Insights into how coronavirus changes shape could aid development of COVID-19 vaccines, drugs

26 February 2021

Angus Liu / FiercePharma

Scientists continue to search for vaccines and drugs to add to the anti-COVID-19 arsenal. Now two research groups have announced discoveries related to the changing structure of the SARS-CoV-2 coronavirus that caused the pandemic, and they believe their insights could aid in the development of new weapons to fight the virus.

A team led by scientists at Yale University used advanced imaging techniques to determine how the coronavirus’ spike protein changes its shape in response to COVID-19 antibodies. The researchers identified two methods antibodies can use to interfere with the virus’s entry into human cells for infection.

The findings could guide the design of antibody drugs or small molecules to block the virus, the researchers said. They published their findings in the journal Cell Host & Microbe and presented them at the Biophysical Society’s annual meeting.

The coronavirus spike protein protein’s receptor-binding domain (RBD) must bind to a host protein called ACE2 to cause COVID-19. 

“The spike protein constantly changes shape, [and] this shape-shifting feature not only allows the virus to enter host cells, it also helps the virus escape from being attacked or recognized by antibodies,” explained co-author Maolin Lu, an associate research scientist at Yale, in a statement.

Scientists had previously identified two types of S protein structure: a closed state in which all RBDs are oriented downward, and an open state with up to three RBDs oriented upward, making them accessible to receptors. But just how these structures are connected is somewhat of a mystery.

For the new study, Lu and colleagues used a technique called smFRET to visualize the dynamics of the protein’s structural changes. The team identified four spike protein shapes, including two intermediates shapes. The researchers showed that ACE2 activates the S protein from the closed state to the receptor-bound open state through at least one intermediate form.

The researchers then analyzed the effects of neutralizing antibodies from patients who had recovered from COVID. Interestingly, they noticed the antibodies used two strategies to tackle the coronavirus. Some antibodies recognized and attached to the spike protein when it was in the open position, competing with ACE2 for binding so that the virus could not reach human cells. Others attached to the closed spike, stabilizing the protein to prevent its transition to the infection-ready open state.

Based on their observations, the researchers argued that targeting the S protein when it’s in the closed position may be a particularly effective strategy for drugs and vaccines.

Other COVID-19 research groups have also turned their focus on better understanding the S protein structure. Researchers at the University of California, San Diego, are focused on sugar molecules called glycans, which coat the S protein and help the coronavirus evade the immune system. A UCSD team found that N-glycans linked to two sites of the S protein helped stabilize RBD’s shape for infection. Modifying those sites significantly reduced viral binding to ACE2, they showed.

Now researchers from the same lab and the University of Pittsburgh demonstrated how glycans operate at the atom level.

Using high performance computing algorithms that run multiple simulations simultaneously, the researchers were able to identify the glycans that are responsible for activating S, according to a release about their presentation at the Biophysical Society annual meeting.

“Surprisingly, one glycan seems to be responsible for initiating the entire opening,” Terra Sztain-Pedone, a member of the team, said in the statement.

The simulations the team developed could be used to help identify drugs that block or prevent SARS-CoV-2 activation, the team said. “Because we have all these structures, we can do small molecule screening with computational algorithms,” Sztain-Pedone said.

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