Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant

Abstract

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report the structure, function, and antigenicity of its full-length spike (S) trimer and those of the Gamma and Kappa variants and compare their characteristics with the G614, Alpha, and Beta variants. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2, and its pseudotyped viruses infect target cells substantially faster than the other five variants, possibly accounting for its heightened transmissibility. Each variant shows different rearrangement of the antigenic surface of the N-terminal domain of the S protein, but only causes local changes in the receptor-binding domain (RBD), making the RBD a better target for therapeutic antibodies.

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM

“…The Beta and Kappa S proteins, both of which bear D614G mutation, showed stronger ACE2 binding than did the G614 S, suggesting that the other mutations within the Beta and Kappa S may enhance receptor recognition. The S/ACE2 affinity for the two variants is also slightly stronger than that of WT S. Overall, our BLI data are consistent with the S/ACE2 affinity results for Beta/Kappa variants reported recently 29,30,45,46 .…”

“…1a). Our affinity data are in general consistent with those generated using a similar BLI protocol 30,43,46 . For example, Cai et al have reported that the affinity of the Beta S to monomeric ACE2 (K D = 71.4 nM) increased as compared to that of the G614 S (K D = 124.0 nM) 30 .…”

“…For example, Cai et al have reported that the affinity of the Beta S to monomeric ACE2 (K D = 71.4 nM) increased as compared to that of the G614 S (K D = 124.0 nM) 30 . It should be mentioned that, for a given variant S protein, its absolute K D values generated from different studies 29,30,[42][43][44][45][46] , including two studies recently reported on BioRxiv 57,58 , may vary significantly, likely due to multiple factors such as the method used (BLI or SPR), S protein construct (full-length S or prefusion-stabilized S ectodomain), ACE2 form (monomeric or dimeric), the protein used to load the sensors (ACE2 or S), and even binding temperature. For example, it has been reported that the full-length G614 S had a K D value of 12.8 nM to dimeric ACE2 but its K D value to monomeric ACE2 was 124 nM 30 .…”

Hypertonic saline and aprotinin based blockage of SARS-CoV-2 specific furin site cleavage by inhibition of nasal protease activity

“…We observed that higher cleavage percentages were achieved with both furin and trypsin for P681R FCS peptide than for wild-type one. It is consistent with that the Delta variant's P681R allows the cleavage to occur more easily than in the wild-type SARS-CoV-2 strain, as Delta variant has a more efficient furin cleavage site [19,20]. However, the cleavage of P681R can still be inhibited by hypertonic saline or aprotinin at an appropriate concentration, even if such inhibition was relatively less in P681R FCS compared to wild-type.…”

Relationship between monomer packing, receptor binding domain pocket status, and pH, in the spike trimer of SARS-CoV-2 variants

“…Previous predictions of potential acid sensor residues, and calculations of the change in solvent accessible surface area (d-SASA) upon spike monomer incorporation in trimer (in various trimer forms) (Lobo and Warwicker, 2021), are supplemented with data for two recent structures of the Delta variant (RCSB/PDB (Berman et al, 2007) identifiers 7v7n (10.2210/pdb7V7N/pdb) and 7sbk (Zhang et al, 2021b)), and consideration of sequence changes around the RBD pocket of the Omicron variant S protein. A new measure is constructed of distance across the RBD pocket in which linoleic acid can bind (Fig.…”