COVID ORIGIN FULL

As noted above, the RBD of SARS-CoV-2 is optimized for binding to human ACE2 with an efficient solution different from those previously predicted 7, 11. It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. Although prediction of O-linked glycosylation is robust, experimental studies are needed to determine if these sites are used in SARS-CoV-2. Several viruses utilize mucin-like domains as glycan shields involved immunoevasion 18. The function of the predicted O-linked glycans is unclear, but they could create a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2 spike protein 18. The acquisition of polybasic cleavage sites by HA has also been observed after repeated passage in cell culture or through animals 17. Acquisition of polybasic cleavage sites in HA, by insertion or recombination, converts low-pathogenicity avian influenza viruses into highly pathogenic forms 16. In avian influenza viruses, rapid replication and transmission in highly dense chicken populations selects for the acquisition of polybasic cleavage sites in the hemagglutinin (HA) protein 16, which serves a function similar to that of the coronavirus spike protein. In addition, efficient cleavage of the MERS-CoV spike enables MERS-like coronaviruses from bats to infect human cells 15. Experiments with SARS-CoV have shown that insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell fusion without affecting viral entry 14. The functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, and it will be important to determine its impact on transmissibility and pathogenesis in animal models.

COVID ORIGIN FULL

Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species. Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans 13. The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678 and S686, which flank the cleavage site and are unique to SARS-CoV-2 (Fig. In addition, a leading proline is also inserted at this site in SARS-CoV-2 thus, the inserted sequence is PRRA (Fig. This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range 12. The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike 8 (Fig. Polybasic furin cleavage site and O-linked glycans This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal 7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding 7, 11. On the basis of structural studies 7, 8, 9 and biochemical experiments 1, 9, 10, SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology 7. Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses 7. The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome 1, 2.

Mutations in the receptor-binding domain of SARS-CoV-2 Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies 7, 8, 9 and biochemical experiments 1, 9, 10, SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2 and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides 8, which additionally led to the predicted acquisition of three O-linked glycans around the site.

Covid origin