Engineered disulfide reveals structural dynamics of locked SARS-CoV-2 spike

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(7), P. e1010583 - e1010583

Published: July 29, 2022

The spike (S) protein of SARS-CoV-2 has been observed in three distinct pre-fusion conformations: locked, closed and open. Of these, the function locked conformation remains poorly understood. Here we engineered a S construct "S-R/x3" to arrest spikes by disulfide bond. Using this determined high-resolution structures confirming that x3 bond ability stabilize otherwise transient conformations. Structural analyses reveal wild-type can adopt two locked-1 locked-2 For D614G spike, based on which all variants concern were evolved, only was observed. Analysis suggests rigidified domain D conformations interacts with hinge C thereby restrains RBD movement. change correlates conformational change. We propose are present acidic high-lipid cellular compartments during virus assembly egress. In model, release virion into neutral pH extracellular space would favour transition or open dynamics be altered mutations modulate structure, as is case for mutation, leading changes viral fitness. S-R/x3 provides tool further structural functional characterization S, well how sequence might alter regulation receptor binding dynamics.

Language: Английский

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The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity

Cells, Journal Year: 2023, Volume and Issue: 12(3), P. 445 - 445

Published: Jan. 30, 2023

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, mucosae with minor salivary glands, and terminal parts major glands open into the cavity. constantly exposed to viral microbial pathogens. Recent studies indicate components plasminogen (Plg)/plasmin (Pm) system are expressed in tissues cavity, such as gland, contribute infection inflammation, periodontitis. Plg/Pm fulfills two functions: (a) destruction fibrin deposits bloodstream or damaged process called fibrinolysis, (b) non-fibrinolytic actions include proteolytic modulation proteins. One can observe both functions during inflammation. virus causes coronavirus disease 2019 (COVID-19) exploits fibrinolytic During COVID-19, well-established coagulopathy development microthrombi requires constant activation function. Furthermore, entry modulated receptors TMPRSS2, which necessary leading derailed immune response peaks cytokine storm syndrome. This paper outlines significance for infectious inflammatory diseases start

Language: Английский

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Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 21, 2023

Abstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants concern. Host proteases, TMPRSS2 CTSL/CTSB cleave spike play a crucial role in two alternative pathways viral entry are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition these proteases determine their complex structures with respective Furthermore, applying inhibitors simultaneously block both synergistic antiviral effect. Notably, devise bispecific compound, 212-148 , exhibiting dual-inhibition ability CTSL/CTSB, demonstrate activity various profiles. Our findings offer an approach for discovery antivirals, well application treatment pathogenic infections similar pathways.

Language: Английский

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The Delta variant wave in Tunisia: Genetic diversity, spatio-temporal distribution and evidence of the spread of a divergent AY.122 sub-lineage

Frontiers in Public Health, Journal Year: 2023, Volume and Issue: 10

Published: Jan. 4, 2023

Introduction The Delta variant posed an increased risk to global public health and rapidly replaced the pre-existent variants worldwide. In this study, genetic diversity spatio-temporal dynamics of 662 SARS-CoV2 genomes obtained during wave across Tunisia were investigated. Methods Viral whole genome partial S-segment sequencing was performed using Illumina Sanger platforms, respectively lineage assignemnt assessed Pangolin version 1.2.4 scorpio 3.4.X. Phylogenetic phylogeographic analyses achieved IQ-Tree Beast programs. Results age distribution infected cases showed a large peak between 25 50 years. Twelve sub-lineages detected nation-wide with AY.122 being predominant representing 94.6% sequences. sequences highly related shared amino-acid change ORF1a:A498V, synonymous mutations 2746T>C, 3037C>T, 8986C>T, 11332A>G in ORF1a 23683C>T S gene respect Wuhan reference (NC_045512.2). Spatio-temporal analysis indicates that larger cities Nabeul, Tunis Kairouan constituted epicenters for sub-lineage subsequent dispersion rest country. Discussion This study adds more knowledge about sub-variants worldwide by documenting genomic epidemiological data from Tunisia, North African region. Such results may be helpful understanding future COVID-19 waves variants.

Language: Английский

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Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

Acta Crystallographica Section D Structural Biology, Journal Year: 2023, Volume and Issue: 79(2), P. 111 - 121

Published: Jan. 20, 2023

The COVID-19 pandemic and concomitant lockdowns presented a global health challenge triggered unprecedented research efforts to elucidate the molecular mechanisms pathogenicity of SARS-CoV-2. spike glycoprotein decorating surface SARS-CoV-2 virions is prime target for vaccine development, antibody therapy serology as it binds host cell receptor central viral entry. electron cryo-microscopy structure protein revealed hydrophobic pocket in receptor-binding domain that occupied by an essential fatty acid, linoleic acid (LA). LA-bound adopts non-infectious locked conformation which more stable than infectious form shields important immunogenic epitopes. Here, impact LA binding on infectivity replication, evolutionary conservation other highly pathogenic coronaviruses, including variants concern (VOCs), are reviewed. importance metabolic products, eicosanoids, regulating human immune response inflammation highlighted. Lipid fatty-acid proteins virion appears be broader strategy employed viruses, picornaviruses Zika virus. Ligand stabilizes their assembly, downregulates infectivity. In case rhinoviruses, this has been exploited develop small-molecule antiviral drugs bind pocket. results suggest treatment based LA-binding

Language: Английский

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