Omicron variants of SARS CoV-2 indicate how small molecules can interfere with spike glycoprotein trimerization

In our search for a possible achilles’ heel of SARS-CoV-2, we explored the variability of 1,382,462 complete sequences of the viral spike glycoprotein, all the ones that we could retrieve from the NCBI SARS-CoV-2 databank as of 6 March 2023. Then, by using the Shannon entropy algorithm, we quantified the sequence variability of SARS-CoV-2 spike glycoprotein. With PDBePISA, we have performed a detailed analysis of protomer-protomer interfaces of the spike glycoprotein for two representative structures of different viral variants. The largest protomer-protomer contact patch that is present in the stem region of both structures is highly conserved. It is remarkable that the Asp796Tyr mutation, centered in this patch, is always present in all the Omicron variants. The structure of the SARS-CoV-2 Omicron spike glycoprotein trimer indicates that Tyr796 and Phe898 of the same protomer form a network of aromatic sidechains with Tyr707 of another protomer, yielding a strong constraint that stabilizes the spike glycoprotein quaternary assembly. We believe that the resulting structural stability of the viral trimer is among the key features for the successful proliferation of Omicron variants. This finding also supports the fact that disrupting this network of aromatic moieties with suitable small molecules would represent a powerful antiviral strategy.