Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(20), P. 15603 - 15671

Published: Sept. 29, 2022

Glycoconjugates are major constituents of mammalian cells that formed via covalent conjugation carbohydrates to other biomolecules like proteins and lipids often expressed on the cell surfaces. Among three classes glycoconjugates, proteoglycans glycoproteins contain glycans linked protein backbone amino acid residues such as Asn for N-linked Ser/Thr O-linked glycans. In glycolipids, a lipid component glycerol, polyisoprenyl pyrophosphate, fatty ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined biosynthetically understood, especially those associated with human diseases, accessible new drug, diagnostic, therapeutic developments. This review describes status advances in biological study applications natural synthetic including proteoglycans, glycoproteins, glycolipids. The scope, limitations, novel methodologies synthesis clinical development vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., their future prospectus discussed.

Language: Английский

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Animal models for COVID-19: advances, gaps and perspectives

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

Published: July 7, 2022

Abstract COVID-19, caused by SARS-CoV-2, is the most consequential pandemic of this century. Since outbreak in late 2019, animal models have been playing crucial roles aiding rapid development vaccines/drugs for prevention and therapy, as well understanding pathogenesis SARS-CoV-2 infection immune responses hosts. However, current some deficits there an urgent need novel to evaluate virulence variants concerns (VOC), antibody-dependent enhancement (ADE), various comorbidities COVID-19. This review summarizes clinical features COVID-19 different populations, characteristics major including those naturally susceptible animals, such non-human primates, Syrian hamster, ferret, minks, poultry, livestock, mouse sensitized genetically modified, AAV/adenoviral transduced, mouse-adapted strain engraftment human tissues or cells. host receptors proteases essential designing advanced modified models, successful studies on are also reviewed. Several improved alternatives future proposed, reselection alternative receptor genes multiple gene combinations, use transgenic knock-in method, strains establishing next generation mice.

Language: Английский

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Angiotensin-converting enzyme 2—at the heart of the COVID-19 pandemic

Cell, Journal Year: 2023, Volume and Issue: 186(5), P. 906 - 922

Published: Feb. 2, 2023

ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of COVID-19 pandemic, it has become one most therapeutically targeted human molecules in biomedicine. serves two fundamental physiological roles: as an enzyme, alters peptide cascade balance; a chaperone, controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities sex, explains broad tropism coronaviruses clinical manifestations SARS COVID-19. ACE2-based therapeutics provide universal strategy to prevent treat SARS-CoV-2 infections, applicable all variants other emerging zoonotic exploiting their cellular receptor.

Language: Английский

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Viral Vector Vaccine Development and Application during the COVID-19 Pandemic

Microorganisms, Journal Year: 2022, Volume and Issue: 10(7), P. 1450 - 1450

Published: July 18, 2022

With the accumulation of mutations in SARS-CoV-2 and continuous emergence new variants, importance developing safer effective vaccines has become more prominent combating COVID-19 pandemic. Both traditional genetically engineered have contributed to prevention control However, recent years, trend vaccination research gradually transitioned from vaccines, with development viral vector attracting increasing attention. Viral several unique advantages compared other vaccine platforms. The spread Omicron also made intranasal urgent, as infection site is upper respiratory tract. Therefore, present review focuses on their application during

Language: Английский

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Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 10, 2023

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), has devastating impacts on the public health and economy. Rapid viral antigenic evolution led to continual generation new variants. Of special note is recently expanding Omicron subvariants that are capable immune evasion from most existing neutralizing antibodies (nAbs). This posed challenges for prevention treatment COVID-19. Therefore, exploring broad-spectrum antiviral agents combat emerging variants imperative. In sharp contrast massive accumulation mutations within SARS-CoV-2 receptor-binding domain (RBD), S2 fusion subunit remained highly conserved among Hence, S2-based therapeutics may provide effective cross-protection against Here, we summarize developed inhibitors (e.g., nAbs, peptides, proteins, small-molecule compounds) candidate vaccines targeting elements in subunit. main focus includes all targetable elements, namely, peptide, stem helix, heptad repeats 1 (HR1-HR2) bundle. Moreover, a detailed summary characteristics action-mechanisms each class cross-reactive inhibitors, which should guide promote future design coronaviruses.

Language: Английский

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Bringing immunofocusing into focus

npj Vaccines, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 9, 2024

Abstract Immunofocusing is a strategy to create immunogens that redirect humoral immune responses towards targeted epitope and away from non-desirable epitopes. methods often aim develop “universal” vaccines provide broad protection against highly variant viruses such as influenza virus, human immunodeficiency virus (HIV-1), most recently, severe acute respiratory syndrome coronavirus (SARS-CoV-2). We use existing examples illustrate five main immunofocusing strategies—cross-strain boosting, mosaic display, protein dissection, scaffolding, masking. also discuss obstacles for like imprinting. A thorough understanding, advancement, application of the we outline here will enable design high-resolution protect future viral outbreaks.

Language: Английский

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Variations within the Glycan Shield of SARS-CoV-2 Impact Viral Spike Dynamics

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(4), P. 167928 - 167928

Published: Dec. 21, 2022

The emergence of SARS-CoV-2 variants alters the efficacy existing immunity, whether arisen naturally or through vaccination. Understanding structure viral spike assists in determining impact mutations on antigenic surface. One class mutation impacts glycosylation attachment sites, which have capacity to influence beyond immediate site attachment. Here, we compare site-specific recombinant mimetics B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), B.1.1.529 (Omicron). strain exhibits two additional N-linked glycan sites compared other analyzed and investigate these glycans by molecular dynamics. acquired N188 is shown exhibit very limited maturation, consistent with enzyme accessibility. Structural modeling dynamics reveal that located within a cavity receptor binding domain, influences domains. These observations suggest mechanism whereby affecting structural across protein

Language: Английский

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Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Dec. 22, 2022

Abstract Sero-surveillance can monitor and project disease burden risk. However, SARS-CoV-2 antibody test results produce false positive results, limiting their efficacy as a sero-surveillance tool. False are associated with malaria exposure, understanding this association is essential to interpret from malaria-endemic countries. Here, pre-pandemic samples eight endemic non-endemic countries four continents were tested by ELISA measure Spike S1 subunit reactivity. Individuals acute infection generated substantial Cross-reactivity was not reactivity other human coronaviruses or proteins, measured peptide protein arrays. ELISAs deglycosylated desialated subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the protein. The functional activity neutralization assays showed did neutralize in vitro. Since routine use glycosylated sialated could result regions, which overestimate exposure population-level immunity, we explored methods increase specificity reducing cross-reactivity. Overestimating lead underestimates risk continued COVID-19 transmission sub-Saharan Africa.

Language: Английский

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Principles of SARS-CoV-2 glycosylation

Current Opinion in Structural Biology, Journal Year: 2022, Volume and Issue: 75, P. 102402 - 102402

Published: May 19, 2022

The structure and post-translational processing of the SARS-CoV-2 spike glycoprotein (S) is intimately associated with function virus sterilising vaccines. surface S protein extensively modified by glycans, their biosynthesis driven both wider cellular context, importantly, underlining local glycan density. Comparison virally derived recombinantly adenovirally induced proteins, reveal hotspots protein-directed glycosylation that drive conserved motifs. Molecular dynamics simulations revealed that, while shielded N-glycans, it presents regions vulnerable to neutralising antibodies. Furthermore, glycans have been shown influence accessibility receptor binding domain receptor. emerging picture one unifying, principles an intimate role in immunogen efficacy.

Language: Английский

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Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2

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

Published: Jan. 19, 2023

Abstract Antibody-mediated immunity plays a crucial role in protection against SARS-CoV-2 infection. We isolated panel of neutralizing anti-receptor-binding domain (RBD) antibodies elicited upon natural infection and vaccination showed that they recognize an immunogenic patch on the internal surface core RBD, which faces inwards is hidden “down” state. These broadly neutralize wild type (Wuhan-Hu-1) SARS-CoV-2, Beta Delta variants some are effective other sarbecoviruses. observed continuum partially overlapping antibody epitopes from lower to upper part inner face RBD extend towards receptor-binding motif. The majority substantially compromised by three mutational hotspots (S371L/F, S373P S375F) Omicron BA.1, BA.2 BA.4/5 RBD. By contrast, IY-2A induces partial unfolding this variable region interacts with conserved conformational epitope tolerate all antigenic variations diverse sarbecoviruses as well. This finding establishes recognition not limited normal structures In conclusion, delineation functionally structurally highlights potential vaccine therapeutic candidates for COVID-19.

Language: Английский

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