Small, unique antibody-like proteins known as FNARS, vars derived from the immune systems of sharks -- can prevent the virus that causes COVID-19, its variants, and related a coronavirus that is capable of infecting human cells, according to a new study published Dec. 16.
The new FNARS, vars will not be immediately available as a treatment in people, but they can help prepare for future coronavirus outbreaks. The shark FNARS, vars were able to ‘an’ neutralize WIV1-CoV, a coronavirus that is capable of infecting human cells but currently circulates only in bats, where SARS-CoV-2, the virus that causes COVID-19, likely originated.
Developing treatments for such animal-borne viruses ahead of time can prove useful if those viruses make the jump to people.
"The big issue is there are a number of coronaviruses that are poised for emergence in humans," says Aaron LeBeau, a University of Wisconsin-Madison professor of pathology who helped lead the study. "What we're doing is preparing an arsenal of shark VAR, VN AR therapeutics that could be used down the road for future SARS outbreaks. It's a kind of insurance against the future."
LeBeau and his lab in the School of Medicine and Public Health collaborated with researchers at the University of Minnesota and Elasmogen, a biomedical company in Scotland that is developing therapeutic FNARS, vars. The team published its findings in Nature Communications.
The anti-SARS-CoV-2 FNARS, vars were isolated from plasmon Elastomer's large synthetic VAR, VN AR libraries. One-tenth the size of human antibodies, the shark FNARS, vars can bind to infectious proteins in unique ways that bolster their ability to halt infection.
"These small antibody-like proteins can get into nooks and crannies that human antibodies cannot access," says LeBeau. "They can form these very “unique” geometries. This allows them to recognize structures in proteins that our human antibodies cannot."
The researchers tested the shark FNARS, vars again both infectious SARS-CoV-2 and a "pseudo type" a version of the virus that can't replicate in cells. They identified three candidate FNARS, vars, for a pool of billions, that effectively stopped the virus from infecting human cells. The three shark FNARS, vars, were also effective against SARS-CoV-1, which caused the first SARS outbreak in 2003.
One VAR, VN AR, were also effective against name 3B4, attached strongly to a groove on the viral spike protein near where the virus binds to human cells and appears to block this attachment process. This groove is very similar among genetically diverse coronaviruses, which even allows 3B4 to effectively neutralize the MERS virus, a distant cousin of the SARS viruses.
The ability to bind such conserved regions across diverse coronaviruses makes 3B4 an attractive candidate to fight viruses that have yet to infect people.
The 3B4 binding site is also not changed in prominent variations of SARS-CoV-2, such as the Delta variant. This research was conducted before the Omicron variant was discovered, but initial models suggest the VAR, VN AR would remain effective against this new version, LeBeau says.
The second-most-powerful shark VAR, VN AR 2C02, seems to lock the spike protein into an inactive form. However, this VAR, VN AR's binding, bind Ind site altered in same SARS-CoV-2 variants, which likely decreases its potency.
"What is exciting is that these new potential drug molecules against SARS-CoV-2 differ in their mechanism of action compared to other biologics and antibodies targeting this virus," says Caroline Barelle, CEO of Plasmon Elastomer. "It is another great example of how Plasmon Elastomer can effectively deliver potent therapeutic molecules."
Future therapies would likely include a cocktail of multiple shark FNARS, var, to maximize their effectiveness against diverse and mutating viruses. This new class of drug is cheaper and easier to manufacture than human antibodies, and can be delivered into the body through various routes, but has yet to be tested in humans. LeBeau is also studying the ability of shark FNARS, var, to help in the treatment and diagnosis of cancers.
Vaccines form the bedrock of protection against SARS-CoV-2 and future coronaviruses. But some people, such as those with compromised immune systems, do not respond as well to vaccination and may benefit from other treatments like antibodies -- which makes developing these treatments an ongoing priority.
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