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1.
Immunol Rev ; 309(1): 64-74, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1922935

ABSTRACT

In this review, we discuss how IgG antibodies can modulate inflammatory signaling during viral infections with a focus on CD16a-mediated functions. We describe the structural heterogeneity of IgG antibody ligands, including subclass and glycosylation that impact binding by and downstream activity of CD16a, as well as the heterogeneity of CD16a itself, including allele and expression density. While inflammation is a mechanism required for immune homeostasis and resolution of acute infections, we focus here on two infectious diseases that are driven by pathogenic inflammatory responses during infection. Specifically, we review and discuss the evolving body of literature showing that afucosylated IgG immune complex signaling through CD16a contributes to the overwhelming inflammatory response that is central to the pathogenesis of severe forms of dengue disease and coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19 , Communicable Diseases , Humans , Immunoglobulin G/chemistry , Immunoglobulin G/metabolism , Polysaccharides/chemistry , Polysaccharides/metabolism , Receptors, IgG
2.
Science ; 377(6604): eabm3125, 2022 07 22.
Article in English | MEDLINE | ID: covidwho-1901907

ABSTRACT

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an "end-on" manner. uSTA-guided modeling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.


Subject(s)
COVID-19 , Host-Pathogen Interactions , SARS-CoV-2 , Sialic Acids , Spike Glycoprotein, Coronavirus , COVID-19/transmission , Cryoelectron Microscopy , Genetic Variation , Humans , Nuclear Magnetic Resonance, Biomolecular , Polysaccharides/chemistry , Protein Binding , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Sialic Acids/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
3.
Proteomics ; 22(15-16): e2100322, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1885450

ABSTRACT

Glycosylation of viral proteins is required for the progeny formation and infectivity of virtually all viruses. It is increasingly clear that distinct glycans also play pivotal roles in the virus's ability to shield and evade the host's immune system. Recently, there has been a great advancement in structural identification and quantitation of viral glycosylation, especially spike proteins. Given the ongoing pandemic and the high demand for structure analysis of SARS-CoV-2 densely glycosylated spike protein, mass spectrometry methodologies have been employed to accurately determine glycosylation patterns. There are still many challenges in the determination of site-specific glycosylation of SARS-CoV-2 viral spike protein. This is compounded by some conflicting results regarding glycan site occupancy and glycan structural characterization. These are probably due to differences in the expression systems, form of expressed spike glycoprotein, MS methodologies, and analysis software. In this review, we recap the glycosylation of spike protein and compare among various studies. Also, we describe the most recent advancements in glycosylation analysis in greater detail and we explain some misinterpretation of previously observed data in recent publications. Our study provides a comprehensive view of the spike protein glycosylation and highlights the importance of consistent glycosylation determination.


Subject(s)
COVID-19 , SARS-CoV-2 , Glycosylation , Humans , Mass Spectrometry/methods , Polysaccharides/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
4.
Anal Chem ; 94(15): 5776-5784, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1882709

ABSTRACT

Characterization of protein glycosylation by tandem mass spectrometry remains challenging owing to the vast diversity of oligosaccharides bound to proteins, the variation in monosaccharide linkage patterns, and the lability of the linkage between the glycan and protein. Here, we have adapted an HCD-triggered-ultraviolet photodissociation (UVPD) approach for the simultaneous localization of glycosites and full characterization of both glycan compositions and intersaccharide linkages, the latter provided by extensive cross-ring cleavages enabled by UVPD. The method is applied to study glycan compositions based on analysis of glycopeptides from proteolytic digestion of recombinant human coronaviruse spike proteins from SARS-CoV-2 and HKU1. UVPD reveals unique intersaccharide linkage information and is leveraged to localize N-linked glycoforms with confidence.


Subject(s)
COVID-19 , Viral Proteins , Glycosylation , Humans , Polysaccharides/chemistry , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tandem Mass Spectrometry/methods , Ultraviolet Rays
5.
Adv Protein Chem Struct Biol ; 131: 277-309, 2022.
Article in English | MEDLINE | ID: covidwho-1881585

ABSTRACT

Molecular Dynamics (MD) is a method used to calculate the movement of atoms and molecules broadly applied to several aspects of science. It involves computational simulation, which makes it, at first glance, not easily accessible. The rise of several automated tools to perform molecular simulations has allowed researchers to navigate through the various steps of MD. This enables to elucidate structural properties of proteins that could not be analyzed otherwise, such as the impact of glycosylation. Glycosylation dictates the physicochemical and biological properties of a protein modulating its solubility, stability, resistance to proteolysis, interaction partners, enzymatic activity, binding and recognition. Given the high conformational and compositional diversity of the glycan chains, assessing their influence on the protein structure is challenging using conventional analytical techniques. In this manuscript, we present a step-by-step workflow to build and perform MD analysis of glycoproteins focusing on the SPIKE glycoprotein of SARS-CoV-2 to appraise the impact of glycans in structure stabilization and antibody occlusion.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Glycoproteins , Humans , Molecular Dynamics Simulation , Polysaccharides/chemistry , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
6.
Nat Commun ; 12(1): 6073, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1860369

ABSTRACT

Large-scale profiling of intact glycopeptides is critical but challenging in glycoproteomics. Data independent acquisition (DIA) is an emerging technology with deep proteome coverage and accurate quantitative capability in proteomics studies, but is still in the early stage of development in the field of glycoproteomics. We propose GproDIA, a framework for the proteome-wide characterization of intact glycopeptides from DIA data with comprehensive statistical control by a 2-dimentional false discovery rate approach and a glycoform inference algorithm, enabling accurate identification of intact glycopeptides using wide isolation windows. We further utilize a semi-empirical spectrum prediction strategy to expand the coverage of spectral libraries of glycopeptides. We benchmark our method for N-glycopeptide profiling on DIA data of yeast and human serum samples, demonstrating that DIA with GproDIA outperforms the data-dependent acquisition-based methods for glycoproteomics in terms of capacity and data completeness of identification, as well as accuracy and precision of quantification. We expect that this work can provide a powerful tool for glycoproteomic studies.


Subject(s)
Glycopeptides/analysis , Proteome/analysis , Proteomics/methods , Algorithms , Blood Proteins/chemistry , Glycoproteins/chemistry , Humans , Mass Spectrometry , Polysaccharides/chemistry , Schizosaccharomyces pombe Proteins/chemistry , Workflow
7.
Carbohydr Res ; 518: 108574, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1821162

ABSTRACT

Can envelope glycans be targeted to stop viral pandemics? Here we address this question by using molecular dynamics simulations to study the binding between 10 synthetic carbohydrate receptors (SCRs) and the 33 N-glycans most commonly found on the surfaces of enveloped viruses, including Zika virus and SARS-CoV-2. Based on association quotients derived from these simulations, we classified the SCRs as weak binders, promiscuous binders, or selective binders. The SCRs almost exclusively associate at the Man3GlcNAc2 core, which is common to all N-glycans, but the binding affinity between the SCR⋅glycan pair depends on the noncovalent interactions between the heterocycle rings and the glycan antennae. Systematic variations in the glycan and SCR structures reveal relationships that could guide the design of SCRs to attain affinity and selectivity towards a chosen envelope glycan target. With these results, envelope glycans, which are currently considered "undruggable", could become viable targets for new therapeutic strategies.


Subject(s)
COVID-19 , Receptors, Artificial , Zika Virus Infection , Zika Virus , Carbohydrates/chemistry , Humans , Molecular Dynamics Simulation , Polysaccharides/chemistry , Receptors, Artificial/chemistry , SARS-CoV-2 , Zika Virus/metabolism
8.
J Biotechnol ; 349: 32-46, 2022 Apr 10.
Article in English | MEDLINE | ID: covidwho-1757477

ABSTRACT

Over the decades, a variety of chemically synthesized drugs are being used to cure existing diseases but often these drugs could not be effectively employed for the treatment of serious and newly emerging diseases. Fortunately, in nature there occurs immense treasure of plants and microorganisms which are living jewels with respect to their richness of medically important metabolites of high value. Hence, amongst the existing microorganism(s), the marine world offers a plethora of biological entities that can contribute to alleviate numerous human ailments. Algae are one such photosynthetic microorganism found in both marine as well as fresh water which are rich source of metabolites known for their nutrient content and health benefits. Various algal species like Haematococcus, Diatoms, Griffithsia, Chlorella, Spirulina, Ulva, etc. have been identified and isolated to produce biologically active and pharmaceutically important high value compounds like astaxanthin, fucoxanthin, sulphur polysaccharides mainly galactose, rhamnose, xylose, fucose etc., which show antimicrobial, antifungal, anti-cancer, and antiviral activities. However, the production of either of these bio compounds is favored under conditions of stress. This review gives detailed information on various nutraceutical metabolites extracted from algae. Additionally focus has been made on the role of these bio compounds extracted from algae especially sulphur polysaccharides to treat several diseases with prospective treatment for SARS-CoV-2. Lastly it covers the knowledge gaps and future perspectives in this area of research.


Subject(s)
COVID-19 , Chlorella , Microalgae , COVID-19/drug therapy , Humans , Polysaccharides/chemistry , Polysaccharides/therapeutic use , Prospective Studies , SARS-CoV-2 , Sulfur
9.
Viruses ; 14(2)2022 02 18.
Article in English | MEDLINE | ID: covidwho-1707748

ABSTRACT

In the current context of the COVID-19 pandemic, it appears that our scientific resources and the medical community are not sufficiently developed to combat rapid viral spread all over the world. A number of viruses causing epidemics have already disseminated across the world in the last few years, such as the dengue or chinkungunya virus, the Ebola virus, and other coronavirus families such as Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). The outbreaks of these infectious diseases have demonstrated the difficulty of treating an epidemic before the creation of vaccine. Different antiviral drugs already exist. However, several of them cause side effects or have lost their efficiency because of virus mutations. It is essential to develop new antiviral strategies, but ones that rely on more natural compounds to decrease the secondary effects. Polysaccharides, which have come to be known in recent years for their medicinal properties, including antiviral activities, are an excellent alternative. They are essential for the metabolism of plants, microorganisms, and animals, and are directly extractible. Polysaccharides have attracted more and more attention due to their therapeutic properties, low toxicity, and availability, and seem to be attractive candidates as antiviral drugs of tomorrow.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Polysaccharides/chemistry , Polysaccharides/pharmacology , Viruses/drug effects , Animals , Disease Outbreaks/prevention & control , Ebolavirus/drug effects , Humans , SARS-CoV-2/drug effects , Virus Diseases/drug therapy , Virus Replication/drug effects , Viruses/classification , Viruses/pathogenicity
10.
Mar Drugs ; 20(2)2022 Jan 24.
Article in English | MEDLINE | ID: covidwho-1707249

ABSTRACT

Fucoidan is a polysaccharide obtained from marine brown algae, with anti-inflammatory, anti-viral, and immune-enhancing properties, thus, fucoidan may be used as an alternative treatment (complementary to prescribed medical therapy) for COVID-19 recovery. This work aimed to determine the ex-vivo effects of treatment with fucoidan (20 µg/mL) on mitochondrial membrane potential (ΔΨm, using a cationic cyanine dye, 3,3'-dihexyloxacarbocyanine iodide (DiOC6(3)) on human peripheral blood mononuclear cells (HPBMC) isolated from healthy control (HC) subjects, COVID-19 patients (C-19), and subjects that recently recovered from COVID-19 (R1, 40 ± 13 days after infection). In addition, ex-vivo treatment with fucoidan (20 and 50 µg/mL) was evaluated on ΔΨm loss induced by carbonyl cyanide 3-chlorophenylhydrazone (CCCP, 150 µM) in HPBMC isolated from healthy subjects (H) and recovered subjects at 11 months post-COVID-19 (R2, 335 ± 20 days after infection). Data indicate that SARS-CoV-2 infection induces HPBMC loss of ΔΨm, even 11 months after infection, however, fucoidan promotes recovery of ΔΨm in PBMCs from COVID-19 recovered subjects. Therefore, fucoidan may be a potential treatment to diminish long-term sequelae from COVID-19, using mitochondria as a therapeutic target for the recovery of cellular homeostasis.


Subject(s)
COVID-19 , Leukocytes, Mononuclear/drug effects , Membrane Potential, Mitochondrial/drug effects , Polysaccharides/pharmacology , SARS-CoV-2 , Adult , Aged , Female , Humans , Leukocytes, Mononuclear/physiology , Male , Middle Aged , Mitochondria/drug effects , Phaeophyta/chemistry , Polysaccharides/chemistry , Young Adult
11.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1674739

ABSTRACT

An antiviral agent is urgently needed based on the high probability of the emergence and re-emergence of future viral disease, highlighted by the recent global COVID-19 pandemic. The emergence may be seen in the discovery of the Alpha, Beta, Gamma, Delta, and recently discovered Omicron variants of SARS-CoV-2. The need for strategies besides testing and isolation, social distancing, and vaccine development is clear. One of the strategies includes searching for an antiviral agent that provides effective results without toxicity, which is well-presented by significant results for carrageenan nasal spray in providing efficacy against human coronavirus-infected patients. As the primary producer of sulfated polysaccharides, marine plants, including macro- and microalgae, offer versatility in culture, production, and post-isolation development in obtaining the needed antiviral agent. Therefore, this review will describe an attempt to highlight the search for practical and safe antiviral agents from algal-based sulfated polysaccharides and to unveil their features for future development.


Subject(s)
Antiviral Agents , COVID-19/therapy , Microalgae/chemistry , Pandemics , Polysaccharides , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/epidemiology , Humans , Polysaccharides/chemistry , Polysaccharides/therapeutic use
12.
Cell Rep ; 38(5): 110318, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1654152

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/administration & dosage , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , Cricetinae , Epitopes , Guinea Pigs , Immunogenicity, Vaccine , Mice , Nanoparticles/chemistry , Nucleic Acid-Based Vaccines/administration & dosage , Nucleic Acid-Based Vaccines/chemistry , Nucleic Acid-Based Vaccines/genetics , Nucleic Acid-Based Vaccines/immunology , Polysaccharides/chemistry , Polysaccharides/genetics , Polysaccharides/immunology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccine Potency
13.
Elife ; 102021 12 20.
Article in English | MEDLINE | ID: covidwho-1592091

ABSTRACT

Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Molecular Dynamics Simulation , Polysaccharides/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , COVID-19/prevention & control , COVID-19/virology , Glycosylation , Humans , Polysaccharides/chemistry , Protein Binding , Protein Engineering , Receptors, Virus/chemistry , Receptors, Virus/genetics , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
14.
Carbohydr Polym ; 280: 119006, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1588175

ABSTRACT

Caulerpa lentillifera (Bryopsidophyceae, Chlorophyta) is an edible seaweed attracting great attention for its expansion of farming scale and increasing consumption in these years. In the present study, a sulfated polysaccharide (CLSP-2) was isolated and separated from C. lentillifera, and its chemical structure was elucidated by a series of chemical and spectroscopic methods. Among these methods, mild acid hydrolysis and photocatalytic degradation were applied to release mono- and oligo-saccharide fragments which were further identified by HPLC-MSn analysis, affording the information of the sugar sequences and the sulfate substitution in CLSP-2. Results indicated that the backbone of CLSP-2 was constructed of →6)-ß-Manp-(1→ with sulfated branches at C2, which were comprised of prevalent →3)-ß-Galp4S-(1→, →3)-ß-Galp2,4S-(1→, and minor Xyl. In addition, the virus neutralization assay revealed that CLSP-2 could effectively protect HeLa cells against SARS-CoV-2 infection with an IC50 of 48.48 µg/mL. Hence, the present study suggests CLSP-2 as a promising agent against SARS-CoV-2.


Subject(s)
COVID-19/virology , Caulerpa/chemistry , Polysaccharides/chemistry , Polysaccharides/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chromatography, High Pressure Liquid/methods , HeLa Cells , Humans , Hydrolysis , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Molecular Weight , Polysaccharides/analysis , SARS-CoV-2 , Seaweed/chemistry , Spectroscopy, Fourier Transform Infrared/methods , Sulfates/chemistry
15.
Viruses ; 14(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1580407

ABSTRACT

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/epidemiology , Polysaccharides/pharmacology , Viruses/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , COVID-19/drug therapy , Heparin/chemical synthesis , Heparin/chemistry , Heparin/pharmacology , Humans , Polysaccharides/chemistry , SARS-CoV-2/drug effects , Structure-Activity Relationship , Sulfates/chemistry , Sulfates/pharmacology , Virus Diseases/drug therapy , Virus Internalization/drug effects , Viruses/pathogenicity
16.
Carbohydr Polym ; 285: 118971, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1549670

ABSTRACT

Ligusticum chuanxiong, the dried rhizome of Ligusticum chuanxiong Hort, has been widely applied in traditional Chinese medicine for treating plague, and it has appeared frequently in the prescriptions against COVID-19 lately. Ligusticum chuanxiong polysaccharide (LCPs) is one of the effective substances, which has various activities, such as, anti-oxidation, promoting immunity, anti-tumor, and anti-bacteria. The purified fractions of LCPs are considered to be pectic polysaccharides, which are mainly composed of GalA, Gal, Ara and Rha, and are generally linked by α-1,4-d-GalpA, α-1,2-l-Rhap, α-1,5-l-Araf, ß-1,3-d-Galp and ß-1,4-d-Galp, etc. The pectic polysaccharide shows an anti-infective inflammatory activity, which is related to antiviral infection of Ligusticum chuanxiong. In this article, the isolation, purification, structural features, and biological activities of LCPs in recent years are reviewed, and the potential of LCPs against viral infection as well as questions that need future research are discussed.


Subject(s)
COVID-19/drug therapy , Ligusticum/chemistry , Polysaccharides/chemistry , Polysaccharides/pharmacology , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Carbohydrate Conformation , Carbohydrate Sequence , Drugs, Chinese Herbal , Humans , Polysaccharides/isolation & purification , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
17.
Glycobiology ; 32(1): 60-72, 2022 02 26.
Article in English | MEDLINE | ID: covidwho-1501077

ABSTRACT

Extensive glycosylation of the spike protein of severe acute respiratory syndrome coronavirus 2 virus not only shields the major part of it from host immune responses, but glycans at specific sites also act on its conformation dynamics and contribute to efficient host receptor binding, and hence infectivity. As variants of concern arise during the course of the coronavirus disease of 2019 pandemic, it is unclear if mutations accumulated within the spike protein would affect its site-specific glycosylation pattern. The Alpha variant derived from the D614G lineage is distinguished from others by having deletion mutations located right within an immunogenic supersite of the spike N-terminal domain (NTD) that make it refractory to most neutralizing antibodies directed against this domain. Despite maintaining an overall similar structural conformation, our mass spectrometry-based site-specific glycosylation analyses of similarly produced spike proteins with and without the D614G and Alpha variant mutations reveal a significant shift in the processing state of N-glycans on one specific NTD site. Its conversion to a higher proportion of complex type structures is indicative of altered spatial accessibility attributable to mutations specific to the Alpha variant that may impact its transmissibility. This and other more subtle changes in glycosylation features detected at other sites provide crucial missing information otherwise not apparent in the available cryogenic electron microscopy-derived structures of the spike protein variants.


Subject(s)
COVID-19/epidemiology , Glycopeptides/chemistry , Mutation , Polysaccharides/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/transmission , COVID-19/virology , Carbohydrate Sequence , Datasets as Topic , Glycopeptides/genetics , Glycopeptides/metabolism , Glycosylation , HEK293 Cells , Humans , Mass Spectrometry , Peptide Mapping , Polysaccharides/metabolism , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
18.
Int J Mol Sci ; 22(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488607

ABSTRACT

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.


Subject(s)
Estrogens/chemistry , Estrogens/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Biological Transport , COVID-19/drug therapy , COVID-19/metabolism , Disease Models, Animal , Estrogens/pharmacology , Glycosylation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice, Inbred C57BL , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Polysaccharides/chemistry , Polysaccharides/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tunicamycin/pharmacology
19.
Biomolecules ; 11(11)2021 10 27.
Article in English | MEDLINE | ID: covidwho-1488476

ABSTRACT

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The "EPN" motif, "NDD" motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.


Subject(s)
COVID-19/immunology , Cell Adhesion Molecules/antagonists & inhibitors , Epitopes/chemistry , Glycosides/chemistry , Lectins, C-Type/antagonists & inhibitors , Polysaccharides/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Amino Acid Motifs , Binding Sites , COVID-19/metabolism , Computer Simulation , Cytokines/metabolism , Flavanones/chemistry , Glucosides/chemistry , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Monosaccharides/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Saponins/chemistry , Spike Glycoprotein, Coronavirus/chemistry
20.
Adv Mater ; 33(52): e2105361, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1453531

ABSTRACT

Solid-state optics has been the pillar of modern digital age. Integrating soft hydrogel materials with micro/nanooptics could expand the horizons of photonics for bioengineering. Here, wet-spun multilayer hydrogel fibers are engineered through ionic-crosslinked natural polysaccharides that serve as multifunctional platforms. The resulting flexible hydrogel structure and reversible crosslinking provide tunable design properties such as adjustable refractive index and fusion splicing. Modulation of the optical readout via physical stimuli, including shape, compression, and multiple optical inputs/outputs is demonstrated. The unique permeability of the hydrogels is also combined with plasmonic nanoparticles for molecular detection of SARS-CoV-2 in fiber-coupled biomedical swabs. A tricoaxial 3D printing nozzle is then employed for the continuous fabrication of living optical fibers. Light interaction with living cells enables the quantification and digitalization of complex biological phenomena such as 3D cancer progression and drug susceptibility. These fibers pave the way for advances in biomaterial-based photonics and biosensing platforms.


Subject(s)
Hydrogels/chemistry , Optical Fibers , Optics and Photonics/methods , Polysaccharides/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biocompatible Materials/chemistry , Biosensing Techniques , COVID-19/diagnosis , COVID-19/virology , Cell Line, Tumor , Cell Proliferation/drug effects , Gold/chemistry , Humans , Metal Nanoparticles/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Printing, Three-Dimensional , SARS-CoV-2/isolation & purification
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