SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity

Abstract

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

Insertions in SARS-CoV-2 genome caused by template switch and duplications give rise to new variants that merit monitoring

“…The copyright holder for this preprint (which this version posted April 26, 2021. ; https://doi.org/10.1101/2021.04.23.441209 doi: bioRxiv preprint cells 38 , could be associated with the escape from the T-cell immunity. Furthermore, recent evidence suggests that this region contains an additional epitope for antibody binding 39 . Because these insertions were detected only in recent samples, it appears that the respective variants have to be further monitored.…”

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells

“…The authors concluded that such a pocket can be considered a “potential target for drug design against SARS-CoV-2”. Remarkably, while the present paper was under review, Rosa et al [ 57 ] showed, using cryo-electron microscopy and X-ray crystallography, that two small molecules (i.e., the products of heme metabolism biliverdin and bilirubin) target the SARS-CoV-2 S protein with nanomolar affinity by interacting with P2. In summary, the computed size, degree of enclosure, hydrophobicity, and druggability, combined with some recent experimental observations, put forward P2 as a relevant site for further structure-based drug discovery approaches to be followed to identify new small molecules able to bind the SARS-CoV-2 S protein.…”

Structure of a germline-like human antibody defines a neutralizing epitope on the SARS-CoV-2 spike NTD

“…We found that mAb PVI.V6-14 belongs to an as of yet undescribed class of antibodies that bind within a hydrophobic cavity, previously identified to bind a heme metabolite, biliverdin 32 . Our functional binding and neutralization data confirm that the antibody competes with biliverdin and also underscores the antibody's capacity to recognize emerging viral variants of concern.…”

“…A previous study reported the structure of a heme metabolite, biliverdin, bound within the hydrophobic NTD pocket 32 . We superposed the structure of our Fab bound NTD with that of the biliverdin bound one and found that our antibody, through its HCDR3 aromatic amino-acid residues, was a molecular mimic of the tetrapyrrole molecule (Figure 3a).…”