Achilles heel that could lead to a universal coronavirus cure

Austin, Texas — Researchers behind the discoveries that led to a vaccine for the virus that causes COVID-19 have identified a potential Achilles heel present in all coronaviruses. These findingsLed by researchers at the University of Texas at Austin, it could also help develop improved treatments for COVID-19 and protect against existing and emerging coronaviruses.

Most vaccines and antibody-based therapies for COVID-19 neutralize the SARS-CoV-2 virus by disrupting the interaction between the viral protein spike and ACE2 receptors on human cells. However, mutations in the spike protein mean that new variants of SARS-CoV-2 may escape the antibody response in humans, making treatments less effective and vaccinated individuals still breaking. The researchers are tackling this question by focusing on the portion of the spike protein that is critical for virus survival and does not mutate.

The SARS-CoV-2 spike protein is composed of two subunits called S1 and S2. The S1 subunit binds to the ACE2 receptor, while the S2 subunit allows the virus to fuse with the membrane of the cell it is trying to access. Most mutations in the spike protein affect its S1 subunit, whereas the S2 portion is relatively constant in all seven human coronaviruses, making it a prime target for therapeutic antibodies and vaccines.

“We know that S2-directed antibodies are produced after COVID-19 infection, and similar subunits of influenza and HIV are also targeted by the body’s antibodies.” Study with co-first authors Yimin Huang and Annalee Nguyen Molecular Biosciences, UT Austin, led the. “But we know very little about the antibodies that bind to the S2 subunit.”

Less than 5% of the approximately 7,000 known anti-SARS-CoV-2 antibodies that target S2 are the only two classes of S2-binding antibodies that have been characterized in detail. Researchers have identified a third class of antibodies that target portions of S2 that are highly similar among coronaviruses.

The researchers found that this class of antibodies binds to the hinge of the S2 subunit, which plays an important role in the subunit’s shape change when the virus fuses with the human cell membrane. Further analysis showed that access to the point at which antibodies bind to this hinge, called the epitope, depends on shape-change dynamics across the spike protein. When Spike binds to her ACE2 receptor, it gains access to Hinge.

Antibodies interfered with the spike protein’s ability to fuse the virus and human cell membranes, but were inferior in its ability to completely neutralize the virus. indirectly kills virus-infected cells by inducing the process of

In one experiment, the antibody induced human natural killer cells to destroy SARS-CoV-2 infected cells. In another example, the S2 antibody engulfed cells called monocytes and destroyed infected cells. This suggests that S2 antibodies may not be potent enough to block infection directly, but could be used to activate or boost immune responses.

“We have identified an epitope in the S2 subunit of SARS-CoV-2 that is constant in all pathogenic coronavirus strains,” said senior author Jennifer Maynard, a professor in the Makketta Department of Chemical Engineering at UT Austin. . “Although targeting this epitope alone is unlikely to be potent enough as a therapy or vaccine, therapeutic strategies that could enhance access to this epitope could allow pre-existing human antibodies to target other antibody-directed cells. We may be able to facilitate viral clearance more effectively through the killing process.”

Students and faculty from the College of Natural Sciences and the Cockrell School of Engineering led the research and collaborated with staff from several other institutions. Team members include his Jason McLellan, Silva, Huang, Ching-Lin Hsieh, Amanda Bohanon, Alison Lee and Dzifa Amengor from the University of Natural Sciences. Maynard, Nguyen, Rebecca Willen, Alam Kerkess, Laura Azouz, Kevin Lee, Yuton Liu and Andrea DiVenere from the Cockrell School. Kevin Dalby and Tamer Kaoud from UT Austin’s School of Pharmacy. Oladimeji Oaluwoye and Sheena D’Arcy of the Department of Chemistry and Biochemistry, University of Texas at Dallas. Jun-Gyu Park, Ahmed M. Khalil, and Luis Martinez-Sobrido of the Texas Biomedical Institute. Shawn Costello, Sophie Shoemaker and Susan Marqusee from UC Berkeley. Eduardo A. Padlan, former National Institutes of Health.