Author(s): FÃ¡tima Pereira de Souza, Mariana Pela Sabgad, Gabriela Campos de Araujo, Haroldo Lima Pimentel Cravo, Thiago PanÃ§onato Salen Teixeira, Valmir Fadel, Deriane Elias Gomes, Marcelo Andres Fossey
Background: Acute respiratory infections (ARI) are the leading cause of infant mortality in the world, and human respiratory syncytial virus (HRSV) is one of the main agents of ARI. One of the key targets of the adaptive host immune response is the RSV G-protein, which is responsible for attachment to the host cell. There is evidence that compounds such as flavonoids can inhibit viral infection in vitro. With this in mind, the main purpose of this study was to determine, using computational tools, the potential sites for interactions between G-protein and flavonoids. Results: Our study allowed the recognition of an hRSV G-protein model, as well as a model of the interaction with flavonoids. These models were composed, mainly, of ï¡-helix and random coil proteins. The docking process showed that molecular interactions are likely to occur. The flavonoid kaempferol-3-O-Î±-L-arabinopyranosil-(2 â†’ 1)-Î±-L-apiofuranoside-7-O-Î±-L-rhamnopyranoside was selected as a candidate inhibitor. The main forces of the interaction were hydrophobic, hydrogen and electrostatic. Conclusions: The model of G-protein is consistent with literature expectations, since it was mostly composed of random coils (highly glycosylated sites) and ï¡-helices (lipid regions), which are common in transmembrane proteins. The docking analysis showed that flavonoids interact with G-protein in an important ectodomain region, addressing experimental studies to these sites. The determination of the G-protein structure is of great importance to elucidate the mechanism of viral infectivity, and the results obtained in this study will allow us to propose mechanisms of cellular recognition and to coordinate further experimental studies in order to discover effective inhibitors of attachment proteins.
hRSV, G-protein, Molecular docking
- Bae EA, Han MJ, Lee M, Kim DH. In vitro inhibitory effect of some flavonoids on rotavirus infectivity. Biol Pharm Bull 2000, 23:1122â€“4
- Chivian D, Kim DE, Malmstrom L, Bradley P, Robertson T, Murphy P, Strauss C. E, Bonneau R, Rohl CA, Baker D. Automated prediction of CASP5 structures using the Robetta server. Proteins 2003, 53(Suppl 6):524-533
- Esteves A, Parreira R, Venenno T, et al. Molecular epidemiology of HIV type 1 infection in Portugal: high prevalence of non-B subtypes, AIDS Res Hum Retroviruses 2002, 18(5):313-325
- Falsey AR, Wash EE. Respiratory syncytial virus infections in adults. Clin Microbiol Rev 2000. 13(3):371-84
- Feldman SA, Audet S, Beeler JA. The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulfate. J Virol 2000, 74:6442â€“6447
- Friesner RA, Banks JL, Murphy RB, et al. S: Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004, 47:1739â€“1749
- Gorman JJ, Ferguson BL, Speelman D, et al. Determination of the disulfide bond arrangement of human respiratory syncytial virus attachment (G) protein by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Protein Sci 1997, 6:1308-1315
- Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 1999, 41:95-98
- Johnson PR, Spriggs MK, Olmsted RA. et al. The G glycoprotein of human respiratory syncytial viruses of subgroups A and B: extensive sequence divergence between antigenically related proteins. Proc Natl Acad Sci USA 1987, 84:5625â€“5629
- Kaul TN, Middleton E Jr, Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Virol 1985, 15:71â€“9.
- Langedijk JP, De Groot BL, Berendsen HJ, et al. Structural homology of the central conserved region of the attachment protein G of respiratory syncytial virus with the fourth subdomain of 55-kDa tumor necrosis factor receptor. Virology 1998, 243:293-302
- Laskowski RA, Rullmannn JA, Macarthur MW, et al. AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 1996, 8:477-486
- Laurie AT, Jackson RM. Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 2005, 21:1908-1916
- Lole KS, Bollinger RC, Paranjape RS, et. al. Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol 1999, 73(1):152-160
- Melero JA, et. al. The soluble form of human respiratory syncytial virus attachment protein differs from the membrane-bound form in its oligomeric state but is still capable of binding to cell surface proteoglycans. J Virol 2004, 78(Suppl l):3524-3532
- Miteva MA, Guyon F, TuffÃ©ry P. Frog2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Res 2010, 38:622-627
- Morris S K, Dzolganovski B, Beyene J, et. al. A meta-analysis of the effect of antibody therapy for the prevention of severe respiratory syncytial virus infection. BMC Infect Dis 2009, 9, n 106
- Nakamura M, Itokazu K, Taira K, et al. Genotypic and phylogenetic of the G gene of respiratory syncytial virus isolates in Okinawa, Japan, 2008. Japan J Infect Dis 2009, 62:326-327
- Ohuchi M, Ohuchi R, Feldmann A, Klenk HD. Regulation of receptor binding affinity of influenza virus hemagglutinin by its carbohydrate moiety. J Virol 1997, 71:8377â€“8384
- Pavlova S, Hadzhiolova T, Abadjieva P, et. al. Aplication of RT-PCR for diagnosis of respiratory syncytial virus and human metapneumovirus infection in Bulgaria, 2006-7 and 2007-8. Eurosurveillance 2009,14, n. 23
- Pencheva T, Lagorce D, Pajeva I, et al. AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening. BMC Bioinformatics 2008, 9:438
- Rost B, Yachdav G, Liu J. The PredictProtein server. Nucleic Acids Res 2004, 32(Web Server issue):W321-6.
- SchrÃ¶dinger; LLC. New York, 2005; http://www.schrodinger.com
- Sullender WM. Respiratory syncytial virus genetic and antigenic diversity. Clin Microbiol Rev 2000. 13(1):1-15.
- Teng MN, Collins PL. The central conserved cysteine noose of the attachment G protein of human respiratory syncytial virus is not required for efficient viral infection in vitro or in vivo. J Virol 2002, 76:6164-6171
- Teng MN, Whitehead SS, Collins PL. Contribution of the respiratory syncytial virus G glycoprotein and its secreted and membrane-bound forms to virus replication in vitro and in vivo. Virology 2001, 289:283â€“296
- Wang HK, Xia Y, Yang ZY, Natschke SL, Lee KH. Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents. Adv Exp Med Biol 1998, 439:191â€“225
- Wertz GW, Collins PL, Huang Y, et al. Nucleotide sequence of the G protein gene of human respiratory syncytial virus reveals an unusual type of viral membrane protein. Proc Natl Acad Sci U S A 1985, 82(12):4075-4079
- Wheeler DL, Barrett T, Benson DA, et. al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2007, 35:5-12
- Zimmer M, Danko JP, Pennings SC, et al. Hepatopancreatic endosymbionts in intertidal isopods (Crustacea: Isopoda), and their contribution to digestion. Mar Biol 2001, 138:955â€“963
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