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Review
. 2021 May 1;29(3):249-262.
doi: 10.4062/biomolther.2021.048.

Multifactorial Traits of SARS-CoV-2 Cell Entry Related to Diverse Host Proteases and Proteins

Jaehwan You  1 , Jong Hyeon Seok  1 , Myungsoo Joo  2 , Joon-Yong Bae  1 , Jin Il Kim  1   3 , Man-Seong Park  1   3 , Kisoon Kim  1
Affiliations
Review

Multifactorial Traits of SARS-CoV-2 Cell Entry Related to Diverse Host Proteases and Proteins

Jaehwan You et al. Biomol Ther (Seoul). .

Abstract

The most effective way to control newly emerging infectious disease, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, is to strengthen preventative or therapeutic public health strategies before the infection spreads worldwide. However, global health systems remain at the early stages in anticipating effective therapeutics or vaccines to combat the SARS-CoV-2 pandemic. While maintaining social distance is the most crucial metric to avoid spreading the virus, symptomatic therapy given to patients on the clinical manifestations helps save lives. The molecular properties of SARS-CoV-2 infection have been quickly elucidated, paving the way to therapeutics, vaccine development, and other medical interventions. Despite this progress, the detailed biomolecular mechanism of SARS-CoV-2 infection remains elusive. Given virus invasion of cells is a determining factor for virulence, understanding the viral entry process can be a mainstay in controlling newly emerged viruses. Since viral entry is mediated by selective cellular proteases or proteins associated with receptors, identification and functional analysis of these proteins could provide a way to disrupt virus propagation. This review comprehensively discusses cellular machinery necessary for SARS-CoV-2 infection. Understanding multifactorial traits of the virus entry will provide a substantial guide to facilitate antiviral drug development.

Keywords: Antiviral drugs; Cell entry; Cellular proteins; SARS-CoV-2.

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Figures

Fig. 1
Fig. 1
RBD conformations of SARS-CoV-2 S protein. Cryo-EM structure of SARS-CoV-2 S protein trimer (PDB ID 6VXX and 6VYB) drawn by surface and ribbon diagrams, S1 and S2 domains, respectively. The three protomers are colored blue, pink, and green, and the human ACE2 receptor binding site (RBS) was highlighted by red color, respectively. Side (upper panel) and top (lower panel) views of the S protein structures are divided by open and closed configurations of the RBD. RBS is hidden and buried in protomers’ interspace (RBD closed) and not accessible to the receptor. When the RBD status has opened, RBS is exposed and ready to interact with the ACE2 receptor. The figures were created with PyMOL (https://www.pymol.org/).
Fig. 2
Fig. 2
Characteristics of each domain and motif represented on S protein of SARS-CoV-2 involving host cell entry. (A) Designated surface and ribbon diagrams of trimeric spike proteins in the SARS-CoV-2. Each protomer’s marginal views that play a critical role in cell entry binding to host cell receptors are colored as pink, blue, and green, respectively (PDB ID 7KMZ). Accessibility to the ACE2 receptor of the three receptor binding sites (RBDs) are colored blue and green when the RBD is open status, whereas closed RBD is colored as pink. Neuropilin-1 (NRP1) binding motif, as a putative cellular entry facilitator, furin cleavage site (S1/S2), and notable mutations in the S protein (N501Y, D614G, and E484K) were marked with red arrows. (B) Superimposed image of opened (blue) and closed (magenta) configurations of the RBD in S1 regions directly interacting with the ACE2. Structural alteration of the NTD (N-terminal domain) and S2 domain of the spike protein after binding ACE2 is negligible. The human ACE2 receptor is colored gray. (PDB ID 7KMZ). The figures were created with PyMOL (https://www.pymol.org/).
Fig. 3
Fig. 3
Schematic diagram of postulated multifactorial SARS-CoV-2 cell entry through endocytosis (A) and direct membrane fusion (B). The SARS-CoV-2 preferentially utilizes ACE2 (angiotensin converting enzyme 2) as a cellular receptor to recognize susceptible cells. Another host factor, NRP1, may facilitate cellular receptors for the virus’ cell entry; once the NRP1 interacts with trimerized viral spike proteins, entry machinery induces conformational alteration of spike proteins in the cell membrane. A variety of membranous proteins participate in the endocytic pathway and/or virus-to-cell fusion process is illustrated. Each cellular and viral factor described in the figure is not on a scale. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane protease serine subtype 2; NRP1, neuropilin-1; ADAM17, a disintegrin and metalloproteinase 17; TGN, trans-Golgi network.
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References

    1. Alexander D. J., Brown I. H. History of highly pathogenic avian influenza. Rev. Sci. Tech. 2009;28:19–38. doi: 10.20506/rst.28.1.1856. - DOI - PubMed
    1. Ami Y., Nagata N., Shirato K., Watanabe R., Iwata N., Nakagaki K., Fukushi S., Saijo M., Morikawa S., Taguchi F. Co-infection of respiratory bacterium with severe acute respiratory syndrome coronavirus induces an exacerbated pneumonia in mice. Microbiol. Immunol. 2008;52:118–127. doi: 10.1111/j.1348-0421.2008.00011.x. - DOI - PMC - PubMed
    1. Andersen K. G., Rambaut A., Lipkin W. I., Holmes E. C., Garry R. F. The proximal origin of SARS-CoV-2. Nat. Med. 2020;26:450–452. doi: 10.1038/s41591-020-0820-9. - DOI - PMC - PubMed
    1. Baron J., Tarnow C., Mayoli-Nüssle D., Schilling E., Meyer D., Hammami M., Schwalm F., Steinmetzer T., Guan Y., Garten W., Klenk H. D., Böttcher-Friebertshäuser E. Matriptase, HAT, and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J. Virol. 2013;87:1811–1820. doi: 10.1128/JVI.02320-12. - DOI - PMC - PubMed
    1. Bassi D. E., Zhang J., Renner C., Klein-Szanto A. J. Targeting proprotein convertases in furin-rich lung cancer cells results in decreased in vitro and in vivo growth. Mol. Carcinog. 2017;56:1182–1188. doi: 10.1002/mc.22550. - DOI - PMC - PubMed

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