As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.
Led by UCSF graduate student Michael Schoof, a team of researchers engineered a completely synthetic, production-ready molecule that straitjackets the crucial SARS-CoV-2 machinery that allows the virus to infect our cells. As reported in a new paper, now available on the preprint server bioRxiv, experiments using live virus show that the molecule is among the most potent SARS-CoV-2 antivirals yet discovered.
In an aerosol formulation they tested, dubbed “AeroNabs” by the researchers, these molecules could be self-administered with a nasal spray or inhaler. Used once a day, AeroNabs could provide powerful, reliable protection against SARS-CoV-2 until a vaccine becomes available. The research team is in active discussions with commercial partners to ramp up manufacturing and clinical testing of AeroNabs. If these tests are successful, the scientists aim to make AeroNabs widely available as an inexpensive, over-the-counter medication to prevent and treat COVID-19.
“Far more effective than wearable forms of personal protective equipment, we think of AeroNabs as a molecular form of PPE that could serve as an important stopgap until vaccines provide a more permanent solution to COVID-19,” said AeroNabs co-inventor Peter Walter, PhD, professor of biochemistry and biophysics at UCSF and a Howard Hughes Medical Institute Investigator. For those who cannot access or don’t respond to SARS-CoV-2 vaccines, Walter added, AeroNabs could be a more permanent line of defense against COVID-19.
“We assembled an incredible group of talented biochemists, cell biologists, virologists and structural biologists to get the project from start to finish in only a few months,” said Schoof, a member of the Walter lab and an AeroNabs co-inventor.
Llama-Inspired Design
Though engineered entirely in the lab, AeroNabs were inspired by nanobodies, antibody-like immune proteins that naturally occur in llamas, camels and related animals. Since their discovery in a Belgian lab in the late 1980s, the distinctive properties of nanobodies have intrigued scientists worldwide.
“Though they function much like the antibodies found in the human immune system, nanobodies offer a number of unique advantages for effective therapeutics against SARS-CoV-2,” explained co-inventor Aashish Manglik, MD, PhD, an assistant professor of pharmaceutical chemistry who frequently employs nanobodies as a tool in his research on the structure and function of proteins that send and receive signals across the cell’s membrane.
For example, nanobodies are an order of magnitude smaller than human antibodies, which makes them easier to manipulate and modify in the lab. Their small size and relatively simple structure also makes
them significantly more stable than the antibodies of other mammals. Plus, unlike human antibodies, nanobodies can be easily and inexpensively mass-produced: scientists insert the genes that contain the molecular blueprints to build nanobodies into E. coli or yeast, and transform these microbes into high-output nanobody factories. The same method has been used safely for decades to mass-produce insulin.
But as Manglik noted, “nanobodies were just the starting point for us. Though appealing on their own, we thought we could improve upon them through protein engineering. This eventually led to the development of AeroNabs.”
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