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Mount Sinai researchers have shown that tiny, robust immune particles derived from the blood of a llama could provide a strong protection against all variants of Covid-19including Omicron, and 18 similar viruses, including SARS-CoV-2 and SARS-CoV-1, responsible for the 2003 SARS outbreak.
The team suggests, in a paper published Tuesday in Cell Reports, that these “superimmune” molecules, known as nanobodies, could be the precursors to a treatment or rapid-acting inhalable antiviral spray that could be stored and used globally against the current pandemic and future viruses.
Llamas, camels and alpacas have a unique immune system compared to the rest of the animal kingdom. They produce antibodies with only one polypeptide chain instead of two, resulting in antibodies that are about a tenth the size of normal ones, are exceptionally stable, and can bind tightly to disease targets.
Due to these unique properties, researchers can easily link multiple nanobodies in a chain, thus if a virus tries to escape by mutating, another nanobody is ready to keep it in check.
“Due to their small size and broad neutralizing activities, these camelid nanobodies are likely to be effective against future variants and outbreaks of SARS-like viruses,” said lead author Dr. Yi Shi, Associate Professor of Pharmacological Sciences, and Director of the Center. in Protein Engineering and Therapeutics at the Icahn School of Medicine at Mount Sinai. “Their superior stability, low production costs, and ability to protect the upper and lower airways against infection mean they could provide a foundational therapy for supplement vaccines and medications of monoclonal antibodies if a new variant of Covid-19 or SARS-CoV-3 emerges, “he adds.
As a fundamental part of their study, Dr. Shi’s team immunized the llama ‘Wally’ with the receptor binding domain (RBD) of SARS-CoV-2, the short or spike fragment of the virus that adheres to the protein in the surface of human cells to enter and spread infection. They found that repeated immunization with the RBD resulted in Wally producing nanobodies that recognized not only SARS-CoV-2, the virus that causes Covid-19, but a wide range of other coronaviruses, conferring what the researchers called “superimmunity.” Building on this discovery, the team isolated and validated a large repertoire of highly potent antiviral nanobodies effective against a broad spectrum of SARS-like viruses.
“We learned that the tiny size of these nanobodies gives them a crucial advantage against a rapidly mutating virus,” explains co-author Ian Wilson, MD, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at Scripps Research, La Jolla, California. “Specifically, it allows them to penetrate more holes, nooks and crannies on the surface of the virus and thus bind to multiple regions to prevent the virus from escaping and mutating,” he adds.
From this structural information, the team designed a ultra-powerful nanobody that can simultaneously bind to two regions in the RBD of SARS-like viruses to prevent mutational escape. The resulting molecule (PiN-31) is extremely stable and, in its aerosol form, can be used as an inhaled treatment or spraywhich the same team has shown in previous work to be effective against SARS-CoV-2.
“While more research is needed, we believe that the ultrapotent, broadly shielded nanobodies we were able to isolate in the lab can be harnessed for use in humans,” said Dr. Shi, who conducted most of the research at the University of Pittsburgh. before moving his lab to Icahn Mount Sinai. What makes this possible form of treatment even more attractive, he adds, is that these highly versatile antiviral agents can be produced quickly virtually anywhere from microbes like E.coli or yeast cells. In the past, nanobody therapies have been clinically shown to be safe and effective against human diseases, such as blood clotting disorder and cancer.
“Winning the race against the current pandemic, as well as future viral outbreaks, will depend on the rapid development and equitable distribution of an arsenal of convenient and cost-effective technologies. We strongly believe that the novel, inhalable and extremely potent nanobodies that we have discovered can meet that demand on a global scale, particularly in developing countries that are most vulnerable to viruses and the lack of therapies to treat them,” emphasizes Dr. Shi.
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