Amyloidogenesis of SARS-CoV‑2 Spike Protein

SARS-CoV-2 infection
is associated with a surprising number of
morbidities. Uncanny similarities with amyloid-disease associated
blood coagulation and fibrinolytic disturbances together with neurologic
and cardiac problems led us to investigate the amyloidogenicity of
the SARS-CoV-2 spike protein (S-protein). Amyloid fibril assays of
peptide library mixtures and theoretical predictions identified seven
amyloidogenic sequences within the S-protein. All seven peptides in
isolation formed aggregates during incubation at 37 °C. Three
20-amino acid long synthetic spike peptides (sequence 192–211,
601–620, 1166–1185) fulfilled three amyloid fibril criteria:
nucleation dependent polymerization kinetics by ThT, Congo red positivity,
and ultrastructural fibrillar morphology. Full-length folded S-protein
did not form amyloid fibrils, but amyloid-like fibrils with evident
branching were formed during 24 h of S-protein coincubation with the
protease neutrophil elastase (NE) in vitro. NE efficiently
cleaved S-protein, rendering exposure of amyloidogenic segments and
accumulation of the amyloidogenic peptide 194–203, part of
the most amyloidogenic synthetic spike peptide. NE is overexpressed
at inflamed sites of viral infection. Our data propose a molecular
mechanism for potential amyloidogenesis of SARS-CoV-2 S-protein in
humans facilitated by endoproteolysis. The prospective of S-protein
amyloidogenesis in COVID-19 disease associated pathogenesis can be
important in understanding the disease and long COVID-19.