Proteolytic activation of SARS‐CoV‐2 spike protein

Microbiology and Immunology, Journal Year: 2021, Volume and Issue: 66(1), P. 15 - 23

Published: Sept. 25, 2021

Spike (S) protein cleavage is a crucial step in coronavirus infection. In this review, process discussed, with particular focus on the novel coronavirus, severe acute respiratory syndrome 2 (SARS-CoV-2). Compared influenza virus and paramyxovirus membrane fusion proteins, activation mechanism of S much more complex. The has two sites (S1/S2 S2'), motif for furin protease at S1/S2 site that results from unique four-amino acid insertion one distinguishing features SARS-CoV-2. viral particle incorporates protein, which already undergone by furin, then undergoes further S2' site, mediated type II transmembrane serine (TMPRSS2), after binding to receptor angiotensin-converting enzyme (ACE2) facilitate plasma membrane. addition, SARS-CoV-2 can enter cell endocytosis be proteolytically activated cathepsin L, although not major mode variants enhanced infectivity have been emerging throughout ongoing pandemic, there close relationship between changes cleavability. All four concern carry D614G mutation, indirectly enhances cleavability furin. P681R mutation delta variant directly increases cleavability, enhancing virulence. Changes significantly impact infectivity, tissue tropism, Understanding these mechanisms critical counteracting pandemic.

Language: Английский

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Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 963 - 971

Published: June 8, 2022

Language: Английский

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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(4), P. e1009500 - e1009500

Published: April 22, 2021

The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which not observed for other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features coronavirus spike (S) protein, optimize virus towards human respiratory tract. First, S proteins exhibit an intrinsic temperature preference, corresponding with or lower airways. Pseudoviruses bearing (SARS-2-S) were more infectious when produced at 33°C instead 37°C, a property shared protein HCoV-229E, common cold coronavirus. In contrast, MERS-CoV favored accordance preference Next, SARS-2-S-driven entry was efficiently activated by only TMPRSS2, but also TMPRSS13 protease, thus broadening cell tropism SARS-CoV-2. Both proteases proved relevant context authentic replication. appeared effective activator virulent low HCoV-229E virus. Activation SARS-2-S these surface requires processing S1/S2 cleavage loop, both furin recognition motif extended loop length critical. Conversely, deletion mutants significantly increased cathepsin-rich cells. Finally, we demonstrate that D614G mutation increases stability, particularly and, enhances its use cathepsin L pathway. This indicates link between stability usage this alternative route entry. Since properties may promote spread, they potentially explain why spike-G614 variant has replaced early D614 become globally predominant. Collectively, our findings adaptive mechanisms whereby adjusted match protease conditions enhance transmission pathology.

Language: Английский

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Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2

Emerging Microbes & Infections, Journal Year: 2022, Volume and Issue: 11(1), P. 2275 - 2287

Published: Aug. 30, 2022

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating variant globally. Omicron BA.1 contains more than 30 mutations spike protein, which contribute to its altered virological features when compared ancestral or previous variants. Recent studies by us others demonstrated that is less dependent on transmembrane serine protease 2 (TMPRSS2), efficient cleavage, fusogenic, adopts an propensity utilize plasma membrane endosomal pathways for virus entry. Ongoing suggest these of are part retained subsequent sublineages. However, exact determinants remain incompletely understood. In this study, we investigated observed characteristics Omicron. By screening individual changes BA.2 spike, identify 69-70 deletion, E484A, H655Y reduced TMPRSS2 usage while 25-27 S375F, T376A result cleavage. Among shared BA.2, S375F reduce spike-mediated fusogenicity. Interestingly, change consistently reduces increases use proteases. keeping with findings, substitution alone entry facilitates WT. Overall, our study identifies key contributes understanding determinant pathogenicity

Language: Английский

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TMPRSS2 is a functional receptor for human coronavirus HKU1

Nature, Journal Year: 2023, Volume and Issue: 624(7990), P. 207 - 214

Published: Oct. 25, 2023

Language: Английский

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Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 30, 2024

Omicron emerged following COVID-19 vaccination campaigns, displaced previous SARS-CoV-2 variants of concern worldwide, and gave rise to lineages that continue spread. Here, we show exhibits increased infectivity in primary adult upper airway tissue relative Delta. Using recombinant forms nasal epithelial cells cultured at the liquid-air interface, mutations unique Spike enable enhanced entry into tissue. Unlike earlier SARS-CoV-2, our findings suggest enters independently serine transmembrane proteases instead relies upon metalloproteinases catalyze membrane fusion. Furthermore, demonstrate this pathway unlocked by enables evasion from constitutive interferon-induced antiviral factors restrict attachment. Therefore, transmissibility exhibited humans may be attributed not only its vaccine-elicited adaptive immunity, but also superior invasion epithelia resistance cell-intrinsic barriers present therein.

Language: Английский

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A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(43)

Published: Oct. 11, 2021

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses essential viral spread in lung. Utilizing rational structure-based design (SBDD) coupled to substrate specificity screening TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) inhibitors which are structurally distinct from significantly improved activity over existing known Camostat Nafamostat. Lead compound MM3122 (4) has IC50 (half-maximal inhibitory concentration) 340 pM against recombinant full-length protein, EC50 effective 430 blocking entry into Calu-3 human lung epithelial cells a newly developed VSV-SARS-CoV-2 chimeric virus, 74 nM inhibiting cytopathic effects induced by SARS-CoV-2 virus cells. Further, blocks Middle East (MERS-CoV) with 870 pM. excellent metabolic stability, safety, pharmacokinetics mice, half-life 8.6 h plasma 7.5 tissue, making it suitable vivo efficacy evaluation promising candidate treatment.

Language: Английский

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SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 1, 2022

Abstract Monitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. Here, we sequenced 892 genomes collected from patients Saudi Arabia March to August 2020. We show that two consecutive mutations (R203K/G204R) nucleocapsid (N) protein are associated with higher viral loads patients. Our comparative biochemical analysis reveals mutant N displays enhanced RNA binding differential interaction key host proteins. found increased of GSK3A kinase simultaneously hyper-phosphorylation adjacent serine site (S206) protein. Furthermore, cell transcriptome suggests produces dysregulated interferon response genes. provide crucial information linking R203K/G204R modulations host-virus interactions underline potential as a drug target during infection.

Language: Английский

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Altered host protease determinants for SARS-CoV-2 Omicron

Science Advances, Journal Year: 2023, Volume and Issue: 9(3)

Published: Jan. 20, 2023

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While role host transmembrane protease serine in SARS-CoV-2 is widely recognized, involvement other proteases capable facilitating entry remains incompletely explored. Here, we show that multiple members from membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin families can mediate entry. Inhibition MT-MMPs significantly reduces replication vitro vivo. Mechanistically, cleave angiotensin-converting enzyme facilitate spike-mediated fusion. We further demonstrate Omicron BA.1 has an increased efficiency on MT-MMP usage, while altered usage for virus compared with ancestral SARS-CoV-2. These results reveal additional determinants enhance our understanding biology

Language: Английский

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Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: May 10, 2024

COVID-19, caused by SARS-CoV-2, affects neuronal cells, causing several symptoms such as memory loss, anosmia and brain inflammation. Curcuminoids (Me08 e Me23) curcumin (CUR) are derived from Curcuma Longa extract (EXT). Many therapeutic actions have been linked to these compounds, including antiviral action. Given the severe implications of especially within central nervous system, our study aims shed light on potential curcuminoids against SARS-CoV-2 infection, particularly in cells. Here, we investigated effects CUR, EXT, Me08 Me23 human neuroblastoma SH-SY5Y. We observed that significantly decreased expression plasma membrane-associated transmembrane protease serine 2 (TMPRSS2) TMPRSS11D, consequently mitigating elevated ROS levels induced SARS-CoV-2. Furthermore, exhibited antioxidative properties increasing NRF2 gene restoring NQO1 activity following infection. Both effectively reduced replication SH-SY5Y cells overexpressing ACE2 (SH-ACE2). Additionally, all compounds demonstrated ability decrease proinflammatory cytokines IL-6, TNF-α, IL-17, while specifically INF-γ levels. Our findings suggest curcuminoid could serve a agent for impact context system involvement.

Language: Английский

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