According to a new study published Dec. 16, small, unique
anti-body-like proteins known as VNARs, which are derived from shark immune
systems, can prevent the virus that causes COVID-19, its variants, and related
coronaviruses from infecting human cells.
The new VNARs will not be available as a treatment for people right away, but they can aid in the prevention of future coronavirus outbreaks. WIV1-CoV, a coronavirus capable of infecting human cells but currently circulating only in bats, where SARS-CoV-2, the virus that causes COVID-19, is thought to have originated, was neutralized by shark VNARs. Treatments for animal-borne viruses can be developed ahead of time, which can be useful if the viruses spread to humans. “The big issue is that a number of coronaviruses are poised for emergence in humans,” says Aaron LeBeau, a pathology professor at the University of Wisconsin-Madison who helped lead the study.
. “What we’re doing is putting together an arsenal of shark VNAR therapeutics that could be used in future SARS outbreaks as a sort of insurance policy.” Researchers from the University of Minnesota and Elasmogen, a bio-medical company based in Scotland that is developing therapeutic VNARs, collaborated with LeBeau and his lab in the School of Medicine and Public Health. Nature Communications published the team’s findings. Elasmogen’s large synthetic VNAR libraries were used to isolate an-ti-SARS-CoV-2 VNARs.
Shark VNARs, which are a tenth of the size of human antibodies, can bind to infectious proteins in unusual ways, enhancing their ability to stop infection. “These small antibody-like proteins can get into places where human antibodies can’t,” LeBeau explains. “Because they can form these very specific geometries, they can recognize structures in proteins that our human antibodies can’t.” The VNARs from sharks were tested against both infectious SARS-CoV-2 and a “pseudotype,” a virus that cannot replicate in cells. From a pool of billions, they found three candidate VNARs that effectively prevented the virus from infecting human cells. SARS-CoV-1, which caused the first SARS outbreak in 2003, was also resistant to the three shark VNARs. One VNAR, 3B4, appears to bind strongly to a groove on the viral spike protein near where the virus binds to human cells and prevents the virus from binding to the cells. This groove is shared by a wide range of coronaviruses, allowing 3B4 to effectively neutralize the MERS virus, a distant cousin of the SARS viruses. Because of its ability to bind such conserved regions across a wide range of coronaviruses, 3B4 is a promising candidate for fighting vi-ruses that have not yet infected humans. The 3B4 binding site is also unaffected in major SARS-CoV-2 variants, such as the delta variant. Al-though this research was done before the omicron variant was dis-covered, preliminary models suggest the VNAR would still be effective against it, according to LeBeau. 2CO2, the second-most powerful shark VNAR, appears to render the spike protein inactive. However, the binding site of this VNAR is altered in some SARS-CoV-2 variants, reducing its potency. “What’s exciting is that the mechanism of action of these new potential drug molecules against SARS-CoV-2 differs from that of other biologics and antibodies targeting this virus,” says Caroline Barelle, CEO of Elasmogen. “It’s yet another example of Elasmogen’s ability to efficiently de-liver potent therapeutic molecules.” To maximize their effectiveness against diverse and mutating viruses, future therapies are likely to include a cocktail of multiple shark
VNARs. This new class of drug is less expensive and easier to make than human antibodies, and it can be delivered into the body in a variety of ways, but it has not yet been tested in humans. LeBeau is also looking into how shark VNARs can aid in cancer treatment and diagnosis. Vaccines are the cornerstone of protection against SARS-CoV-2 and other coronaviruses in the future. However, some people, such as those with weakened immune sys-tems, do not respond well to vacci-nation and may benefit from other treatments, such as antibodies, which is why research into these treatments is ongoing.
This work was supported in part by the National Institutes of Health (grants RO1 CA237272, RO1 CA233562, R01 CA245922, T32 HL007741, NIH T32 A1055433, R01 GM088790, R35 GM118047, P01 CA234228, P30 GM124165 and S10 RR029205) and in the U.K. by Elas-mogen Ltd. and funding from Scot-tish Gov RAPID RESEARCH IN COVID-19 PROGRAMME COV/AB-N/20/01.