Scientists are exploring every possible option when it comes to the development of COVID-19 treatments. A potential therapeutic could be found in Single-domain Variable New Antigen Receptors (VNARs) derived from the immune system of sharks. These unique, antibody-like proteins are the smallest naturally occurring binding domains found in nature. New research suggests that they can prevent variants of SARS-CoV-2, and related coronaviruses, from infecting human cells.

The VNARs will not be immediately available as a treatment in people, but they could be useful in future coronavirus outbreaks. The shark VNARs were able to neutralize WIV1-CoV, a coronavirus that is capable of infecting human cells but currently circulates only in bats, where SARS-CoV-2, likely originated.

This work is published in Nature Communications in the paper, “Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography.

“The big issue is there are a number of coronaviruses that are poised for emergence in humans,” said Aaron LeBeau, PhD, associate professor of pathology at the University of Wisconsin–Madison. “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.”

The shark VNARs were tested against both infectious SARS-CoV-2 and a “pseudotype,”—a version of the virus that can’t replicate in cells. The researchers identified three candidate VNARs from a pool of billions that effectively stopped the virus from infecting human cells. The three shark VNARs were also effective against SARS-CoV-1, which caused the SARS outbreak in 2003.

“These small antibody-like proteins can get into nooks and crannies that human antibodies cannot access,” said LeBeau. “They can form these very unique geometries. This allows them to recognize structures in proteins that our human antibodies cannot.”

The authors wrote that the ability of the VNARs to neutralize pseudotype and authentic live SARS-CoV-2 virus, “rivaled or exceeded that of full-length immunoglobulins and other single-domain antibodies.”

One VNAR, 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 conserved among genetically diverse coronaviruses, which allows 3B4 to effectively neutralize the MERS virus, a cousin of the SARS viruses and makes 3B4 an attractive candidate for 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 VNAR would remain effective against this new version, LeBeau said.

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.

“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,” said Caroline Barelle, PhD, CEO of Elasmogen—a biomedical company in Scotland that is developing therapeutic VNARs. The anti-SARS-CoV-2 VNARs were isolated by screening Elasmogen’s large VNAR phage display library against the SARS-CoV-2 receptor-binding domain (RBD).

Future therapies would likely include a cocktail of multiple shark VNARs 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.