Priming Time: How Cellular Proteases Arm Coronavirus Spike Proteins

Hoffmann, Markus; Hofmann-Winkler, Heike; Pöhlmann, Stefan

doi:10.1007/978-3-319-75474-1_4

Cited by 107 publications

(131 citation statements)

References 184 publications

(252 reference statements)

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“…The nascent S protein has two subunits, S1 and S2 16 . The S protein is modified in the endoplasmic reticulum (ER) of the host cell with N-linked glycans that would protect it against neutralizing antibodies [16][17][18] . After passing the ER quality control, the S protein is transported to the surface of the virus and is incorporated into the viral membrane where it is cleaved (primed) into two segments: (1) the N-terminal S1 segment contains a signal peptide and the receptor binding domain (RBD) that interact with the host cell receptor ( Fig.…”

Section: Covid-19mentioning

confidence: 99%

COVID19: an announced pandemic

2020

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A severe upper respiratory tract syndrome caused by the new coronavirus has now spread to the entire world as a highly contagious pandemic. The large scale explosion of the disease is conventionally traced back to January of this year in the Chinese province of Hubei, the wet markets of the principal city of Wuhan being assumed to have been the specific causative locus of the sudden explosion of the infection. A number of findings that are now coming to light show that this interpretation of the origin and history of the pandemic is overly simplified. A number of variants of the coronavirus would in principle have had the ability to initiate the pandemic well before January of this year. However, even if the COVID-19 had become, so to say, ready, conditions in the local environment would have had to prevail to induce the loss of the biodiversity’s “dilution effect” that kept the virus under control, favoring its spillover from its bat reservoir to the human target. In the absence of these appropriate conditions only abortive attempts to initiate the pandemic could possibly occur: a number of them did indeed occur in China, and probably elsewhere as well. These conditions were unfortunately present at the wet marked in Wuhan at the end of last year.

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Section: Covid-19mentioning

confidence: 99%

COVID19: an announced pandemic

2020

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“…Indeed, furin belongs the pro-protein convertase subtilisin/kexin family and it plays an important role in the entry of SARS-COV-2 in the host cell by cleaving the 2 subunits of the spike glycoprotein at a specific multibasic S1/S2 site [113,114]. However, the membrane fusion between the transmembrane subunit of spike protein S2 and the host cell membrane depends on S protein cleavage by the host cell protease furin at the S1/S2 site resulting in S protein activation and facilitate the entry into the host cell [115]. Interestingly, it has been reported that furin inhibitors can be considered as a treatment option for COVID-19 [16].…”

Section: Furthermore Diabetes Is Characterized By An Abundant Producmentioning

confidence: 99%

SARS-CoV-2 S Protein Binding hACE2: Viral Entry, Pathogenesis, Prognosis, and Potential Therapeutic Targets

Al-Zaidan¹,

Mestiri²,

Raza³

et al. 2020

Preprint

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Pneumonia cases of unknown etiology in Wuhan, China, were reported to the WHO on 31st of December 2019. Later the pathogen was reported to be a novel coronavirus designated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 is a novel pathogenic beta coronavirus that infects humans causing severe respiratory illness. However, multifarious factors can contribute to the susceptibility to COVID-19 related morbidity and mortality such as age, gender and underlying comorbidities. Importantly, SARS-CoV and SARS-CoV-2 entry into the host cells is mediated via ACE2 receptor. However, ACE2 receptor binding affinity to SARS-CoV-2 is 4 folds higher than that to SARS-CoV. Identification of different aspects such as binding affinity, differential antigenic profiles of spike glycoproteins, and ACE2 polymorphisms might influence the investigation of potential therapeutic strategies targeting SARS-CoV-2/ACE2 binding interface. Here we aim to elaborate on SARS-CoV-2 S1/ACE2 ligand that facilitates viral internalization as well as to highlight the differences between SARS-CoVs binding affinity to ACE2. We also discuss the possible immunogenic sequences of spike glycoprotein and the effect of ACE2 polymorphism on viral binding/infectivity and host susceptibility to disease. Furthermore, targeting of ACE2 will be discussed to understand its role in therapeutics.

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“…SARS-CoV-2 entry requires the binding of its spike protein, S, to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al, 2020b;Walls et al, 2020). In addition, S must be cleaved by host proteases, as with other coronaviruses (Hoffmann et al, 2018) and influenza viruses (Karakus et al, 2020), for successful entry, a step often limiting the zoonotic potential of coronaviruses (Letko et al, 2020). In vitro studies have suggested that this cleavage, also termed S protein activation, can be accomplished by the transmembrane serine protease TMPRSS2 and endosomal cysteine proteases Cathepsin B and Cathepsin L (Hoffmann et al, 2020b;Ou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The proteases TMPRSS2 and Cathepsin B/L are unrelated and work independently (Hoffmann et al, 2018), suggesting that SARS-CoV-2 can enter cells via two independent pathways. Studies on SARS-CoV have shown that TMPRSS2 is expressed on the target cell surface and acts by cleaving S and facilitating the fusion of viral and cell membranes at the target cell surface, whereas Cathepsin B/L are expressed in endosomes and act after the virus has been endocytosed, facilitating the fusion of viral and endosomal membranes (Glowacka et al, 2011;Matsuyama et al, 2010;Shulla et al, 2011;Simmons et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

Padmanabhan¹,

Desikan²,

Dixit³

2020

Preprint

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The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through ‘repurposing’ drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.

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Priming Time: How Cellular Proteases Arm Coronavirus Spike Proteins

Cited by 107 publications

References 184 publications

COVID19: an announced pandemic

COVID19: an announced pandemic

SARS-CoV-2 S Protein Binding hACE2: Viral Entry, Pathogenesis, Prognosis, and Potential Therapeutic Targets

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

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