COVID-19 News

Berkeley Lab aids UCSF development of COVID-19 antiviral nasal spray

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Researchers at the University of California, San Francisco (UCSF) reported on August 11 that they have formulated a nasal spray that can help ward off the coronavirus. Lawrence Berkeley National Laboratory's Advanced Light Source was involved in research supporting the product; that research was funded in part by the National Institutes of Health.

The UCSF team is working with business partners to get it clinically tested and manufactured. They call the aerosol spray AeroNabs. It’s not a cure, but it is an antiviral aimed at preventing COVID-19, the respiratory illness that has killed hundreds of thousands worldwide.

“Far more effective than wearable forms of personal protective equipment, we think of AeroNabs as a molecular form of PPE [personal protective equipment] that could serve as an important stopgap until vaccines provide a more permanent solution to COVID-19,” said AeroNabs co-inventor Peter Walter, professor of biochemistry and biophysics at UCSF.

Clinical trials could begin in a few months, he said, and AeroNabs could potentially be used in other forms besides a nasal spray. For instance, the UCSF researchers said during an August 12 news conference, they think the molecule is stable enough to integrate into air-conditioning filters or nebulizers that could be used in schools, shopping malls or other environments.

UCSF graduate student Michael Schoof led a team of researchers who developed a synthetic molecule that puts a straitjacket on mechanisms within the virus that allow it to infect human cells. In a new paper, Schoof and company lay out the experiments in which they used live virus to show that their man-made molecule is among the most potent antivirals yet against the coronavirus, scientifically known as SARS-CoV-2.

“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 Walter’s lab and a co-inventor of AeroNabs.

He and Walter said they were inspired by antibody-like immune proteins called nanobodies that naturally occur in llamas, camels and other related animals.

Dr. Aashish Manglik, an assistant professor of pharmaceutical chemistry, frequently has used nanobodies in his research on the structure and function of proteins that send and receive signals across cell membranes. A co-inventor of AeroNabs, he said Wednesday that this sort of molecular biotechnology has been used to treat another illness.

“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,” he explained.

Smaller than human antibodies, nanobodies are easier to manipulate and modify in the lab setting, UCSF scientists said, and they have a simple structure that also makes them more stable. This also makes them easier and less expensive to mass-produce, giving them another advantage over human antibodies.

Scientists put genes containing the molecular blueprints to build nanobodies into E. coli or yeast, and these microbes become high-output nanobody factories. The scientists then use protein engineering to develop those nanobodies into the synthetic molecule in AeroNabs.

The key, they said, was preventing so-called spike proteins on the surface of the coronavirus, allowing the virus to dock to receptors in other cells and enter them. Those spikes also give the virus a crown-like appearance when viewed through an electron microscope, and that’s why this family of pathogens is known as “coronavirus.”

Once the virus has attached to the ACE2 receptors in other cells, it then turns its host in a coronavirus manufacturer. The UCSF researchers looked for nanobodies that could prevent interactions between the coronavirus’ spike proteins and human cells’ ACE2 receptors.

They carefully reviewed a library of more than 2 billion synthetic nanobodies recently developed in Manglik’s lab, identifying 21 nanobodies that could shut down the spike-receptor interaction.

Then they turned to a scientist in France to determine whether the nanobodies worked: Veronica Rezelj, a virologist in the lab of Marco Vignuzzi, at Pasteur Institute in Paris, pitted the three most promising nanobodies against live SARS-CoV-2 and found them to be potent, preventing infection even at extremely low doses.

The most potent of these nanobodies not only put a sheath over the spike protein’s binding mechanisms but also acted like a molecular mousetrap, clamping down on spike while it was in its closed, inactive state. The researchers like that this added another layer of protection against the spike ACE2 interactions.

Still not satisfied, though, the scientists did other experiments that allowed them to find other ways to undermine SARS-CoV-2. One linked triple nanobody was 200,000 times more potent than any of the single nanobodies alone.

“They put two resulting modified nanobodies together, and “it was so effective that it exceeded our ability to measure its potency,” Walter said.

“We’re not alone in thinking that AeroNabs are a remarkable technology,” Manglik said. “Our team is in ongoing discussions with potential commercial partners who are interested in manufacturing and distributing AeroNabs, and we hope to commence human trials soon. If AeroNabs prove as effective as we anticipate, they may help reshape the course of the pandemic worldwide.”

Currently, Manglik said, they view the product as most viable as a preventative measure or as one that could help people who may have been exposed but are not yet symptomatic. However, he said Wednesday that they expect it will be tested for efficacy on the sickest coronavirus patients.

Walter did not provide a timeline for when AeroNabs could be ready to market, but in the Wednesday news conference, he said he envisions it as a solution that could be used at least until a vaccine is approved. And, it would continue to be useful for people who can’t access a vaccine or don’t respond to them.

Manglik and Walter said they anticipated that any product would be widely available, inexpensive and sold over the counter.

Read more from the Sacramento Bee: https://www.sacbee.com/news/local/health-and-medicine/article244895427.html

Read the study: https://www.biorxiv.org/content/10.1101/2020.08.08.238469v1.full.pdf