The loss of QTQTN motif on SARS-CoV-2 spike removes a furin landing site and weakens furin cleavage efficiency but preserves binding affinity for Heparan Sulfate Proteoglycans (HSPG). There is a tradeoff between furin cleavage and heparan sulfate binding, as coronaviruses often lose FCS efficiency in exchange for heparan sulfate binding during serial passage in cell culture, perhaps because HSPG are very abundant on cell surface while the dedicated receptors are rarer. During cell culture passage, Feline CoV and HCoV-OC43 both mutate from furin-cleavage-efficient RRSRR motif to heparan-sulfate-binding RRSRG motif. The poly-basic motif functions as heparan-sulfate-binding Cardin-Weintraub motif (XBBXBX or XBBBXXBX) if not cleaved by furin. [1] Kakeya Hideki hypothesizes that some of the Covid variants like Delta and Omicron may be lab-made as well. Maybe the Delta and Omicron variants are products of serial passage or rational design in lab. The Delta and Omicron variants are even more efficient at binding heparan sulfate due to extra positively charged residues at spike protein. Compared to Wuhan-Hu-1, Delta variant spike carries 4 extra positive residues, while Omicron variant spike carries 9 extra positive residues. At the S1/S2 juncture, Delta spike contains a XBBBXBX motif (one extra positive charge) that binds heparan sulfate even more tightly than WT FCS (XBBXBX). At S1/S2 juncture, Omicron spike is even better at binding heparan sulfate with XBXBBBXBX motif. Even RBD contains extras positive charge that may enhance binding to either heparan sulfate or ACE2. [2] References: 1. de Haan CA, Haijema BJ, Schellen P, Wichgers Schreur P, te Lintelo E, Vennema H, Rottier PJ. Cleavage of group 1 coronavirus spike proteins: how furin cleavage is traded off against heparan sulfate binding upon cell culture adaptation. J Virol. 2008 Jun;82(12):6078-83. doi: 10.1128/JVI.00074-08. Epub 2008 Apr 9. PMID: 18400867; PMCID: PMC2395124. 2. Nie C, Sahoo AK, Netz RR, Herrmann A, Ballauff M, Haag R. Charge Matters: Mutations in Omicron Variant Favor Binding to Cells. Chembiochem. 2022 Mar 18;23(6):e202100681. doi: 10.1002/cbic.202100681. Epub 2022 Feb 2. PMID: 35020256; PMCID: PMC9015620.