Domains and Functions of Spike Protein in SARS-Cov-2 in the Context of Vaccine Design

Abstract

The spike protein in SARS-CoV-2 (SARS-2-S) interacts with the human ACE2 receptor to gain entry into a cell to initiate infection. Both Pfizer/BioNTech’s BNT162b2 and Moderna’s mRNA-1273 vaccine candidates are based on stabilized mRNA encoding prefusion SARS-2-S that can be produced after the mRNA is delivered into the human cell and translated. SARS-2-S is cleaved into S1 and S2 subunits, with S1 serving the function of receptor-binding and S2 serving the function of membrane fusion. Here, I dissect in detail the various domains of SARS-2-S and their functions discovered through a variety of different experimental and theoretical approaches to build a foundation for a comprehensive mechanistic understanding of how SARS-2-S works to achieve its function of mediating cell entry and subsequent cell-to-cell transmission. The integration of structure and function of SARS-2-S in this review should enhance our understanding of the dynamic processes involving receptor binding, multiple cleavage events, membrane fusion, viral entry, as well as the emergence of new viral variants. I highlighted the relevance of structural domains and dynamics to vaccine development, and discussed reasons for the spike protein to be frequently featured in the conspiracy theory claiming that SARS-CoV-2 is artificially created.

Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes

“…In its mature form, spike contains four regions, a signal sequence, ectodomain, transmembrane domain and endodomain, which is further divided into the S1 and S2 subunits. The 12-residue N-terminal signal sequence (SP) directs spike to its destination in the viral membrane [31]. CamSol calculated SP to be poorly soluble and all aggregation prediction servers identified it as an APR ( Table S1 ).…”

SARS-CoV-2 induces transcription of human endogenous retrovirus RNA followed by type W envelope protein expression in human lymphoid cells.

“…This activation was also obtained with a recombinant trimer tested for an effective binding to ACE2 receptors, but not stabilized in a speci c conformation. Pre-and post-fusion variable conformations of this spike protein may confer divergent properties 52 , whereas vaccine preparations are likely to stabilize its structure [53][54][55] with a good safety pro le 54,56 . Here again, further studies are needed to de ne sequence-related and protein conformational properties involved in a proteinreceptor interaction leading to HERV activation in susceptible individuals.…”

SARS-CoV-2 Genetic Variability and Non-Specific Immunity Associated with the Use of Different BCG Strains—A Molecular and Clinical Approach

“…As a result, the variant shows faster proliferation in the environment. The morphology of the compared viruses and their neutralization in vitro were similar, suggesting that vaccines against SARS-CoV-2 may be effective against the described British variant [79][80][81]. SARS-CoV-2 variants have been shown to undergo differential glycosylation, which is important with respect to their infectivity and antibody reactivity.…”

“…Analyzing the rate of virus spread in the world and the number of cases of infection in individual countries, it is possible to notice a correlation that a significant increase in the number of described cases is associated with the appearance of SARS-CoV-2 variants in a given region of the world [87] (Figure 3). The described mutations mainly affect the rate of spread of the virus, without much influence on its pathogenicity and the effectiveness of vaccination against it [79][80][81]. In addition, the mutations are within the ORF3a protein, which may be involved in the pathogenesis of the virus [90].…”