Thursday, May 26, 2022

Shark antibody-like proteins neutralize the COVID-19 virus

The proteins could help prepare for future coronaviruses.

Deriving small, unique antibody-like proteins known as VNARs from sharks’ immune systems could help prevent the COVID-19 virus and its variants.

Although the VNARs will not be immediately available for treatment, they can help prepare for future coronavirus outbreaks.

A study on VNAR shows that the protein can neutralize WIV1-CoV, a coronavirus capable of infecting human cells but currently circulates only in bats.

Developing treatments for such animal-borne viruses could be proven promising if that virus transmits to people.

Aaron LeBeau, a University of Wisconsin-Madison professor of pathology who helped lead the study, said, “The big issue is there are several 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 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 developing therapeutic VNARs.

Scientists derived the VNARs from Elasmogen’s large synthetic VNAR libraries for their study. 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.

preparing an arsenal of shark
‘What we are doing is preparing an arsenal of shark VNAR therapteutics that could be used down the road for future SARS outbreaks’, says scientist Aaron LeBeau. Credit: Bryce Richter

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

Scientists tested VNAR against both infectious SARS-CoV-2 and a pseudotype. This pseudotype is a version of the virus that can’t replicate in cells.

Three candidates VNARs among all were effective at stopping the virus from infecting cells. The three shark VNARs were also effective against SARS-CoV-1, which caused the first SARS outbreak in 2003.

One VNAR, named 3B4, is attached firmly to a groove on the viral spike protein near the virus binds to human cells and appears to block this attachment process. This groove is very similar among genetically diverse coronaviruses, allowing 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.

LeBeau said, “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.”

Caroline Barelle, CEO of Elasmogen, 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. It is another great example of how Elasmogen can effectively deliver potent therapeutic molecules.”

Future therapies would likely include a cocktail of multiple shark VNARs to maximize their effectiveness against diverse and mutating viruses.

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 it has yet to be tested in humans.

Journal Reference:

  1. Obinna C. Ubah, Eric W. Lake et al. Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-27611-y

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