Characterization of Proprotein Convertases and Their Involvement in Virus Propagation

Garten, Wolfgang

doi:10.1007/978-3-319-75474-1_9

Cited by 28 publications

(43 citation statements)

References 271 publications

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“…The S1/S2 cleavage site of the novel emerged SARS-CoV-2 has been shown to possess a minimal furin consensus motif of the sequence R-R-A-R↓ with an alanine instead of a basic residue in the P2 position ( Fig 1B ; ( 22 , 23 )). Only few furin substrates possess a nonbasic residue in the P2 position, such as Pseudomonas aeruginosa exotoxin A or Shiga toxin ( 10 , 19 ). To test, whether the S1/S2 sequence of SARS-CoV-2 S protein is efficiently cleaved by furin, a small series of FRET substrates was synthesized ( Fig 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…Many proteases have been found to activate CoVs in vitro, including furin, cathepsin L, and trypsin-like serine proteases such as the transmembrane serine protease 2 (TMPRSS2), TMPRSS11A, and TMPRSS11D (reviewed in references 6 , 7 , and 8 ). Among them, TMPRSS2 and furin play major roles in proteolytic activation of a broad range of viruses (reviewed in references 9 , 10 , and 11 ). TMPRSS2 is a type II transmembrane serine protease (TTSP) that is widely expressed in epithelial cells of the respiratory, gastrointestinal, and urogenital tract ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furin cleaves the precursors of a broad range of proteins, including hormones, growth factors, cell surface receptors, and adhesion molecules during their transport along the secretory pathway at multibasic motifs of the preferred consensus sequence R-X-R/K-R↓ (reviewed in reference 10 ). Moreover, furin has been identified as an activating protease for the fusion proteins of a broad range of viruses, including highly pathogenic avian influenza A viruses (HPAIV), HIV, Ebola virus, measles virus, and yellow fever virus as well as bacterial toxins such as Shiga toxin or anthrax toxin at multibasic motifs (reviewed in references 9 , 10 , and 19 ). Acquisition of a multibasic cleavage site by insertion of basic amino acids has long been known to be a prime determinant of avian influenza A virus pathogenicity in poultry.…”

Section: Introductionmentioning

confidence: 99%

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TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

et al. 2020

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The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2′ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

et al. 2020

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“…Furin plays a key role in the cleavage of a wide range of critical cell surface proteins including adhesion molecules, surface receptors, growth factors, and hormones to produce mature proteins. Additionally, furin cleaves envelope glycoproteins of different viruses, thus, improving the fusion of viral membrane with the host cell (Garten, 2018). Data indicate that the existence of a redundant furin cleavage site at S protein of SARS-CoV-2 is responsible for its infectious nature than other CoVs, leading to its higher efficiency to fuse to the host membrane (Wu et al, 2020b).…”

Section: Furinmentioning

confidence: 99%

Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza

Saadat

Khatibi

Vahed

et al. 2021

Front. Mol. Biosci.

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The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.

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“…Furin, a member of the proprotein convertase family, is ubiquitously expressed in mammalian cells and activates various proprotein substrates [9][10][11]. Furin regulates not only pathogenic pathways but also several physiological pathways, involving hormones, growth factors, adhesion molecules, and cell surface receptors [12]. Furin is involved in calcium-dependent proteolytic cleavage at the C-terminus of a consensus amino acid motif R-X-X-R↓ (the arrow indicates the cleavage position) [9].…”

Section: Introductionmentioning

confidence: 99%

Screening for inhibitory effects of crude drugs on furin-like enzymatic activities

Kiba

Misawa

et al. 2021

J Nat Med

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The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a cleavage motif R-X-X-R for furin-like enzymes at the boundary of the S1/S2 subunits. The cleavage of the site by cellular proteases is essential for S protein activation and virus entry. We screened the inhibitory effects of crude drugs on in vitro furin-like enzymatic activities using a fluorogenic substrate with whole-cell lysates. Of the 124 crude drugs listed in the Japanese Pharmacopeia, aqueous ethanolic extract of Cnidii Monnieris Fructus, which is the dried fruit of Cnidium monnieri Cussion, significantly inhibited the furin-like enzymatic activities. We further fractionated the plant extract and isolated the two active compounds with the inhibitory activity, namely, imperatorin and osthole, whose IC 50 values were 1.45 mM and 9.45 µM, respectively. Our results indicated that Cnidii Monnieris Fructus might exert inhibitory effects on furin-like enzymatic activities, and that imperatorin and osthole of the crude drug could be potential inhibitors of the motif cleavage.

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Characterization of Proprotein Convertases and Their Involvement in Virus Propagation

Cited by 28 publications

References 271 publications

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza

Screening for inhibitory effects of crude drugs on furin-like enzymatic activities

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