Abstract
Spike (S) protein is a key protein in coronaviruses life cycle. SARS-CoV-2 Omicron BA.1 variant of concern (VoC) presents an exceptionally high number of 30 substitutions, 6 deletions and 3 insertions in the S protein. Recent works revealed major changes in the SARS-CoV-2 Omicron biological properties compared to earlier variants of concern (VoCs). Here, these major changes could be explained, at least in part, by the mutations N764K and/or N856K in S2 subunit. These mutations were not previously detected in other VoCs. N764K and N856K generate two potential cleavage sites for SKI-1/S1P serine protease, known to cleave viral envelope glycoproteins. The new sites where SKI-1/S1P could cleave S protein might impede the exposition of the internal fusion peptide for membrane fusion and syncytia formation. Based on the human protein atlas, SKI-1/S1P protease is not found in lung tissues (alveolar cells type I/II and endothelial cells), but present in bronchus and nasopharynx. This may explain why Omicron has change of tissue tropism. Viruses have evolved to use several host proteases for cleavage/activation of envelope glycoproteins. Mutations that allow viruses to change of protease may have a strong impact in host range, cell and tissue tropism, and pathogenesis.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
-The lineage of omicron in this work is BA.1. -in the end of paragraph "Molecular docking of peptides from S protein into SKI-1/S1P", addition of: In addition, during the writing of this manuscript two sub-lineages BA.2 and BA.3 of Omicron have been discovered. Interestingly, BA.2 and BA.3 do not have the mutation N856K, thus no potential cleavage site 856KGLT859↓VL for SKI-1/S1P serine protease. The first medical observations about BA.2 lineage suggest there is no great difference in disease severity compared to BA.1. These observations and molecular docking results suggest that SKI-1/S1P probably cleave 764KRAL767 ↓TG site in BA.1, BA.2 and BA.3 lineages.
