found in Howe Sound, B.C.; bafilomycin D from bacteria found in ocean sediments in Vancouver Island’s Barkley Sound; and holyrine A from a bacteria found off the coast of Newfoundland.
(A fourth potent compound was isolated in a bacteria collected on lichen near B.C.’s Pitt River, but researchers have yet to analyze it and the compound was not included in the study.)
The sponge-derived compound produced some of the most interesting results. Instead of targeting the virus, the ancient metabolite appeared to reduce the availability of ACE2 receptors on the surface of human cells. Those are the places where the SARS-CoV-2 virus binds to human cells like a lock into a key.
The fewer cellular locks are available, the harder it is for a viral key to infect a human cell, said Andersen.
“It doesn’t kill the virus. It acts on the host cell,” he said. “It’s a mechanism of action nobody has seen before.”
It’s also one that could have deep evolutionary roots.
Evolving well over 500 million years ago, sponges represent the oldest multicellular animals in the world. Today, they inhabit every single marine habitat in the world, proliferating as the planet’s “best biofermentors” under the ice caps, along tropical reefs and in the deep sea, the UBC scientist said.
Despite their abundance and staying power, under the sea sponges remain relatively out of reach and scientists are still learning their secrets.
If the lock-closing mechanism — still a working hypothesis — proves accurate, alotaketal C could represent a powerful blueprint for a broad-spectrum anti-viral drug.
The researchers have already tested the sponge compound on several of the Delta and Omicron variants of SARS-CoV-2. Because it trains human cells to protect themselves, Andersen says he expects it to have a similar effect on the so-called ‘Kraken’ strain of the virus.
And in another test, the Vancouver Island-sourced bafilomycin D was combined with the recently discovered COVID-19 antiviral molecule N-0385, producing “synergistic” results and “an extremely valuable” starting point to develop multi-drug regimens in the treatment of the BA.2 Omicron sub-variant, the study said.
This isn't the first time marine special metabolites have shown they could help treat some of the world's most concerning infectious diseases, says Andersen.
“Some of these compounds have already been tested against dengue and zika,” he said. “Some of them have really broad spectrum activity against other viruses.”
Andersen says in the past many of the natural compounds that have inspired drugs have come from tropical ecosystems. The latest find, he said, shows that biological diversity on any corner of the planet can lead to scientific breakthroughs.
“I find it very exciting,” Andersen said, pointing to the Canadian discoveries. “This shows you don’t have to go far. You can find these things on your doorstep if you know what you’re doing.”
“These are resources that need to be protected.”
Finding a compound in nature that could form a blueprint for the next powerful drug is just the start. You need to have enough of the compound to run tests, and if all goes well through animal and human trials, produce the drug at scale.
Andersen says they have already found a way to make a synthetic analogue of alotaketal C, one that’s more potent and can easily be replicated without diving to the ocean floor. The natural compounds from Barkley Sound and Newfoundland, meanwhile, have been replicated through a fermentation process.
“We’ve got a handle on the supply problem,” Andersen said. “The next step is to make sure it works on animals.”
Factor in human trials and even the best-case scenario would require another six to eight years of development.
Regardless of how long it takes to develop a drug, Andersen says humanity needs new broad-spectrum anti-viral drugs, if not to treat COVID-19 then to protect the first wave of patients during the next pandemic as scientists scramble to develop vaccines.
“It’s one thing to come up with a vaccine. But people still get sick and go to the hospital in the early stages [of a pandemic],” he said.
“We need to have these drugs in our back pocket.”
