Coronaviruses, like the one that causes COVID-19, have many raised bumps that salten their surfaces. When the coronavirus lifts one of these spiky proteins — like opening a finger fully open — it is able to invade a human cell. The pointed spike can insert its corkscrew-like domain into the keyhole protein (ACE2) in the outer wall of a human cell, binding to it. The spike protein becomes a gateway to cell infection.
But in those moments, the coronavirus reveals its Achilles’ heel.
The surfaces of coronaviruses are often covered with sugars or glycans. In recent years, researchers have learned that glycans provide coronavirus camouflage protection from antibodies, which are proteins that protect you when a potentially harmful substance enters your body. Antibodies need an exposed beachhead to attack the coronavirus, but glycans mask landing zones (epitopes) and help thwart attacks.
A team of researchers was looking for sugar-free sites on coronavirus spikes where antibodies have a better chance of attaching to and stopping infection of human cells.
“We tested and compared seven known antibodies, and some of them work well at gripping the exposed part of the spike protein,” says Atanu Acharya, assistant professor in the Department of Chemistry and a member of the BioInspired Institute. “Different antibodies target different spots on the spike protein.”
As a co-author, Acharya recently published a study in Biology of Communication with lead author James C. Gombart, associate professor in the School of Physics at Georgia Institute of Technology. Acharya conducted this research while a postdoctoral fellow at Georgia Tech and continuing his studies of coronavirus antibodies in his Syracuse University lab.
To simulate the non-sugar sites exposed when the spiky proteins open and close, the team used the fastest computer available in the United States to model the corona of the novel coronavirus SARS-CoV-2 – the virus that causes COVID-19. The Summit supercomputer is located at Oak Ridge National Laboratory in Tennessee.
“We used this ‘computational microscope’ to look at the atomic details of the entire pathway with the spike open and how antibodies might play a role by attacking this gate when that happens,” says Acharya. “We wanted to understand why one antibody is better than another and why some antibodies are more successful at attacking parts of the spike protein.”
Antibodies race to stop a coronavirus infection from crossing the spike gate and entering a cell. The coronavirus hastens to complete the infection process before antibodies destroy it. Sometimes this continues even when the spike key enters the keyhole of the cell. “There are moments when antibodies can attack the coronavirus spike even when they are already bound to the cell,” says Acharya.
In his lab, Acharya hopes to find a “pan-coronavirus” antibody that can treat multiple types of the novel coronavirus and future coronaviruses.
The great puzzle in developing antibodies for therapy is the complex role of glycans. These polysaccharides are more than just shields against invading antibodies. Glycans also play multiple roles in the opening and closing of spike proteins. For example, glycans act as sticky substances, helping to stabilize the spike in an “up” position, giving the coronavirus a chance to bind to the cell.
“Glycans play a role in stabilizing the open state of the spike protein, which is essential for cell injury,” says Acharya.
Glycans can also help stabilize the spike in a closed position, limiting its ability to become a gateway for infection.
The infectious ability of the coronavirus may depend on how quickly the spike protein can move from a closed state to an open state and continue to retain it to invade a human cell despite antibody threats. Therefore, the researchers want to identify the most effective and fast-acting antibodies for the job, the ones that can instantly locate the best spot to attack on the spike protein.