Researchers discover key ‘weakness’ of coronavirus that causes COVID-19
Cryo-electron microscopy shows how VH Ab6 antibody fragments (red) attach to vulnerable sites of the SARS-CoV-2 spike protein (grey) to prevent the virus from binding to the human ACE2 cell receptor (blue).
The study, published in the journal Nature Communications, used cryo-electron microscopy (cryo-EM) to determine the atomic structure of vulnerable regions, or epitopes, on the viral spike protein. The study also reports a VH Ab6 antibody fragment that binds to this position and neutralizes every major variant.
“This is a highly adaptive virus that has evolved to evade most existing antibody treatments, as well as much of the immunity conferred by vaccines and natural infection,” said Dr Sriram Subramaniam, a professor at UBC’s School of Medicine and the study’s senior author. This study reveals a weakness that is largely unchanged across variants and can be neutralized by a single antibody fragment. It sets the stage for the design of pan-variant treatments that have the potential to help many vulnerable populations.”
The Master Key to Identifying COVID-19
Our bodies naturally make antibodies to fight infections, but they may also be made in the lab and given to patients as a treatment. Although some antibody treatments have been created for COVID-19, their efficacy has declined in the face of highly mutated variants like Omicron.
“Antibody attaches to the virus in a very specific way, like a key that goes into a lock. But when the virus mutates, the key doesn’t work anymore,” Dr. Subramaniam said. “We’re always looking for the master key — antibodies that continue to neutralize the virus even after extensive mutation.
The new paper identifies the antibody fragment VH Ab6 as the “master key” that has been found to be effective against Alpha, Beta, Gamma, Delta, Kappa, Epsilon and Omicron variants. The fragment neutralizes the virus by binding to an epitope on the spike protein and preventing SARS-CoV-2 from infecting human cells.
The discovery is the latest culmination of a long and productive collaboration between Dr. Subramaniam’s team and colleagues led by University of Pittsburgh’s Mitko Dimitrov and Wei Li, Ph.D. The Pittsburgh team has been screening large antibody libraries and testing their effectiveness against COVID-19, while the UBC team has been using cryo-electron microscopy to study the molecular structure and characteristics of the spike protein.
Focus on COVID-19 Weak Points
The UBC team is known for its expertise in using cryo-electron microscopy to observe protein-protein and protein-antibody interactions at atomic resolution. In another paper published in Science earlier this year, they reported for the first time the structure of the contact zone between the Omicron spike protein and the human cellular receptor ACE2, providing a molecular explanation for Omicron’s enhanced viral fitness.
By mapping the molecular structure of each spike protein, the team has been looking for vulnerable regions that could inform new treatments.
Dr Subramaniam said: “Most of the epitopes we describe in this paper are far from hotspots of mutation, which is why its ability is preserved in different variants. We have now characterized this site in detail. structure, it opens up a whole new realm of therapeutic possibilities.”
This critical weakness can now be exploited by drugmakers, and because the site is relatively mutation-free, Dr. Subramaniam said, the resulting treatments could be effective against existing, and even future, variants.