Cell Discovery, Год журнала: 2024, Номер 10(1)
Опубликована: Авг. 8, 2024
Язык: Английский
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Март 13, 2024
Abstract The unceasing circulation of SARS-CoV-2 leads to the continuous emergence novel viral sublineages. Here, we isolate and characterize XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 JN.1 variants, representing >80% circulating variants in January 2024. XBB subvariants carry few but recurrent mutations spike, whereas harbor >30 additional changes. These replicate IGROV-1 no longer Vero E6 are not markedly fusogenic. They potently infect nasal epithelial cells, with EG.5.1.3 exhibiting highest fitness. Antivirals remain active. Neutralizing antibody (NAb) responses from vaccinees BA.1/BA.2-infected individuals lower compared BA.1, without major differences between variants. An breakthrough infection enhances NAb against both BA.2.86 displays affinity ACE2 higher immune evasion properties BA.2.86.1. Thus, while distinct, evolutionary trajectory these combines increased fitness evasion.
Язык: Английский
Процитировано
128
Cell, Год журнала: 2024, Номер 187(16), С. 4231 - 4245.e13
Опубликована: Июль 3, 2024
The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. molecular basis of binding TMPRSS2 determinants receptor tropism remain elusive. We designed an active construct enabling high-yield recombinant production in cells this key therapeutic target. determined a cryo-electron microscopy structure the RBD bound TMPRSS2, providing blueprint interactions supporting viral entry explaining specificity for among orthologous proteases. identified orthologs from five mammalian orders promoting S-mediated into along with residues governing usage. Our data show that motif is site vulnerability neutralizing antibodies suggest uses S conformational masking glycan shielding balance immune evasion engagement.
Язык: Английский
Процитировано
16
Cell, Год журнала: 2024, Номер 187(16), С. 4261 - 4271.e17
Опубликована: Авг. 1, 2024
Язык: Английский
Процитировано
16
Cell, Год журнала: 2025, Номер unknown
Опубликована: Фев. 1, 2025
Язык: Английский
Процитировано
5
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Ноя. 21, 2023
The unceasing circulation of SARS-CoV-2 leads to the continuous emergence novel viral sublineages. Here, we isolated and characterized XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 JN.1 variants, representing >80% circulating variants in January 2024. XBB subvariants carry few but recurrent mutations spike, whereas harbor >30 additional changes. These replicated IGROV-1 no longer Vero E6 were not markedly fusogenic. They potently infected nasal epithelial cells, with EG.5.1.3 exhibiting highest fitness. Antivirals remained active. Neutralizing antibody (NAb) responses from vaccinees BA.1/BA.2-infected individuals lower compared BA.1, without major differences between variants. An breakthrough infection enhanced NAb against both BA.2.86 displayed affinity ACE2 higher immune evasion properties BA.2.86.1. Thus, while distinct, evolutionary trajectory these combines increased fitness evasion.
Язык: Английский
Процитировано
32
Cell, Год журнала: 2024, Номер 187(16), С. 4246 - 4260.e16
Опубликована: Авг. 1, 2024
Язык: Английский
Процитировано
14
Cell Research, Год журнала: 2024, Номер 34(7), С. 526 - 529
Опубликована: Апрель 19, 2024
Dear Editor,Human coronaviruses are pathogens capable of causing respiratory illnesses in humans, with seven identified species, 1 three which have caused epidemics or global pandemics the past two decades, namely, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), 2 Middle East (MERS-CoV), 3 and (SARS-CoV-2). 4Along these viruses, HCoV-HKU1 (HKU1) belongs to β-coronavirus genus.With serotypes (HKU1-A, HKU1-B, HKU1-C), HKU1 infection commonly causes common cold, but also leads severe lower tract infections. 5The spike (S) protein plays a crucial role cell invasion by binding host receptors, transmembrane serine protease TMPRSS2 recently as its receptor. 6TMPRSS2 comprises intracellular, transmembrane, LDL receptor A (LDLR-A, residues 112-149), scavenger cysteine-rich (SRCR, 150-242), C-terminal (SP, 256-489) domains.However, structural basis interaction S remains elusive.Here we present cryo-electron microscopy (cryo-EM) structures HKU1-B apo receptor-bound states.The exhibits multiple conformations state, including closed conformation active conformations.In conformations, one receptor-binding domains (RBD) "up" position.Binding results more open protein, changing network triggering trend towards post-fusion thus facilitating initiation into cells.Our research enhances understanding process, providing insights for development optimization vaccines therapeutic interventions.The forms trimeric structure, each protomer featuring furin cleavage site "RRKRR", akin SARS-CoV-2.The is cleaved subunits, S1 S2.S1 four domains: N-terminal lectin-like domain (NTD), RBD, subdomain (SD1), (SD2).S2 includes fusion peptide (FP), heptad repeat regions (HR1), central helix (CH), connector (CD), (HR2), (TM), C-tail (CT) (Fig. 1a).We first solved structure state using cryo-EM, revealing that included contained RBD position named "1up" "2up", respectively 1b-d).For ease description, unless specified otherwise following context, term "S protein" refers containing 1up defined 1, while other
Язык: Английский
Процитировано
10
Journal of Nanobiotechnology, Год журнала: 2024, Номер 22(1)
Опубликована: Окт. 26, 2024
Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well cartilaginous fish. Their unique structural and functional properties, such their small size, ability to be engineered for high antigen-binding affinity, stability under extreme conditions, ease of production, have made them promising tools diagnostics therapeutics. This potential was realized 2018 with approval caplacizumab, world's first Nb-based drug. Currently, Nbs being investigated clinical trials a broad range treatments, including targeted therapies against PDL1 Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory neurodegenerative disorders Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis. They also studied detecting imaging autoimmune conditions infectious diseases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety methods now available generate target-specific quickly efficiently at low costs, increasing accessibility. article examines these diverse applications roles. Only most recent articles published last five years been used summarize advanced developments field.
Язык: Английский
Процитировано
10
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Янв. 9, 2024
The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. molecular basis of binding TMPRSS2 determinants receptor tropism remain elusive. Here, we designed an active construct enabling high-yield recombinant production in cells this key therapeutic target. We determined a cryo-electron microscopy structure the RBD bound providing blueprint interactions supporting viral entry explaining specificity for among type proteases. found that human, rat, hamster camel promote S-mediated into identified residues governing usage. Our data show serum antibodies targeting binding-site are neutralization uses conformational masking glycan shielding balance immune evasion engagement.
Язык: Английский
Процитировано
8
Chemical Biology & Drug Design, Год журнала: 2024, Номер 104(2)
Опубликована: Июль 29, 2024
Abstract Transmembrane protease/serine (TMPRSS2), a type II transmembrane serine protease, plays crucial role in different stages of cancer. Recent studies have reported that the triggering epidermal growth factor receptor (EGFR) activation through protease action promotes metastasis. However, there are no reports on interaction TMPRSS2 with EGFR, especially triple‐negative triple negative (TNBC). The current study investigates unexplored between and which key partners mediating This is explored for potential targeting using quercetin (QUE) taxifolin (TAX). expression patterns breast cancer (BC) tissues subtypes been predicted, prognostic significance assessed GENT2.0 database. Validation was performed normal TNBC tissues, including drug‐resistant cell lines, utilizing GEO datasets. further validated as predictive biomarker FDA‐approved chemotherapeutics transcriptomic data from BC patients. demonstrated association EGFR silico analysis validates findings cohorts TIMER2.0 web server TCGA dataset C‐Bioportal. Molecular docking molecular dynamic simulation identified QUE TAX best leads TMPRSS2. They inhibited cell‐free activity like clinical inhibitor TMPRSS2, Camostat mesylate. In cell‐based assays focused paclitaxel‐resistant (TNBC/PR), potent inhibitory against extracellular membrane‐bound low IC 50 values. Furthermore, ELISA AlphaLISA inhibit EGFR. Additionally, exhibited significant inhibition proliferation cycle accompanied by notable alterations morphology TNBC/PR cells. provides valuable insights into overexpressing TNBC.
Язык: Английский
Процитировано
4