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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

Related Products: SARS-CoV-2 Spike Proteins | ACE2 Antibodies | TMPRSS2 Antibodies

Produkt
Kat. Nr.
Klonalität
Source
Menge
Kat. Nr.ABIN521006
KlonalitätMonoclonal
SourceMouse
Menge100 μg
Kat. Nr.ABIN1169449
KlonalitätMonoclonal
SourceMouse
Menge100 μg
Kat. Nr.ABIN730808
KlonalitätPolyclonal
SourceRabbit
Menge100 μL

Translation of Viral Replication Machinery (2) and Replication (3)

After the viral RNA is released into the host cell, polyproteins are translated. The coronavirus genomic RNA encodes nonstructural proteins (NSPs) that have a critical role in viral RNA synthesis, and structural proteins which are important for virion assembly. First, polyproteins pp1a and pp1ab, are translated which are cleaved by the Papain-like protease (Pl pro ) and 3C-like protease(3CL pro ) (Inhibitor VII) to form functional NSPs as Helicase or the RNA replicase–transcriptase complex (RdRp). 3 RdRp especially can be inhibited by virostatica like Favipiravir or Penciclovir (Inhibitor V) ; the replication of viral RNA in general by kinase signaling pathway inhibitors like Saracatinib (Inhbitor VI) . 4 Expression level of N protein can be decreased by resveratrol (Inhibitor IX) . 5

Related Products: SARS-CoV-2 Non-Structural Proteins | SARS-CoV-2 N Proteins | SARS-CoV-2 N Antibodies

Produkt
Kat. Nr.
Klonalität
Source
Menge
Kat. Nr.ABIN6952454
Klonalität
SourceHEK-293 Cells
Menge100 μg
Kat. Nr.ABIN1382276
Klonalität
Source
Menge0.05 mg
Kat. Nr.ABIN6952440
KlonalitätPolyclonal
SourceRabbit
Menge100 μL
Kat. Nr.ABIN6952432
KlonalitätMonoclonal
SourceMouse
Menge0.1 mg
Kat. Nr.ABIN1031551
KlonalitätPolyclonal
SourceRabbit
Menge0.1 mg

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.

Related Products: SARS-CoV-2 Spike Proteins | SARS-CoV-2 S1 Proteins | SARS-CoV-2 S2 Proteins | SARS-CoV-2 S Antibodies

Produkt
Kat. Nr.
Klonalität
Source
Menge
Kat. Nr.ABIN1382273
Klonalität
Source
Menge0.05 mg
Kat. Nr.ABIN1030641
KlonalitätPolyclonal
SourceRabbit
Menge0.1 mg
Kat. Nr.ABIN6952495
KlonalitätMonoclonal
SourceRabbit
Menge50 μL

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

References

  • 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
  • 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]
  • Zhavoronkov et al.: Potential COVID-2019 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches, ChemRxiv (2020), [ DOI]
  • Shin et al.: Saracatinib Inhibits Middle East Respiratory Syndrome-Coronavirus Replication In Vitro, Viruses, 10(6):283 (2018), [ DOI]
  • 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]
  • McKimm‐Breschkin: Influenza neuraminidase inhibitors: Antiviral action and mechanisms of resistance. Influenza and Other Respiratory Viruses 7(Suppl. 1), 25–36., [ PMC]
Julian Pampel
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