We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us

Download Mobile App





Experimental Drug Blocks SARS-CoV-2 from Entering Lung Cells

By HospiMedica International staff writers
Posted on 21 Sep 2020
Print article
Illustration
Illustration
In a new study, an experimental compound has prevented the SARS-CoV-2 virus that causes COVID-19 from entering human airway cells.

Researchers at the NYU Grossman School of Medicine (New York City, NY) have been focusing their research on the structure of SARS-CoV-2. The 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. For this reason, molecular biologists have sought to engineer forms of ACE2 that, instead of being woven onto the cell surface, float freely. They hope that free-floating ACE2 could serve as a decoy that competes with the membrane-bound counterpart for the viral spike protein, thereby blocking the virus’ entry.

In a new investigative effort, the researchers 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." To build the microbody, the team 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 researchers 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.

The researchers wanted the Fc domain on the microbody because such proteins form strong disulfide bonds when they encounter one other. The binding of two fusion proteins through their Fc domains creates a dimer, a stable structure that attaches more strongly to the virus because it now has two ACE2 ectodomains to cling to viral spikes, according to the researchers. To determine how strongly their experimental drug could interact with the COVID-19 virus, the research team used a "pseudotyped" virus, a vital tool used in decades of HIV research. To make it, the researchers started with HIV viruses, but removed the disease-causing part of their genetic material to make them safe to work with. To these engineered viral particles the team then added the SARS-CoV-2 spike protein, as well as a gene encoding the firefly protein luciferase.

Like the current coronavirus, the pseudotyped virus could infect cells by using the SARS-CoV-2 spike to attach to ACE-2. With the firefly gene included, cells infected by the test virus glowed, and glowed brighter the more viral particles they were infected with. By mixing the ACE-2 microbody with the pseudotyped virus, infecting cells and then measuring the glow, the researchers could tell how well their new molecule blocked viral entry. The researchers have cautioned that any signals of effectiveness for the experimental drug would need to be confirmed in animal studies, and then in human trials if appropriate.

"In our tests, the ACE-2 microbody was about ten times as effective at blocking virus entry as unmodified forms of ACE2 studied previously," said 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."

"An advantage of the study drug is that, by competing for the spike with the ACE2 membrane-bound receptor, infection is blocked before it can start," said first study author Takuya Tada, PhD, a post-doctoral scholar in Landau's lab. "Coronaviruses are quick to evolve around treatments, like therapeutic antibodies, that target one structural feature on the virus, but will have a harder time changing the entire first step by which they enter cells."

Related Links:
NYU Grossman School of Medicine

Gold Member
12-Channel ECG
CM1200B
Gold Member
Solid State Kv/Dose Multi-Sensor
AGMS-DM+
Silver Member
Compact 14-Day Uninterrupted Holter ECG
NR-314P
New
Bilirubin Lamp
Bilibluelight

Print article

Channels

Critical Care

view channel
Image: Researchers have developed an advanced shear-thinning hydrogel for aneurysm repair (Photo courtesy of TIBI)

New Hydrogel Features Enhanced Capabilities for Treating Aneurysms and Halting Progression

Aneurysms can develop in blood vessels in different body areas, often as a result of atherosclerosis, infections, inflammatory diseases, and other risk factors. These conditions lead to chronic inflammation,... Read more

Surgical Techniques

view channel
Image: The living replacement knee will be tested in clinical trials within five years (Photo courtesy of ARPA-H)

Living Knee Replacement to Revolutionize Osteoarthritis Treatment

Osteoarthritis is the most prevalent type of arthritis, characterized by the progressive deterioration of cartilage, or the protective tissue covering the bone ends, resulting in pain, stiffness, and impaired... Read more

Patient Care

view channel
Image: The newly-launched solution can transform operating room scheduling and boost utilization rates (Photo courtesy of Fujitsu)

Surgical Capacity Optimization Solution Helps Hospitals Boost OR Utilization

An innovative solution has the capability to transform surgical capacity utilization by targeting the root cause of surgical block time inefficiencies. Fujitsu Limited’s (Tokyo, Japan) Surgical Capacity... Read more

Health IT

view channel
Image: First ever institution-specific model provides significant performance advantage over current population-derived models (Photo courtesy of Mount Sinai)

Machine Learning Model Improves Mortality Risk Prediction for Cardiac Surgery Patients

Machine learning algorithms have been deployed to create predictive models in various medical fields, with some demonstrating improved outcomes compared to their standard-of-care counterparts.... Read more

Point of Care

view channel
Image: The new eye-safe laser technology can diagnose traumatic brain injury (Photo courtesy of 123RF)

Novel Diagnostic Hand-Held Device Detects Known Biomarkers for Traumatic Brain Injury

The growing need for prompt and efficient diagnosis of traumatic brain injury (TBI), a major cause of mortality globally, has spurred the development of innovative diagnostic technologies.... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.