SARS-CoV-2 Life Cycle: Stages and Inhibition Targets

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the enveloped positive-sense RNA viruses. This virus is characterized by club-like spikes on the surface, and a unique replication strategy. In the following the replication cycle of SARS-Cov-2 is explained together with possible inhibitors and their respective targets. This compilation is based on current literature however we make no claim to accuracy.

Stages of the SARS-CoV-2 Life Cycle: Virus Entry, Translation of Viral Replication Machinery, Replication, Translation of Viral Structure Proteins, Virion Assembly, Release of Virus

SARS-Cov-2 Replication Cycle

SARS-CoV-2 Life Cycle: Stages and Inhibition Targets
SARS-Cov-2 Replication Cycle and Inhibitors. Possible targets for inhibitors are marked in red and numbered in roman numerals. enlarge view

Virus Entry (1)

SARS-CoV-2 can hijack the cell in two ways, either via endosomes or via plasma membrane fusion. (In both ways) Spike proteins (S1, S2) of SARS-CoV-2 mediate attachment to the membrane of a host cell and engage angiotensin-converting enzyme 2 (ACE2) as the entry receptor. 1 Inhibitors like Griffithsin (Inhibitor II) bind to the spike glycoprotein, thus preventing viral entry. 1

When virions are taken up into endosomes, cathepsin L activates the spike protein. the pH dependent cysteine protease can be blocked by lysosomotropic agents, like bafilomycin A1 or ammonium chloride (Inhibitor Classes III, IV) Alternatively, the spike protein can be activated by the cellular serine protease TMPRSS2 in close proximity to the ACE2 receptor, which initiates fusion of the viral membrane with the plasma membrane (Inhibitor I: Camostat) . 1 The plasma membrane fusion entry is less likely to trigger host cell antiviral immunity and therefore more efficient for viral replication. 2

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anti-ACE2 Antikörper (Angiotensin I Converting Enzyme 2) ABIN1169449 Monoclonal Mouse 100 μg element-ABIN1169449
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Translation of Viral Replication Machinery (2) and Replication (3)

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Translation of Viral Structure Proteins (4) and Virion Assembly (5)

RdRp is responsible for replication of structural protein RNA. Structural proteins S1, S2, Envelope (E), Membrane (M) are translated by ribosomes that are bound to the endoplasmic reticulum (ER) and presented on its surface as preparation of viron assembly. The nucleocapsids (N) remain in cytoplasm and are assembled from genomic RNA. They fuse with the virion precursor which is then transported from the ER through the Golgi Apparatus to the cell surface via small vesicles.

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SARS-Coronavirus Spike Protein (SARS-CoV S) (C-Term) Peptid ABIN1382273 0.05 mg element-ABIN1382273
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Release of Virus (6)

Virions are then released from the infected cell through exocytosis and search a another host cell. Oseltamivir inhibits cleavage of sialic acids by neuroamidase from the cell receptors thus preventing release of newly formed (influenza) virions from the cell surface (Inhibitor X) . 6

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References

  1. Hoffmann et al.: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell (2020), PDF
  2. Shirato, K., Kawase, M. & Matsuyama, S.: Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry, Virology 517, 9–15 (2018), [ DOI]
  3. Zhavoronkov et al.: Potential COVID-2019 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches, ChemRxiv (2020), [ DOI]
  4. Shin et al.: Saracatinib Inhibits Middle East Respiratory Syndrome-Coronavirus Replication In Vitro, Viruses, 10(6):283 (2018), [ DOI]
  5. Lin, S. C., Ho, C. T., Chuo, W. H., Li, S., Wang, T. T., & Lin, C. C. : Effective inhibition of MERS-CoV infection by resveratrol, BMC Infectious Diseases, 17(1)(2017), [ DOI]
  6. McKimm‐Breschkin: Influenza neuraminidase inhibitors: Antiviral action and mechanisms of resistance. Influenza and Other Respiratory Viruses 7(Suppl. 1), 25–36., [ PMC]