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Cornell, Columbia: Nasal Spray Blocks COVID-19 Infection in Ferrets
New York Ag Connection - 02/19/2021

Researchers at Cornell, Columbia University Irving Medical Center and Erasmus Medical Center in the Netherlands have developed a nasal formulation that blocks the spread of COVID-19 among ferrets -- and are hopeful the formulation could have the same effect on humans, and potentially generate therapeutic treatments as well.

Ferrets are one of the best animal models for COVID-19, because they take the virus quite readily, and undergo both direct contact and airborne transmission. Ferrets, similar to humans, also generate antibodies against the virus, yet display limited clinical signs.

The team's paper, "Intranasal Fusion Inhibitory Lipopeptide Prevents Direct Contact SARS-CoV-2 Transmission in Ferrets," published Feb. 17 in Science.

"This is a simple nasal formulation that we think can prevent the transmission of SARS-CoV-2 in humans," said Chris Alabi, associate professor of chemical and biomolecular engineering and a co-senior author of the paper. "The beauty of the research is its simplicity. The ultimate goal is to create a nasal spray drug product that can be made widely available, one that can be kept readily in a purse or pocket. A key feature of this research is that it's a plug-and-play platform technology that can be adapted and applied to other viruses or mutations."

The project is part of an ongoing collaboration between the Porotto and Moscona labs at Columbia and the Alabi lab at Cornell, which was launched in 2015. The collaboration paired the Columbia group's virology research with Alabi's work in engineering multifunctional macromolecules, with the initial goal of targeting the flu virus.

Alabi's lab is particularly adept at making various macromolecular conjugates, including peptide lipid conjugates, for applications in drug discovery and delivery. Peptides are essentially fragments of larger proteins composed of amino acid monomers that are strung together like beads in a necklace. The researchers take one or more peptide sequences and tag them with a fatty, greasy molecule called a lipid, which helps the peptide adhere to the lipid-covered surface of a cell membrane. These lipopeptides can be used to inhibit viruses from fusing with the host cell.

In recent years, the collaborators have been using the technique to develop antiviral peptide-lipid conjugates that prevent measles and Ebola. When COVID-19 emerged and scientists identified the sequence of the viral proteins, the Columbia and Cornell groups were able to adapt their approach, because all three viruses share a similar fusion mechanism. They swapped out the measles or the Ebola peptide for the HRC peptide in SARS-CoV-2 and tagged it with a cholesterol lipid.

"The Porotto and Moscona labs at Columbia identified the crucial peptide sequence, and then they worked with us to create the peptide cholesterol conjugate," Alabi said. "Given our previous work, we were able to make the monomer and dimer conjugates along with a variety of other macromolecular combinations, purify them, assess their solubility, and then send them out to our collaborators at Columbia for antiviral testing. The lead candidate was then sent to the Netherlands for ferret studies."

Researchers at Erasmus Medical Center in the Netherlands tested the formulation on ferrets, which turns out to be an ideal model for replicating the way SARS-CoV-2 spreads among, and proliferates inside, humans.

"It's the best of both worlds," Alabi said. "They mimic the disease indication seen in humans, but they can recover at a given dose. It's a similar mechanism that allows certain cohorts of the human population to also clear the virus."

The Erasmus Medical Center team found that the lipopeptide fusion inhibitors successfully prevented transmission of the SARS-CoV-2 virus.

The researchers envision their formulation as a prophylactic agent that people would apply to their nasal passages -- where COVID-19 most readily enters the body -- two to six hours or more before potential exposure. The lipopeptide is robust and stable at room temperature, eliminating the need for refrigeration or cold-chain storage.

"So, for example, if you want to go to a gathering, say a basketball game or somewhere where you're nervous that you might be exposed to the virus, this product is something that you would spray in your nose at the beginning of the day, and should enable a 24-hour or more protection from the virus," Alabi said.

The collaborators are currently studying the spray's effectiveness as a therapeutic treatment for subjects who are already infected, as well as its ability to combat other strains and viruses.

"I think the unique feature of this collaboration is just that: the collaboration," Alabi said. "It's difficult for one lab to have the expertise to do this all alone. The peptide lipid conjugation and isolation are difficult. The peptide and lipid are like oil and water -- they don't like to mix. Furthermore, most chemistry groups don't have a virology arm necessary to test these conjugates. Each group in the collaboration has the requisite expertise within our own fields to be able to pull this off together."

Co-authors include Cornell postdoctoral researcher Sudipta Biswas and key researchers from Columbia University Irving Medical Center, Erasmus Medical Center, the University of Campania in Italy and University of Wisconsin, Madison.

The research was supported by the National Institutes of Health, the Sharon Golub Fund at Columbia University Irving Medical Center, the Children's Health Innovation Nucleation Fund of the Pediatrics Department at CUIMC and a Harrington Discovery Institute COVID-19 Award.


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