Researchers at Boston Children’s Hospital have analysed the structure of the SARS-CoV-2 variants, and have found that a tougher spike protein is likely responsible for their greater transmissibility.
Using a cryo electron microscope, the researchers imaged the spike protein down to the atomic level and discovered that the D614G mutation (a substitution of in a single amino acid ‘letter’ in the spike protein’s genetic code) produced a sturdier spike protein.
In the original, wild-type SARS-CoV-2, the spike protein would latch onto a cell’s ACE2 receptor and then fold in on itself, allowing the virus’ outer membrane to more easily fuse with the cell’s surface. However, they were susceptible to folding early, rendering those spike proteins useless. Around half of a SARS-CoV-2’s spike proteins would be folded in this way. However, this also made the virus harder for the immune system to lock on to.
“Because the original spike protein would dissociate, it was not good enough to induce a strong neutralising antibody response,” said research leader Bing Chen, PhD at Boston Children’s Hospital.
When Chen and colleagues imaged the mutated spike protein, fewer are folded early because the D614G mutation blocks the shape change. While the spike protein is sturdier, it comes at the cost of being able to attach less easily to the ACE2 receptor.
“Say the original virus has 100 spikes,” Dr Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that are functional, so even though they don’t bind as well, the chances are greater that you will have infection.”
Dr Chen proposed that vaccines currently being updated should be modified for this new spike protein mutation, which should also have the side benefit of making the vaccines more effective.
Applying structural biology to the spike protein, the team had come up with a ‘decoy’ molecule that bound to the spike protein 200 times more strongly than to the body’s ACE2 receptors. This was shown to inhibit the virus in the culture, opening up the door to a new type of treatment.
Source: Medical Xpress
Journal information: Jun Zhang et al. Structural impact on SARS-CoV-2 spike protein by D614G substitution, Science (2021). DOI: 10.1126/science.abf2303
