Novel Opportunities to Study and Block Interactions between Viruses and Cell Surface Heparan Sulfates by using Dispirotripiperazines

2004 ◽  
Vol 1 (4) ◽  
pp. 293-299 ◽  
Author(s):  
M. Schmidtke ◽  
P. Wutzler ◽  
V. Makarov
Keyword(s):  
Cell Surface ◽  
Heparan Sulfates

scholarly journals The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

2015 ◽  
Vol 59 (9) ◽  
pp. 5250-5259 ◽  
Author(s):  
Valeria Cagno ◽  
Manuela Donalisio ◽  
Antonella Bugatti ◽  
Andrea Civra ◽  
Roberta Cavalli ◽  
...  
Keyword(s):  
Cell Surface ◽  
Viral Infections ◽  
Human Papillomaviruses ◽  
Sexually Transmitted ◽  
Human Papillomavirus 16 ◽  
Virus Attachment ◽  
Hpv Types ◽  
Heparan Sulfates ◽  
Further Development ◽  
Topical Microbicide

ABSTRACTThe agmatine-containing poly(amidoamine) polymer AGMA1 was recently shown to inhibit the infectivity of several viruses, including human papillomavirus 16 (HPV-16), that exploit cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The aim of this work was to assess the antiviral activity of AGMA1 and its spectrum of activity against a panel of low-risk and high-risk HPVs and to elucidate its mechanism of action. AGMA1 was found to be a potent inhibitor of mucosal HPV types (i.e., types 16, 31, 45, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 0.34 μg/ml and 0.73 μg/ml, and no evidence of cytotoxicity was observed. AGMA1 interacted with immobilized heparin and with cellular heparan sulfates, exerting its antiviral action by preventing virus attachment to the cell surface. The findings from this study indicate that AGMA1 is a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections.

scholarly journals The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus infectivity

2019 ◽  
Author(s):  
Mohammad H. Hasan ◽  
Rinkuben Parmar ◽  
Quntao Liang ◽  
Hong Qiu ◽  
Vaibhav Tiwari ◽  
...  
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Virus Entry ◽  
Degree Of Polymerization ◽  
Convincing Evidence ◽  
Host Cells ◽  
Virus Infectivity ◽  
Cmv Infection ◽  
Virus Binding ◽  
Heparan Sulfates

AbstractHerpesviruses attach to host cells by interacting with cell surface heparan sulfate (HS) proteoglycans prior to specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions results in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide convincing evidence that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) infection and binding by following line of evidences. First, purified CMV extracellular virions preferentially bound to the sulfated longer chain of HS on a glycoarray compared to unsulfated glycosaminoglycans and shorter chain unsulfated HS. Second, the fraction of glycosaminoglycans (GAG) displaying higherdpand sulfation had a major impact on CMV infectivity and titers. Finally, cell lines knocked out for specific sulfotransferases Glucosaminyl 3-O-sulfotransferase (3-O-ST-1 and −4 and double −1/4) produced significantly reduced CMV titers compared to wild-type cells. Similarly, a peptide generated against sulfated-HS significantly reduced virus titers compared to the control peptide. Taken together, the above results highlight the significance of the chain length and sulfation patterns of HS in CMV binding and infectivity.ImportanceThe cell surface heparan sulfates (HS) are exploited by multiple viruses as they provide docking sites during cell entry and therefore are a promising target for the development of novel antivirals. In addition, the molecular diversity in HS chains generates unique binding sites for specific ligands and hence offers preferential binding for one virus over other. In the current study several HS mimics were analyzed for their ability to inhibit cytomegalovirus (CMV) infection. The results were corroborated by parallel studies in mutant mouse cells and virus binding to glycoarrays. Combined together, the data suggests that virus particles preferentially attach to specifically modified HS and thus the process is amenable to targeting by specifically designed HS mimics.

Quantitative assessment of FGF regulation by cell surface heparan sulfates

2004 ◽  
Vol 314 (4) ◽  
pp. 994-1000 ◽  
Author(s):  
David Berry ◽  
Zachary Shriver ◽  
Ganesh Venkataraman ◽  
Ram Sasisekharan
Keyword(s):  
Cell Surface ◽  
Quantitative Assessment ◽  
Heparan Sulfates

Identification of cell-binding site of angiomodulin (AGM/TAF/Mac25) that interacts with heparan sulfates on cell surface

1999 ◽  
Vol 75 (2) ◽  
pp. 187-195 ◽  
Author(s):  
Junji Sato ◽  
Satoshi Hasegawa ◽  
Kotaro Akaogi ◽  
Hidetaro Yasumitsu ◽  
Shuhei Yamada ◽  
...  
Keyword(s):  
Cell Surface ◽  
Binding Site ◽  
Cell Binding ◽  
Heparan Sulfates

Heparan sulfate glycomics: towards systems biology strategies

2010 ◽  
Vol 38 (5) ◽  
pp. 1356-1360 ◽  
Author(s):  
Jeremy E. Turnbull
Keyword(s):  
Systems Biology ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Biological Functions ◽  
Combined Application ◽  
Cellular Events ◽  
Structure Activity ◽  
Future Potential ◽  
Heparan Sulfates ◽  
Molecular Code

HSs (heparan sulfates) are a complex family of cell-surface and matrix polysaccharides that have diverse biological functions, underpinned by structurally diverse patterns of backbone chain modification, especially by sulfate groups. These variant structures represent a molecular code, the ‘heparanome’, that confers the ability to interact selectively with a wide interactome of proteins, the ‘heparactome’, and thereby influence a network of cellular events. It is becoming increasingly apparent that understanding the structure–activity relationships of these enigmatic molecules requires the development of a holistic systems biology view of their structure and interactions. In the present paper, I describe some of the new tools available to realize this strategy, and discuss the future potential for the combined application of glycomics and other ‘-omics’ approaches to define the molecular code of the heparanome.

scholarly journals Glycosaminoglycans are specific endosomal receptors for Yersinia pseudotuberculosis Cytotoxic Necrotizing Factor

2020 ◽  
Author(s):  
Stefanie Kowarschik ◽  
Julian Schöllkopf ◽  
Thomas Müller ◽  
Songhai Tian ◽  
Julian Knerr ◽  
...  
Keyword(s):  
Cell Surface ◽  
Conformational Change ◽  
Mammalian Cells ◽  
Yersinia Pseudotuberculosis ◽  
Double Resonance ◽  
Cytotoxic Necrotizing Factor ◽  
Endosomal Membrane ◽  
Terminal Domain ◽  
Successful Infection ◽  
Heparan Sulfates

AbstractThe Cytotoxic Necrotizing Factor Y (CNFY) is produced by the gram-negative, enteric pathogen Yersinia pseudotuberculosis. The bacterial toxin belongs to a family of deamidases, which constitutively activate Rho GTPases, thereby balancing inflammatory processes. We identified heparan sulfate proteoglycans as essential host cell factors for intoxication with CNFY. Using flow cytometry, microscopy, knockout cell lines, pulsed electron–electron double resonance and bio-layer interferometry, we studied the role of glucosaminoglycans in the intoxication process of CNFY. To analyze toxin-glucosaminoglycan interaction we utilized a truncated CNFY (CNFY709-1014). Especially this C-terminal part of CNFY, which encompasses the catalytic activity, binds with high affinity to heparan sulfates. CNFY binding with the N-terminal domain to its protein receptor seems to induce a first conformational change supporting the interaction between the C-terminal domain and heparan sulfates, which seems sterically hindered in the full toxin. A second conformational change occurs by acidification of the endosome, probably allowing insertion of the hydrophobic regions of the toxin into the endosomal membrane. Our findings suggest that heparan sulfates play a major role for intoxication within the endosome, rather than being relevant for an interaction at the cell surface. Lastly, cleavage of heparin sulfate chains by heparanase is likely required for efficient uptake of the toxic enzyme into the cytosol of mammalian cells.Author SummaryThe RhoA deamidating Cytotoxic Necrotizing Factor Y (CNFY) from Yersinia pseudotuberculosis is a crucial virulence factor that is important for successful infection of mammalian cells by the pathogen. The mode of action by which CNFY is able to intoxicate cells can be divided into the following steps: Binding to the cell surface, internalization, translocation from the endosome to the cytosol and deamidation of RhoA. We show, that CNFY uses heparan sulfates to maximize the amount of molecules entering the cytosol. While not being necessary for toxin binding and uptake, the sugars hold a key role in the intoxication process. We show that CNFY undergoes a conformational change at a low endosomal pH, allowing the C-terminal domain to be released from the endosomal membrane by the action of heparanase. This study reveals new insights into the CNFY-host interaction and promotes understanding of the complex intoxication process of bacterial toxins.

scholarly journals Specific interaction of Penetratin with cell surface partners measured with biomembrane force probe

2020 ◽  
Author(s):  
P Soule ◽  
F Illien ◽  
S Kulifaj ◽  
A Joliot ◽  
C Gourier ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Specific Interaction ◽  
Cell Plasma Membrane ◽  
Biomembrane Force Probe ◽  
Cell Plasma ◽  
A Cell ◽  
Heparan Sulfates ◽  
Chemical Groups ◽  
Molecular Description

ABSTRACTPenetratin is a Cell Penetrating Peptide able to cross the cell plasma membrane possibly bound to a cargo molecule to be delivered into the cell. The mechanism of its entry is poorly known. A key to a molecular description of this mechanism is to identify the partners of Penetratin at the cell surface during its adhesion and internalization. We used the Biomembrane Force Probe to identify the partners during the first second of adhesion of Penetratin on the cell plasma membrane. We evidenced that heparan sulfates are the first partners after contact as well as unknown partners hidden by sialic acids. Experiments of binding of Penetratin on vesicles bearing charged or sulfated lipids showed no adhesion pointing that a negatively charged partner is not enough and there is a specificity for certain chemical groups bearing the charges. A model of the measured forces of interaction enabled to determine the adhesion energy of a Penetratin with heparan sulfates on a cell to be in the range 18 to 22 kBT.

scholarly journals Correlation between cell substrate attachment in vitro and cell surface heparan sulfate affinity for fibronectin and collagen.

1983 ◽  
Vol 96 (6) ◽  
pp. 1820-1823 ◽  
Author(s):  
S C Stamatoglou ◽  
J M Keller
Keyword(s):  
Cell Adhesion ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Cell Attachment ◽  
Myeloma Cell ◽  
Collagen Type I ◽  
Type I ◽  
Heparan Sulfates ◽  
Sepharose 4B

Heparan sulfate glycosaminoglycan, isolated from the cell surface of nonadhering murine myeloma cells (P3X63-Ag8653), does not bind to plasma fibronectin, but binds partially to collagen type I, as assayed by affinity chromatography with proteins immobilized on cyanogen bromide-activated Sepharose 4B. Identical results were obtained when myeloma heparan sulfate was cochromatographed, on the same fibronectin and collagen columns, with cell surface heparan sulfates collagen columns, with cell surface heparan sulfates from adhering Swiss mouse 3T3 and SV3T3 cells. These latter heparan sulfates do, however, bind to both fibronectin and collagen, as reported earlier (Stamatoglou, S.C., and J.M. Keller, 1981, Biochim. Biophys. Acta., 719:90-97). Cell adhesion assays established that hydrated collagen substrata can support myeloma cell attachment, but fibronectin cannot. Saturation of the heparan sulfate binding sites on the collagen substrata with heparan sulfate or heparin, prior to cell inoculation, abolished the ability to support cell adhesion, whereas chondroitin 4 sulfate, chondroitin 6 sulfate, and hyaluronic acid had no effect.

Degradation of Cell Surface Heparan Sulfates Decreases the High Affinity Binding of Basic FGF to Endothelial Cells, but Not to FRTL-5 Rat Thyroid Cells

Thyroid ◽  
1995 ◽  
Vol 5 (6) ◽  
pp. 455-460 ◽  
Author(s):  
NAOYA EMOTO ◽  
OSAMU ISOZAKI ◽  
EIJI OHMURA ◽  
KAZUO SHIZUME ◽  
TOSHIO TSUSHIMA ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Affinity Binding ◽  
Thyroid Cells ◽  
High Affinity Binding ◽  
Basic Fgf ◽  
High Affinity ◽  
Heparan Sulfates ◽  
Rat Thyroid
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