On the origins of SARS-CoV-2 main protease inhibitors

RSC Medicinal Chemistry, Год журнала: 2023, Номер 15(1), С. 81 - 118

Опубликована: Окт. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Язык: Английский

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Activation of cGAS-STING suppresses coxsackievirus replication via interferon-dependent signaling

Antiviral Research, Год журнала: 2024, Номер 222, С. 105811 - 105811

Опубликована: Янв. 21, 2024

Coxsackievirus B3 (CVB3) is a non-enveloped, single-stranded, positive RNA virus known for its role in provoking inflammatory diseases that affect the heart, pancreas, and brain, leading to conditions such as myocarditis, pancreatitis, meningitis. Currently, there are no FDA-approved drugs treating CVB3 infection; therefore, identifying potential molecular targets antiviral drug development imperative. In this study, we examined possibility of activating cyclic GMP–AMP (cGAMP) synthase (cGAS)–stimulator interferon genes (STING) pathway, cytosolic DNA-sensing pathway triggers type-I (IFN) response, inhibiting infection. We found activation cGAS-STING through application cGAS (poly dA:dT herring testes DNA) or STING agonists (2′3′-cGAMP diamidobenzimidazole), overexpression STING, significantly suppresses replication. Conversely, gene-silencing enhances viral Mechanistically, demonstrated combats infection by inducing IFN response. Notably, discovered knockdown IFN-α/β receptor, key membrane receptor signaling, inhibition downstream JAK1/2 signaling with ruxolitinib, mitigates effects activation, resulting increased protein production. Furthermore, investigated interplay between pathway. showed does not trigger activation; instead, it antagonizes TBK1 induced cGAMP. summary, our results provide insights into interaction an highlighting agonist anti-CVB3 drugs.

Язык: Английский

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A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Июнь 27, 2024

Abstract The ORF9b protein, derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting innate response. Despite its significance, precise regulatory mechanisms underlying function remain elusive. In present study, we unveil that of including emerging mutant strains like Delta Omicron, can undergo ubiquitination at K67 site subsequent degradation via proteasome pathway, despite certain mutations among these strains. Moreover, our investigation further uncovers pivotal role translocase outer mitochondrial membrane 70 (TOM70) a substrate receptor, bridging with heat shock 90 alpha (HSP90α) Cullin 5 (CUL5) to form complex. Within this complex, CUL5 triggers ORF9b, acting host antiviral factor, while HSP90α functions stabilize it. Notably, treatment HSP90 inhibitors such GA or 17-AAG accelerates leading pronounced inhibition SARS-CoV-2 replication. Single-cell sequencing data revealed up-regulation lung epithelial cells COVID-19 patients, suggesting potential mechanism which may exploit evade immunity. Our study identifies CUL5-TOM70-HSP90α complex critical regulator stability, shedding light on intricate host–virus response dynamics offering promising avenues drug development against clinical settings.

Язык: Английский

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The influence of HLA genetic variation on plasma protein expression

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 31, 2024

Abstract Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but molecular effects HLA polymorphism are unclear. Here we examined genetic on expression 2940 plasma proteins across 45,330 Europeans UK Biobank, replication analyses multiple ancestry groups. We detected 504 affected by variants (HLA-pQTL), including widespread trans autoimmune disease alleles. More than 80% HLA-pQTL fine-mapped to amino acid positions peptide binding groove. HLA-I and II expressed similar cell types different pathways both adaptive innate immunity. Finally, investigated potential integrating HLA-disease signals Biobank. Our data reveal diverse aid interpretation associations between alleles diseases.

Язык: Английский

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ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

Enterovirus 71 (EV71) is a major cause of hand, foot, and mouth disease, particularly affecting pediatric populations worldwide. The role ZYG11B, CUL2-complex-associated E3 ubiquitin ligase from the Zyg-11 family, in antiviral defense against EV71 remains unclear. To our knowledge, this study first to reveal that ZYG11B targets VP1 for proteasomal degradation via ubiquitin-proteasome pathway, with CRL2ZYG11B complex activity specifically driving K33-linked ubiquitination. Mass spectrometry immunoprecipitation analyses confirmed interaction between identified key domains required binding both CUL2. Comparative showed ubiquitination sites are highly conserved across related enteroviruses, including CA6, CA16, EVD68. Functional assays further demonstrated restricts these viruses, highlighting its potential as broad-spectrum target. These findings establish critical effector host responses support therapeutic managing enterovirus infections. ligases deubiquitinases have become important topics competition viruses hosts. Here, we an capable degrading structural protein making factor. We proposed inhibitory effect on connecting substrates CUL2, providing new design drugs.

Язык: Английский

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lncRNA Ubr5 promotes BMSCs apoptosis and inhibits their proliferation and osteogenic differentiation in weightless bone loss

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Апрель 2, 2025

Weightless bone loss is a common pathological phenomenon in weightless environments, yet its specific molecular mechanism remain incompletely elucidated. The aim of this study was to systematically investigate the differential expression profiles mRNAs and long noncoding RNAs (lncRNAs) explore pathogenesis underlying loss. Transcriptome sequencing performed on marrow mesenchymal stem cell (BMSCs) samples from Ground control group simulated microgravity (SMG) using Illumina technology. Using DESeq2 algorithm, we accurately identify analyzed differentially expressed genes (DEGs). Subsequently, functions signaling pathways enriched by DEG were comprehensively GO KEGG. In addition, constructing lncRNA-mRNA coexpression network, screened verified key lncRNAs as potential further their role occurrence development A total 215 (DElncRNAs) 381 (DEmRNAs) identified, SMG group. DEmRNAs primarily involved response mechanical stimulation, microtubule motility TNF pathway. Meanwhile, DElncRNAs are significantly differentiation, fatty acid metabolic process biosynthesis amino acids. levels related via qRT-PCR. network found that lncRNA Ubr5 closely osteoblast proliferation differentiation. Further experimental results revealed knocking down can promote apoptosis BMSCs inhibit osteogenic This loss, identified intervention target, provided an important scientific basis strategic guidance for prevention treatment

Язык: Английский

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Targeting Ser78 phosphorylation of Hsp27 achieves potent antiviral effects against enterovirus A71 infection

Emerging Microbes & Infections, Год журнала: 2024, Номер 13(1)

Опубликована: Июнь 19, 2024

A positive-sense (+) single-stranded RNA (ssRNA) virus (e.g. enterovirus A71, EV-A71) depends on viral polypeptide translation for initiation of replication after entry. We reported that EV-A71 hijacks Hsp27 to induce hnRNP A1 cytosol redistribution initiate protein translation, but the underlying mechanism is still elusive. Here, we show phosphorylation-deficient Hsp27-3A (Hsp27

Язык: Английский

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Scorpion Venom Antimicrobial Peptide Derivative BmKn2-T5 Inhibits Enterovirus 71 in the Early Stages of the Viral Life Cycle In Vitro

Biomolecules, Год журнала: 2024, Номер 14(5), С. 545 - 545

Опубликована: Май 1, 2024

Enterovirus 71 (EV71), a typical representative of unenveloped RNA viruses, is the main pathogenic factor responsible for hand, foot, and mouth disease (HFMD) in infants. This seriously threatens health lives humans worldwide, especially Asia–Pacific region. Numerous animal antimicrobial peptides have been found with protective functions against bacteria, fungi, parasites, other pathogens, but there are few studies on use scorpion-derived viruses. Here, we investigated antiviral activities scorpion venom peptide BmKn2 five derivatives, finding that its derivative BmKn2-T5 exhibit significant inhibitory effect EV71. Although both characteristics amphiphilic α-helices terms their secondary structure, displayed lower cellular cytotoxicity than BmKn2. was further to inhibit EV71 dose-dependent manner vitro. Moreover, time-of-drug-addition experiments showed mainly restricts EV71, not virion or replication, at early stages viral cycle. Interestingly, also suppress replication enveloped viruses DENV, ZIKV, HSV-1 cycle, which suggests they may share common infection step Together, results our study identified valuable properties vitro, making it potential new candidate therapeutic molecule.

Язык: Английский

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Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5688 - 5688

Опубликована: Май 23, 2024

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, virus has developed various sophisticated strategies evade host antiviral responses establish productive Thus, virus–host interactions conflicts, well ability govern biological events at this of defense, contribute significantly pathogenesis outcomes In review, we update recent progress on addition, discuss underlying employed by escape responses. A better understanding interplay between immunity may unravel potential targets, that improve patient outcomes.

Язык: Английский

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ERp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation

Emerging Microbes & Infections, Год журнала: 2024, Номер 13(1)

Опубликована: Окт. 15, 2024

It is believed that DNA double-strand breaks induced by Zika virus (ZIKV) infection in pregnant women a main reason of brain damage (e.g., microcephaly, severe malformation and neuropathy) newborn babies1,2, but its underlying mechanism poorly understood. In this study, we report the depletion ERp57, member protein disulfide isomerase (PDI) family, leads to limited production ZIKV nerve cells. ERp57 knockout not only suppresses viral reactive oxygen species (ROS) mediated host damage, also decreases apoptosis. Strikingly, depends on ERp57-bridged complex formation NS2B/NS3. LOC14, an inhibitor, restricts virus-induced damage. Our work reveals important role both propagation suggesting potential target against infection.

Язык: Английский

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