According to a new study published in December, small, unique antibody-like proteins called VNARs—from the shark’s immune system—can prevent the virus SARS-CoV-2 that causes COVID-19, its variants, and related coronaviruses from infecting human cells. 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.”

These new proteins will not be used for human treatment immediately, but they can help prepare for future coronavirus outbreaks. Shark's VNARs can neutralize WIV1-CoV, which is a coronavirus that can infect human cells, but currently only spreads in bats. The virus that causes COVID-19 may have originated in bats. If these viruses can be transmitted to humans, the development of treatments for these animal-borne viruses in advance may prove useful.

The single domain variable new antigen receptors (VNARs) from the shark immune system is the smallest natural binding domain found in nature. VNAR has a flexible paratope that can recognize protein motifs that are inaccessible to classic antibodies, and has not been used to develop SARS-CoV-2 therapies.

In this study, these scientists detailed a series of VNARs identified from the VNAR phage display library screened for the SARS-CoV-2 receptor binding domain (RBD). The ability of VNAR to neutralize pseudotyped and real live SARS-CoV-2 viruses is comparable to or exceeds that of full-length immunoglobulins and other single domain antibodies. The crystallographic analysis of the two VNARs revealed that they identified different epitopes on the RBD and had distinctly different virus neutralization mechanisms unique to VNARs. Structural and biochemical data indicate that VNAR would be an effective therapeutic agent for emerging SARS-CoV-2 mutants (including Delta variants) and coronaviruses that span multiple phylogenetic lineages. This study emphasizes the usefulness of VNAR as an effective treatment against coronavirus and may become a key milestone in approaching a paradigm shift in the larger biological landscape.

Among the significant mutations of SARS-CoV-2, such as the delta variant, the 3B4 binding site has not changed. The researchers stated that this study was conducted before the Omicron mutation was discovered, but the initial model indicated that the VNAR would still be valid for this new version.

Future treatments may include a cocktail of multiple shark VNARs to maximize their effectiveness against different and mutant viruses. This new type of drug is cheaper and easier to manufacture than human antibodies, and can enter the human body through a variety of ways, but has not yet been tested in humans. The researchers are also studying the ability of shark VNARs to help treat and diagnose cancer.

Vaccines are the cornerstone of preventing SARS-CoV-2 and future coronaviruses. But some people, such as those with compromised immune systems, do not respond as well to vaccines and may benefit from other therapies such as antibodies—making the development of these treatments a current priority.

1.Ubah, Obinna C., et al. Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography. Nature Communications. 2021. 1-12.

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