Millions of years An unknown common ancestor of today’s llamas, camels and alpacas underwent an unusual genetic mutation. This evolutionary occurrence gave llamas and their relatives a strange type of antibody that no other mammal has, which, surprisingly, could end up aiding in the fight against Covid-19. This Monday in the newspaper Nature Structural and Molecular BiologyResearchers from the Rosalind Franklin Institute and the University of Oxford reported on the discovery of two flame antibodies, also called “nanobodies,” that could prevent the virus that causes Covid-19 to infect human cells.
“These [nanobodies] it can block, quite potently block, the interaction between the virus and the human cell, “says Ray Owens, a professor of molecular biology at Oxford University and one of the study’s lead authors.” They basically neutralize the virus. “
Like all antibodies, the nanobodies that Owens and his team developed have the ability to recognize and bind to a specific location on a specific protein, in this case, so-called “spike proteins” that cover the surface of the new coronavirus. When these spikes adhere to ACE2, a protein found on the outside of many human cells, the coronavirus can enter and infect those cells. However, if the spike proteins are blocked from binding to ACE2, the virus will float harmlessly, unable to invade.
Most species, including humans, produce very similar antibodies. Typically, antibodies developed for medical treatments are first produced in laboratory animals like rabbits, then isolated and genetically engineered to look more like human antibodies. But some species, including llamas, their fellow camelids, and sharks, are rare antibody critters. These animals make nanobodies, so called because they are substantially smaller than their antibody cousins.
These small molecules have their own particular benefits. “Sometimes there may be a particular pocket that forms on the surface of an embedded protein,” says Jason McLellan, associate professor of molecular biosciences at the University of Texas at Austin, who also discovered a flame nanobody that blocks the protein. spike. binding to ACE2. The larger antibodies, he says, “cannot bind within that pocket.”
Even when used in exactly the same places, nanobodies can have an advantage over human antibodies. “They are very stable,” says Owens. Unlike most antibodies, they maintain their shape in extreme environments, such as the human stomach.
Given these advantages, nanobodies have been developed as treatments for diseases, and one has even been approved by the FDA as a cancer treatment. The proven method of developing nanobodies is to inject a harmless chunk of the pathogen into a flame and wait for the animal to generate an immune response. But inoculating a flame and extracting its nanobodies is a month-long process, slow by Covid-19 era research standards. So Owens and his colleagues took a different tactic.
They started with a huge set of nanobodies that had previously been isolated from the flames. “We have a complete collection of different sequences with different binding potentials,” says Owens. They then used the spike protein to “fish” for any nanobody that binds to it. This strategy allowed them to quickly identify a nanobody that had potential against SARS-CoV-2.
Unfortunately, this nanobody did not bind to the protein strong enough to effectively block the new coronavirus from entering cells. So Owens and his team randomly mutated the region of the nanobody that connected to the spike protein, hoping to create a perfect fit. And they succeeded: In the presence of large enough amounts of one of these mutated nanobodies, SARS-CoV-2 was completely unable to enter human cells. “They literally can’t develop an infection,” says Owens.
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