Scientists have analyzed every possible mutation to one key part of the coronavirus. The data could help guide vaccine and drug development and hint at how the virus might spread.

HHMI scientists are joining many of their colleagues worldwide in working to combat the new coronavirus. Theyre developing diagnostic testing, understanding the viruss basic biology, modeling the epidemiology, and developing potential therapies or vaccines. Over the next several weeks, we will be sharing stories of some of this work.

As the novel coronavirus spreads, its picking up new mutations for better and for worse.

Now, Howard Hughes Medical Institute Investigator Jesse Bloom and his colleagues have cataloged how nearly 4,000 different mutations alter SARS-CoV-2s ability to bind to human cells.

Their data, publicly available online as an interactive map, is a new resource for researchers developing antiviral drugs and vaccines to fight COVID-19, the infectious disease caused by SARS-CoV-2. The work also reveals how individual mutations may affect the viruss behavior, the team reports August 11, 2020in the journal Cell.

We dont know how the virus will evolve, but now we have a way to look at the mutations that can occur and see their effects, says Bloom, a virologist at the Fred Hutchinson Cancer Research Center.

Each time a virus replicates, it can pick up new genetic mutations. Many of these mutations have no effect on a viruss behavior. Others could make the virus better or worse at infecting people. To what extent mutations might be making SARS-CoV-2 more dangerous has been an open and controversial question. Doctors and scientists have analyzed genetic differences in virus samples collected from COVID-19 patients around the world, hunting for clues to the diseases spread. But until now, no one had comprehensively linked potential mutations to their functional effect on SARS-CoV-2.

We dont know how the virus will evolve, but now we have a way to look at the mutations that can occur and see their effects.

Jesse Bloom, HHMI Investigator at the Fred Hutchinson Cancer Research Center

The new study focused on mutations to a key part of SARS-CoV-2 its spike protein. This protein binds to a protein on human cells called ACE2, a necessary step for infection. Mutations in the spike protein could change how well SARS-CoV-2 sticks to and thus infects human cells.

Blooms team bred yeast cells to display a fragment of the spike protein on their surface. This fragment, called the receptor binding domain, makes direct contact with ACE2. The researchers systematically created thousands of versions of the fragment each with different mutations. Then they measured how well these mutated fragments stuck to ACE2. That let them assess how various mutations might affect the function of the binding domain.

The data show that many possible mutations could make the virus bind to human cells more strongly. But those mutations dont seem to be gaining a foothold in circulating versions of the virus.

This would suggest that theres some sort of sweet spot, where if the virus can bind ACE2 pretty well, then its able to infect humans, Bloom says. Maybe theres no evolutionary need for it to get better.

Other mutations made it harder for the spike protein to bind to cells or prevented the protein from properly folding into its final shape, the team found. Versions of the virus with these mutations might be less likely to gain a foothold because they cant infect cells as effectively. The teams targeted lab tests arent a perfect proxy for how mutations will affect the virus in the wild, where many other factors influence how effectively it can spread but theyre a useful starting place.

The data will also be valuable for researchers designing drugs and vaccines to fight COVID-19, says Tyler Starr, a postdoc in Blooms lab who led the project alongside graduate student Allie Greaney. Understanding the consequences of different mutations can guide the development of drugs that will continue to work as the virus changes over time. Plus, Starr says, its becoming clear that antibodies that stick to this part of the virus are really good, protective antibodies that we would want to elicit with a vaccine.

Study coauthor Neil King and his lab at the University of Washington is already working on such vaccines. His team is designing artificial proteins that mimic components of the virus. As part of a vaccine, such proteins could potentially train peoples immune systems to produce antibodies that target the coronavirus. The researchers modify the artificial proteins to make them more stable and easier to produce in large quantities than the natural versions of the proteins.

The data from Blooms team offers a roadmap to making those modifications. Normally, when were trying to figure out how to make a protein better, were shooting in the dark, says Daniel Ellis, a graduate student in Kings lab. The information theyve given us is kind of like a cheat sheet. It makes our lives amazingly easier.

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Citation

Tyler N. Starr et al. Deep mutationalscanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell. Published online on August 11, 2020. doi:10.1016/j.cell.2020.08.012

Original post:
A New Map Catalogs the Effects of Coronavirus Mutations - Howard Hughes Medical Institute