Structural Studies of a Lipid-Binding Peptide from Tunicate Hemocytes with Anti-Biofilm Activity.
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ABSTRACT:
SUBMITTER: Silva ON
PROVIDER: S-EPMC4904370 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:BackgroundDevelopment of VEGF antagonists, which inhibit its interaction with the receptors, is a widely used strategy for the inhibition of angiogenesis and tumor growth.ObjectivesIn the present study, a VEGFR-1 antagonistic peptide was designed and its potential for binding to VEGFR-1 and VEGFR-2 was evaluated by theoretical studies.Materials and methodsBased on the X-ray structure of VEGF-B/VEGFR-1 D2 (PDB ID: 2XAC), an antagonistic peptide (known as VGB1) was designed, and its model structure was constructed using homology modeling in the MODELLER, version 9.16. The validity of the modeled structures was estimated employing several web tools. Finally, one model was chosen and molecular dynamics (MD) simulation was applied using the GROMACS package, version 5.1.4, to allow conformational relaxation of the structure. Next, docking process of the peptide with VEGFR-1 and VEGFR-2 was performed by HADDOCK web server and the docking structures were optimized by MD simulation for 20 ns. The far-UV circular dichroism (CD) spectrum of VGB1 was recorded to evaluate the overall structure of the peptide.ResultsThe far-UV CD spectrum indicated that VGB1 contains α helix structure. The results from docking studies suggested that Van der Waals and nonpolar interactions play the most important role in the peptide binding to VEGFR-1. In addition, our results implicated the relevance of both Van der Waals and electrostatic interactions in the formation of complex between VGB1 and VEGFR-2. In addition to the common binding residues in the corresponding region of VEGF-A and VEGF-B, additional binding residues also were predicted for the interaction of VGB1 with VEGFR-1 and VEGFR-2.ConclusionsThe results of MD and molecular docking simulations predicted that VGB1 recognizes both VEGFR-1 and VEGFR-2, which may lead to the prevention of the downstream signaling triggered by these receptors.
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Project description:Streptococcus mutans is the primary agent of dental cavities, in large part due to its ability to adhere to teeth and create a molecular scaffold of glucan polysaccharides on the tooth surface. Disrupting the architecture of S. mutans biofilms could help undermine the establishment of biofilm communities that cause cavities and tooth decay. Here we present a synthetic peptide P1, derived from a tick antifreeze protein, which significantly reduces S. mutans biofilm formation. Incubating cells with this peptide decreased biofilm biomass by approximately 75% in both a crystal violet microplate assay and an in vitro tooth model using saliva-coated hydroxyapatite discs. Bacteria treated with peptide P1 formed irregular biofilms with disconnected aggregates of cells and exopolymeric matrix that readily detached from surfaces. Peptide P1 can bind directly to S. mutans cells but does not possess bactericidal activity. Anti-biofilm activity was correlated with peptide aggregation and β-sheet formation in solution, and alternative synthetic peptides of different lengths or charge distribution did not inhibit biofilms. This anti-biofilm peptide interferes with S. mutans biofilm formation and architecture, and may have future applications in preventing bacterial buildup on teeth.
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Project description:AR-23 is a melittin-related peptide with 23 residues. Like melittin, its high α-helical amphipathic structure results in strong bactericidal activity and cytotoxicity. In this study, a series of AR-23 analogues with low amphipathicity were designed by substitution of Ala1, Ala8 and Ile17 with positively charged residues (Arg or Lys) to study the effect of positively charged residue distribution on the biological viability of the antimicrobial peptide. Substitution of Ile17 on the nonpolar face with positively charged Lys dramatically altered the hydrophobicity, amphipathicity, helicity and the membrane-penetrating activity against human cells as well as the haemolytic activity of the peptide. However, substitution on the polar face only slightly affected the peptide biophysical properties and biological activity. The results indicate that the position rather than the number of positively charged residue affects the biophysical properties and selectivity of the peptide. Of all the analogues, A(A1R, A8R, I17K), a peptide with Ala1-Arg, Ala8-Arg and Ile17-Lys substitutions, exhibited similar bactericidal activity and anti-biofilm activity to AR-23 but had much lower haemolytic activity and cytotoxicity against mammalian cells compared with AR-23. Therefore, the findings reported here provide a rationalization for peptide design and optimization, which will be useful for the future development of antimicrobial agents.
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Project description:ObjectiveBiofilm formation under cariogenic conditions contributes to dental caries development, in which Streptococcus mutans (S. mutans) is regarded as the major cariogenic bacteria. Here, we synthesized a series of imidazolium salts. Their properties of antimicrobial and anti-biofilm were investigated.MethodsThe microdilution method crystal violet staining, and cell counting Kit-8 assay were used to screen imidazolium salts. Then, the bacterial composition in multi-species biofilm composed of S. mutans, Actinomyces naeslundii, and Streptococcus gordonii was quantified by quantitative PCR. The exopolysaccharide and morphology of the structure of multi-species biofilm were further observed by confocal laser scanning microscopy and scanning electron microscope, respectively.ResultsImidazolium salts exhibited highly antimicrobial activity against oral pathogens, especially for S. mutans . Compounds with ortho-diisopropyl and para-methoxyl on N-moieties as well as bearing ancenaphthyl skeleton (C5) showed the lowest cytotoxicity and most efficient anti-biofilm activity. C5 inhibited approximately 50% of multi-species biofilm at 0.98 μg/mL. Notably, C5 resulted in 98.97% live S. mutans and 77.65% A. naeslundii decreased. Furthermore, the exopolysaccharide was reduced by 88%, along with a sparse and scattered microstructure.ConclusionThe imidazolium salts present low cytotoxicity and remarkable antimicrobial activity against S. mutans in multi-species biofilm, suggesting that they may have a great potential in anti-biofilm clinical applications.
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