Peptide from SARS-CoV-2 spike protein forms amyloids

The spike protein of SARS-CoV-2, the virus that causes COVID-19, has been the focus of a lot of research these past two years. It’s what the virus uses to invade host cells and it has been the target of COVID vaccines. Researchers have also speculated that regions of the protein can clump up to form amyloid fibrils like those seen in diseases like Alzheimer’s. Some scientists have wondered if spike protein fibrils could contribute to the severity of COVID and long COVID. Sofie Nyström and Per Hammarström of Linköping University now show that peptides from the spike protein do indeed form these fibrils (J. Am. Chem. Soc. 2022, DOI: 10.1021/jacs.2c03925).

“We see amyloid everywhere, because that’s our bread and butter,” Hammarström says. “But it seemed that this could actually be a mechanism of interest for this virus and particularly for this protein.”

Nyström and Hammarström started to look for spike protein amyloids by buying a library that consisted of the protein broken into 316 peptides that were 15 amino acids long. They oberved amyloid fibrils forming, so they set out to determine which peptides were forming them.

The pair used an algorithm developed by Frederic Rousseau and Joost Schymkowitz at Katholieke Universiteit Leuven to predict which peptides were most likely to form amyloids. The algorithm identified seven candidates. Of these, the one called Spike192, named for the position of its first amino acid in the spike protein sequence, was especially good at forming amyloids in lab experiments.

Nyström and Hammarström thought that enzymes from human cells might digest the spike protein into these fibril-forming peptides. In lab studies, they found that neutrophil elastase, which some immune cells release when responding to inflammation during infections, chops up the spike protein into a peptide nearly identical to Spike192.

“What I like about the paper is not only that they synthesize the fragments and study their aggregation, but that they also give a mechanism for the generation of the fragments,” says Ulrich H. E. Hansmann, who studies amyloid proteins at the University of Oklahoma. The new findings help bolster previous work by other researchers, he says.

Etheresia Pretorius of Stellenbosch University, Douglas B. Kell of the University of Liverpool, and their colleagues have previously shown that the spike protein can induce the formation of blood clots. They find it interesting that Nyström and Hammarström could use the spike peptides to induce amyloids in fibrinogen, the protein that forms blood clots to control bleeding. These clots are supposed to degrade, but that doesn’t happen in COVID.

Nyström and Hammarström plan to further study the relationship between the spike amyloid and blood clot formation in severe COVID and long COVID. “A review of autopsy studies of patients that died from COVID states that 91% of them had blood clots in their system,” Nyström says. “It’s really a major part of severe COVID.”