Structural biology of SARS-CoV-2 and implications for therapeutic development

Nature Reviews Microbiology, Journal Year: 2021, Volume and Issue: 19(11), P. 685 - 700

Published: Sept. 17, 2021

Language: Английский

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SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: July 7, 2021

There are still many unanswered questions concerning viral SARS-CoV-2 pathogenesis in COVID-19. Accessory proteins consist of eleven whose roles during infection not completely understood. Here, a review on the current knowledge accessory is summarized updating new research that could be critical understanding interaction with host. Some such as ORF3b, ORF6, ORF7a and ORF8 have been shown to important IFN-I antagonists inducing an impairment host immune response. In addition, ORF3a involved apoptosis whereas others like ORF9b ORF9c interact cellular organelles leading suppression antiviral response infected cells. However, possible ORF7b ORF10 awaiting described. Also, ORF3d has reassigned. Relevant information knowns unknowns these analyzed, which crucial for further design strategies counteracting their actions evading responses

Language: Английский

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Structural biology of SARS-CoV-2: open the door for novel therapies

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Jan. 27, 2022

Abstract Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of pandemic disease COVID-19, which so far without efficacious treatment. The discovery therapy reagents for treating COVID-19 are urgently needed, and structures potential drug-target proteins in viral life cycle particularly important. SARS-CoV-2, a member Orthocoronavirinae subfamily containing largest RNA genome, encodes 29 including nonstructural, structural accessory involved adsorption, entry uncoating, nucleic acid replication transcription, assembly release, etc. These individually act as partner machinery or forming complexes with host cellular factors to participate essential physiological activities. This review summarizes representative typically agents that target SARS-CoV-2 some critical pathogenesis, providing insights into mechanisms underlying infection, prevention Indeed, these studies open door COVID therapies, leading ways prevent treat especially, treatment caused by variants imperative.

Language: Английский

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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1716 - 1716

Published: Feb. 2, 2022

The review aims to consolidate research findings on the molecular mechanisms and virulence pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome 2 (SARS-CoV-2), their relevance four typical stages in development viral infection. These are invasion; primary blockade antiviral innate immunity; engagement virus’s protection against factors adaptive acute, long-term complications COVID-19. invasion stage entails recognition spike protein (S) SARS-CoV-2 target cell receptors, namely, main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, potential alternative receptors. presence a diverse repertoire receptors allows infect various types cells, including those not expressing ACE2. During second stage, majority polyfunctional structural, non-structural, extra proteins synthesizes infected cells involved blockage immunity. A high degree redundancy systemic action characterizing these pathogenic overcome at initial invasion. third includes passive active virus from immunity, overcoming barrier function focus inflammation, generalization body. fourth is associated with deployment variants SARS-CoV-2’s ability induce autoimmune autoinflammatory pathways tissue both immunosuppressive hyperergic inflammation critical this

Language: Английский

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Structure and Function of Major SARS-CoV-2 and SARS-CoV Proteins

Bioinformatics and Biology Insights, Journal Year: 2021, Volume and Issue: 15

Published: Jan. 1, 2021

SARS-CoV-2 virus, the causative agent of COVID-19 pandemic, has a genomic organization consisting 16 nonstructural proteins (nsps), 4 structural proteins, and 9 accessory proteins. Relative SARS-CoV-2, SARS-CoV, organization, which is very similar. In this article, function structure SARS-CoV are described in great detail. The nsps expressed as single or two polyproteins, then cleaved into individual using proteases chymotrypsin-like protease papain-like protease. released serve centers virus replication transcription. Some these modulate host’s translation immune systems, while others help evade host system. form replication-transcription complex at double-membrane vesicles. Others, including one RNA-dependent RNA polymerase exonuclease, polymerization newly synthesized minimize mutation rate by proofreading. After synthesis viral RNA, it gets capped. capping consists adding GMP methylation mark, called cap 0 additionally methyl group to terminal ribose cap1. Capping accomplished with helicase, also helps remove phosphate, methyltransferases, scaffolding factor. Among S protein forms receptor latches on angiotensin-converting enzyme 2 N binds protects virus. found viruses small modulatory roles. Besides functions solved X-ray cryogenic electron microscopy structures related along comparisons other coronavirus homologs have been article. Finally, residues proteome during 2020 pandemic described. mutated more often than but significance rates not fully understood.

Language: Английский

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Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19

Acta Pharmacologica Sinica, Journal Year: 2022, Volume and Issue: 43(12), P. 3021 - 3033

Published: Jan. 20, 2022

Language: Английский

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SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 120(1)

Published: Dec. 27, 2022

Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β2-microglobulin (β2m), bind peptides in endoplasmic reticulum that generated by cytosolic turnover cellular proteins. In virus-infected cells, these may include those derived from viral Peptide-MHC-I complexes then traffic through secretory pathway displayed at cell surface where containing can be detected CD8+ T lymphocytes kill infected cells. Many viruses enhance their vivo survival encoding genes down-regulate MHC-I expression to avoid recognition. Here, we report two accessory proteins encoded SARS-CoV-2, causative agent ongoing COVID-19 pandemic, using distinct mechanisms. First, ORF3a, viroporin, reduces global trafficking proteins, including MHC-I, pathway. The second, ORF7a, interacts specifically with chain, acting as molecular mimic β2m inhibit its association. This slows exit properly assembled molecules reticulum. We demonstrate ORF7a antigen presentation human allele HLA-A*02:01. Thus, both ORF3a act post-translationally lower expression, exhibiting specific mechanism allows immune evasion SARS-CoV-2.

Language: Английский

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Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 14, 2022

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome oxidative stress have independently been implicated in COVID-19, it poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment CD14highCD16- monocytes displaying activation evidenced caspase-1/ASC-speck formation severe COVID-19 patients when compared mild ones healthy controls, respectively. Those cells also showed aberrant levels mitochondrial superoxide lipid peroxidation, both hallmarks response, which strongly correlated caspase-1 activity. In addition, that NLRP3 inflammasome-derived IL-1β secretion SARS-CoV-2-exposed vitro was partially dependent on peroxidation. Importantly, altered responses persisted after short-term patient recovery. Collectively, our findings suggest stress/NLRP3 signaling pathway as a potential target for host-directed therapy mitigate early hyperinflammation its long-term outcomes.

Language: Английский

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Evolution of SARS-CoV-2 Variants: Implications on Immune Escape, Vaccination, Therapeutic and Diagnostic Strategies

Viruses, Journal Year: 2023, Volume and Issue: 15(4), P. 944 - 944

Published: April 10, 2023

The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of has given rise to multiple variants varying pathogenicity transmissibility, such as Delta Omicron variants. Individuals advanced age or underlying comorbidities, including hypertension, diabetes cardiovascular diseases, are at higher risk increased disease severity. Hence, this resulted in an urgent need for development better therapeutic preventive approaches. This review describes origin human coronaviruses, particularly well sub-variants. Risk factors that contribute severity implications co-infections also considered. In addition, various antiviral strategies against COVID-19, novel repurposed drugs targeting viral host proteins, immunotherapeutic strategies, discussed. We critically evaluate current emerging vaccines their efficacy, immune evasion new impact on diagnostic testing examined. Collectively, global research public health authorities, along all sectors society, prepare upcoming future coronavirus outbreaks.

Language: Английский

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Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: May 15, 2023

Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in genome this virus. S, M, H, E proteins, NSPs include accessory replicase proteins. The NSP components SARS-CoV-2 play an important role its infectivity, some them may be pathogenesis chronic diseases, including cancer, coagulation disorders, neurodegenerative cardiovascular diseases. interact with targets such angiotensin-converting enzyme (ACE2) receptor. In addition, can stimulate pathological intracellular signaling pathways triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, Eph receptors, which roles progression diseases like Alzheimer's disease, epilepsy, multiple sclerosis, cancers glioblastoma, lung malignancies, leukemias. Several compounds polyphenols, doxazosin, baricitinib, ruxolitinib could inhibit these interactions. It has been demonstrated that spike protein stronger affinity for human ACE2 than SARS-CoV, leading current study to hypothesize newly produced variant Omicron receptor-binding domain (RBD) binds more strongly primary strain. SARS Middle East (MERS) viruses against have become resistant previous vaccines. Therefore, review recent studies performance vaccines their effects on COVID-19 related vital need deal conditions. This examines potential initiation it anticipated serve effective vaccine or treatment Video Abstract.

Language: Английский

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