An experimental compound prevents the virus that causes COVID-19 from entering human airway cells, a new study finds.
Posted online recently on the pre-print server bioRxiv, the work revolves around the structure of SARS-CoV-2, the virus causing the current pandemic. This virus has on its surface a spike protein that can attach to angiotensin converting enzyme 2 (ACE2), a protein on the surface of cells lining human lungs. Once attached, the spike pulls the virus close to a cell, which lets it fuse to it and enter it, and then hijack the cell's machinery to make copies of itself, researchers say.
For this reason, molecular biologists have sought to engineer forms of ACE2 that, instead of being woven onto the cell surface, float freely. They hoped that free-floating ACE2 could serve as a decoy that competes with the membrane-bound counterpart for the viral spike protein, thereby blocking virus entry.
Led by researchers at the NYU Grossman School of Medicine, a new investigative effort made key changes to a free ACE2 molecule, and then fused one part of it to a piece of an antibody, an immune system protein, with the goal of strengthening its antiviral effect. The team calls their molecule an "ACE-2 microbody."
"In our tests, the ACE-2 microbody was about ten times as effective at blocking virus entry as unmodified forms of ACE2 studied previously," says corresponding study author Nathaniel Landau, PhD, professor in the Department of Microbiology at NYU Langone Health. "We call our compound a microbody because, by using just the key parts of each protein, the drug molecule is smaller and potentially easier to make than versions made up of complete proteins."
The researchers caution that any signals of effectiveness for the experimental drug would need to be confirmed in animal studies, and then in human trials if appropriate.
Building on HIV Experience
To build the microbody, the study authors used a standard technique in molecular biology, which creates a "fusion protein" by building a DNA molecule in which two genes, each with instructions for a different protein, are linked. The linked genes are then introduced into a mammalian cell, which makes the hybrid protein from the hybrid instructions.
For the current work, the researchers started with the ectodomain of ACE2, the part of the protein that sticks out from a cell's surface and attaches to the viral spike protein. They changed the ectodomain's genetic code to swap out one amino acid building block, replacing a histidine at position 345 in the protein's structure with an alanine. The modification kept ACE-2 from interacting with angiotensin, a hormone that regulates blood pressure, its natural role and a possible source of side effects.
For the second piece of their fusion compound, the study authors used an Fc domain, the part of an antibody's structure that turns on other parts of the immune system when the antibody encounters an invading microbe. The team intentionally shortened the domain, however, to prevent off-target immune effects.
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September 20, 2020 at 07:16PM
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Experimental drug blocks COVID-19 viral entry into lung cells - Amsterdam News
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