Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site

Jaimes, Javier A.; Millet, Jean K.; Whittaker, Gary R.

doi:10.1016/j.isci.2020.101212

Cited by 310 publications

(354 citation statements)

References 27 publications

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“…Furthermore, viral genome region harboring the furin cleavage motif is very stable during SARS-CoV-2 replication in human airway organoids, in contrast to the rapid acquisition of the deletion mutation in Vero E6 cells. Despite contradictory to the findings of some in vitro studies, 16,17 our observation is actually compatible to the real-life scenarios in human and related animal hosts. The furin cleavage motif is absent in closely-related bat coronavirus RaTG13 and pangolin coronavirus, leading to a speculation that acquisition of the motif may be essential for the cross-species transmission and productive infection of SARS-CoV-2 in humans.…”

Section: One Of the Notable Features Of Sars-cov-2 Is The Presence Ofcontrasting

confidence: 80%

“…16 Jaimes et al documented that the PRRA insertion allows furin cleavage of SARS-CoV-2 spike protein and may enhance spike protein cleavage by other proteases. 17 However, a recent study suggested the furin cleavage motif is not essential for the fusion activity of SARS-CoV-2 spike protein in the environment where serine proteases are present, such as the human airway. 18 Given the controversies, we sought to evaluate the role of the PRRA motif for SARS-CoV-2 replication in human airway organoids.…”

Section: One Of the Notable Features Of Sars-cov-2 Is The Presence Ofmentioning

confidence: 99%

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Human airway organoids model SARS-CoV-2 high infectiousness and evasion of interferon response

Zhou¹,

Chiu²,

Li³

et al. 2020

Preprint

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SARS-CoV-2 is more infectious and transmissible in humans than SARS-CoV, despite the genetic relatedness and sharing the same cellular receptor. We sought to assess whether human airway organoids can model SARS-CoV-2 infection in the human airway and elucidate the cellular basis underlying its higher transmissibility. We demonstrate that SARS-CoV-2 can establish a productive infection in human airway organoids, in which ciliated cell and basal cell are infected. Wildtype SARS-CoV-2 carrying a furin cleavage motif exhibits comparable replication kinetics to a mutant virus without the motif. Human airway organoids sustain higher replication of SARS-CoV-2 than SARS-CoV, whereas interferon response is more potently induced in the latter than the former. Overall, human airway organoids can model SARS-CoV-2 infection and recapitulate the disposable role of furin cleavage motif for virus transmission in humans. SARS-CoV-2 stealth growth and evasion of interferon response may underlie pre-symptomatic virus shedding in COVID-19 patients, leading to its high infectiousness and transmissibility.

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Section: One Of the Notable Features Of Sars-cov-2 Is The Presence Ofcontrasting

confidence: 80%

Section: One Of the Notable Features Of Sars-cov-2 Is The Presence Ofmentioning

confidence: 99%

Human airway organoids model SARS-CoV-2 high infectiousness and evasion of interferon response

Zhou¹,

Chiu²,

Li³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The viral entry mechanisms elucidated for SARS-CoV infection appear to be shared by SARS-CoV-2 (9,10). Additionally, SARS-CoV-2 uniquely possesses a "furin-like" cleavage site and is subject to processing during viral packaging by the intracellular proprotein convertase furin (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry

Chen

Evankovich

Larsen

et al. 2020

Preprint

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SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat COVID-19 infection.

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“…The efficiency of spike protein cleavage is known to associate with coronavirus replication (Hoffmann et al, 2020;Jaimes et al, 2020). We found that introduction of the D614G mutation into the Wuhan-Hu-1 prototype sequence enhanced SARS-CoV-2 spike cleavage in cells ( Figure 5B).…”

Section: D614g Variant Demonstrates Higher Transmissibility In Hamstersmentioning

confidence: 91%

SARS-CoV-2 spike D614G variant exhibits highly efficient replication and transmission in hamsters

Mok

Cremin

Lau

et al. 2020

Preprint

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SummarySARS-CoV-2 causes disease varying in severity from asymptomatic infections to severe respiratory distress and death in humans. The viral factors which determine transmissibility and pathogenicity are not yet clearly characterized. We used the hamster infection model to compare the replication ability and pathogenicity of five SARS-CoV-2 strains isolated from early cases originating in Wuhan, China, in February, and infected individuals returning from Europe and elsewhere in March 2020. The HK-13 and HK-95 isolates showed distinct pathogenicity in hamsters, with higher virus titers and more severe pathological changes in the lungs observed compared to other isolates. HK-95 contains a D614G substitution in the spike protein and demonstrated higher viral gene expression and transmission efficiency in hamsters. Intra-host diversity analysis revealed that further quasi species were generated during hamster infections, indicating that strain-specific adaptive mutants with advantages in replication and transmission will continue to arise and dominate subsequent waves of SARS-CoV-2 dissemination.

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Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site

Cited by 310 publications

References 27 publications

Human airway organoids model SARS-CoV-2 high infectiousness and evasion of interferon response

Human airway organoids model SARS-CoV-2 high infectiousness and evasion of interferon response

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry

SARS-CoV-2 spike D614G variant exhibits highly efficient replication and transmission in hamsters

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