How new insights into the coronavirus spike protein might inspire vaccine development

Many researches searching for solutions to the COVID-19 pandemic have focused on the spike protein, which plays a key role in the virus’s ability to bind to and infect healthy cells. A team led by scientists at the University of California, San Diego (UCSD) focused instead on glycans, which are interlocking sugar molecules that shield the spike protein.

In a new study published in the journal ACS Central Science, the team revealed an essential role of N-glycans at two sites on SARS-CoV-2—the coronavirus behind COVID-19—in recognizing target cells and promoting infection. They suggest the findings offer a novel strategy for vaccine development.

Glycans that surround viral proteins are known to be important for viruses to thrive. For example, the thick glycan shield around HIV-1 has been shown to allow the virus to evade the immune system. But unlike HIV-1, which has viral proteins that are coated by a non-immunogenic glycan shield, SARS-CoV-2 appears to have a spike protein that's covered in a different glycan pattern. The UCSD-led team figured certain glycans might be key in infection and could be targeted with vaccines.

The researchers built a full-length model of the SARS-CoV-2 spike protein with its sugar coat. The computer simulation presented a detailed snapshot of every atom in the spike glycoprotein.

SARS-CoV-2’s spike protein enters host cells by locking its receptor binding domain (RBD) to the ACE2 protein on the cell surface. In the study, the UCSD researchers found that N-glycans linked to the spike protein at sites N165 and N234 helped stabilize RBD’s shape for subsequent infection. Deleting these glycans by introducing mutations at N165 and N234 significantly reduced binding to ACE2, the team reported.

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In addition, the UCSD researchers also showed that the spike protein’s stalk, which fixes the RBD-containing spherical head to the virus surface, is densely covered by glycans. That makes them difficult to target with large molecules like antibodies. In comparison, the head appears to be less shielded, indicating it may be an easier target, the team suggested.

While the majority of COVID-19 vaccine development is focused on inducing neutralizing antibodies by targeting the spike protein, there’s a growing interest in looking elsewhere for solutions to defeating the virus. Eliciting T-cell immune responses is one such idea. A team led by TScan Therapeutics, for example, studied memory CD8+ T cells from patients who recovered from COVID-19 and found that most sites targeted by T cells fell outside of the spike protein.

The UCSD-led team hopes that revealing the critical role N165 and N234 play in SARS-CoV-2 infection will point to new opportunities in vaccine development, the researchers said.