Antiviral Activity and Structural Characteristics of the Nonglycosylated Central Subdomain of Human Respiratory Syncytial Virus Attachment (G) Glycoprotein

Gorman, Jeffrey J.; McKimm-Breschkin, Jennifer L.; Norton, Raymond S.; Barnham, Kevin J.

doi:10.1074/jbc.m106288200

Cited by 21 publications

(13 citation statements)

References 58 publications

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“…Targeting G protein may also be a reasonable strategy. Infection can be effectively inhibited by treatment with a pool of anti-G protein mAb [Martinez and Melero, 1998], molecules that bind G protein ([e.g., surfactant protein D [Hickling et al, 1999] or the selectin, annexin II (Malhotra et al, 2003]), or a peptide representing the central non-glycosylated ectodomain of G protein [Gorman et al, 2001]. F [Feldman et al, 2000] and G [Feldman et al, 1999] proteins also possess positively charged amino acids that constitute heparin-binding domains (HBD).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5)

Elliott

Tebbey

Pryharski

et al. 2004

Journal of Medical Virology

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Respiratory syncytial virus (RSV) is a major cause of respiratory tract disease in infants, aged adults, and immunosuppressed patients. The only approved medicines for RSV disease are administration of prophylatic antibodies or treatment with a synthetic nucleoside. Both approaches are expensive and the latter is not without risk and of controversial benefit. The present investigation studied whether pharmaceutical or biologic compounds based upon chemokines might be useful in preventing RSV disease. Of interest was RANTES/CCL5, which inhibits infection by HIV strains that use chemokine receptor (CCR)-5 as co-receptor. Herein, we report that prior or simultaneous treatment of HEp-2 cells with recombinant human CCL5 provides dose-dependent inhibition of infection with RSV. Other recombinant chemokines (MIP-1alpha/CCL3, MIP-1beta/CCL4, MCP-2/CCL8, eotaxin/CCL11, MIP-1delta/CCL15, stromal cell derived factor (SDF)-1alpha/CXCL12) were not inhibitory. The data suggested that CCL5 might inhibit infection by blocking fusion (F) protein-epithelial cell interactions. Infections by mutant RSV strains deleted of small hydrophobic and/or attachment proteins and only expressing F protein in the envelope were inhibited by prior treatment with CCL5 or a biologically inactive N-terminally modified met-CCL5. Inhibition was also observed when virus adsorption and treatment with CCL5 were performed at 4 degrees C. Flow cytometry further revealed that epithelial cells were positive for CCR3, but not CCR1 or CCR5. Thus, novel mimetics of CCL5 may be useful prophylatic agents to prevent respiratory tract disease caused by RSV.

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Section: Discussionmentioning

confidence: 99%

Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5)

Elliott

Tebbey

Pryharski

et al. 2004

Journal of Medical Virology

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“…Its unglycosylated central region contains 4 cysteines that form disulfide bonds in a cysteine noose pattern [44]. NMR analyses of this region have identified loop structures [45, 46] that are similar to a domain in the tumor necrosis factor receptor (TNFR) [45]. And the 4 cysteines of the G protein are in the same position as the 4 cysteines in this TNFR domain [45].…”

Section: Rsv Biologymentioning

confidence: 99%

Targeting RSV with Vaccines and Small Molecule Drugs

Costello¹,

Ray²,

Chaiwatpongsakorn³

et al. 2012

IDDT

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Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.

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“…Recently, Gorman et al showed that a series of peptides containing residues 154 to 170 of RSV G could efficiently inhibit RSV cytopathic effect in an in vitro assay in which cells were infected with RSV in the presence of peptide and cytopathic effect was scored 5 days later (13). Alanine replacements and truncations indicated that residues 166 to 170 were critical for the inhibitory effect.…”

mentioning

confidence: 99%

The Central Conserved Cystine Noose of the Attachment G Protein of Human Respiratory Syncytial Virus Is Not Required for Efficient Viral Infection In Vitro or In Vivo

Teng

Collins

2002

J Virol

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The G glycoprotein of human respiratory syncytial virus (RSV) was identified previously as the viral attachment protein. Although we and others recently showed that G is not essential for replication in vitro, it does affect the efficiency of replication in a cell type-dependent fashion and is required for efficient replication in vivo. The ectodomain of G is composed of two heavily glycosylated domains with mucin-like characteristics that are separated by a short central region that is relatively devoid of glycosylation sites. This central region contains a 13-amino acid segment that is conserved in the same form among RSV isolates and is overlapped by a second segment containing four cysteine residues whose spacings are conserved in the same form and which create a cystine noose. The conserved nature of the cystine noose and flanking 13-amino acid segment suggested that this region likely was important for attachment activity. To test this hypothesis, we constructed recombinant RSVs from which the region containing the cysteine residues was deleted together with part or all of the conserved 13-amino acid segment. Surprisingly, each deletion had little or no effect on the intracellular synthesis and processing of the G protein, the kinetics or efficiency of virus replication in vitro, or sensitivity to neutralization by soluble heparin in vitro. In addition, neither deletion had any discernible effect on the ability of RSV to infect the upper respiratory tract of mice and both resulted in a 3-to 10-fold reduction in the lower respiratory tract. Thus, although the G protein is necessary for efficient virus replication in vivo, this activity does not require the central conserved cystine noose region.Human respiratory syncytial virus (RSV), the prototype of the Pneumovirus genus in the paramyxovirus family, is the most important viral etiologic agent of pediatric respiratory disease worldwide (6). Its genome consists of a single, negative-sense RNA of 15,190 to 15,225 nucleotides (for the three strains sequenced to date) encoding 10 major subgenomic mRNAs and 11 viral proteins. Three of these proteins, G, F, and SH, are transmembrane virion glycoproteins. The G glycoprotein has been identified as the viral attachment protein (25) although, as described below, under certain conditions it is completely dispensable for efficient replication in vitro. The F protein mediates membrane fusion and also appears to be able to serve as an auxiliary attachment protein (17,21,22,34,36). Expression of the SH protein can be eliminated with little effect on virus replication in vitro and in vivo and its function remains unknown (3, 41), although its counterpart in simian virus 5 was recently shown to function as an antagonist of apoptosis (16).RSV G is a highly glycosylated type II transmembrane protein with a single hydrophobic region near the N terminus which serves as both signal sequence and membrane anchor. The protein backbone is 292 to 299 amino acids long, depending on the virus strain (19,33), and has an M r of approxim...

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Antiviral Activity and Structural Characteristics of the Nonglycosylated Central Subdomain of Human Respiratory Syncytial Virus Attachment (G) Glycoprotein

Cited by 21 publications

References 58 publications

Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5)

Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5)

Targeting RSV with Vaccines and Small Molecule Drugs

The Central Conserved Cystine Noose of the Attachment G Protein of Human Respiratory Syncytial Virus Is Not Required for Efficient Viral Infection In Vitro or In Vivo

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