Antibody-like proteins from the immune systems of sharks could help to prepare for future coronaviruses, according to new research
Small, unique antibody-like proteins known as VNARs, which are derived from the immune systems of sharks, can avert the virus that causes COVID-19 as well as its variants, and related coronaviruses from infecting human cells.
These new VNARs cannot yet become available to treat people, however they could help prepare for future coronavirus outbreaks, as the shark VNARs have been able to neutralise WIV1-CoV, a coronavirus that is capable of infecting human cells but currently circulates only in bats. This is the likely origin for SARS-CoV-2, the virus that causes COVID-19.
Developing treatments for animal-borne viruses ahead of time
Aaron LeBeau, a University of Wisconsin-Madison professor of pathology who helped lead the study, said: “The big issue is there are a number of coronaviruses that are poised for emergence in humans. What we’re doing is preparing an arsenal of shark VNAR therapeutics that could be used down the road for future SARS outbreaks. It’s a kind of insurance against the future.”
LeBeau, at 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 VNARs.
The findings, published in Nature Communications, demonstrated that the anti-SARS-CoV-2 VNARs were isolated from Elasmogen’s large synthetic VNAR libraries. One-tenth the size of human antibodies, the shark VNARs can bind to infectious proteins in unique ways that bolster their ability to halt infection.
LeBeau added: “These small antibody-like proteins can get into nooks and crannies that human antibodies cannot access. They can form these very unique geometries. This allows them to recognise structures in proteins that our human antibodies cannot.”
Testing the shark VNARs
The researchers tested the shark VNARs against both infectious SARS-CoV-2 and a “pseudotype,” – a version of the virus that can’t replicate in cells. Through this, they recognised three candidate VNARs from a pool of billions which effectively halted the virus from infecting human cells. The three shark VNARs were also effective against SARS-CoV-1– which was known to cause the first SARS outbreak in 2003.
Vaccines are the fundamental protection against SARS-CoV-2 and future coronaviruses, but some people, such as those with compromised immune systems, will not respond as well to vaccination. Therefore these people may benefit from other treatments like antibodies – which makes developing these treatments a continual priority.
For instance, one VNAR named 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 neutralise the MERS virus, a distant relative to 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 LeBeau suggests initial models entail the VNAR would remain effective against this new version.
The second-most-powerful shark VNAR, 2C02, seems to lock the spike protein into an inactive form. However, this VNAR’s binding site is altered in some SARS-CoV-2 variants, which likely decreases its potency.
Potential for future treatments
Future treatments could potentially include a ‘cocktail’ of multiple shark VNARs – maximising their effectiveness against diverse and mutating viruses, as this new class of drug is cheaper and easier to manufacture than human antibodies, and can be delivered into the body through various routes.
However, has yet to be tested in humans. LeBeau is therefore continuing to study the ability of shark VNARs to help in the treatment and diagnosis of cancers.
Caroline Barelle, CEO of Elasmogen, added: “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. It is another great example of how Elasmogen can effectively deliver potent therapeutic molecules.”
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