Beta-sheet is the bioactive conformation of the anti-angiogenic anginex peptide.
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ABSTRACT:
SUBMITTER: Dings RP
PROVIDER: S-EPMC1223486 | biostudies-other | 2003 Jul
REPOSITORIES: biostudies-other
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Project description:BackgroundOligomeric forms of amyloid-β (Aβ) and tau are increasing being recognized as key toxins in the pathogenesis of Alzheimer's disease (AD).MethodsWe developed a novel monoclonal antibody (mAb), GW-23B7, that recognizes β-sheet secondary structure on pathological oligomers of neurodegenerative diseases.ResultsThe pentameric immunoglobulin M kappa chain (IgMκp) we developed specifically distinguishes intra- and extracellular pathology in human AD brains. Purified GW-23B7 showed a dissociation constant in the nanomolar range for oligomeric Aβ and did not bind monomeric Aβ. In enzyme-linked immunosorbent assays, it recognized oligomeric forms of both Aβ and hyperphosphorylated tau. Aged triple-transgenic AD mice with both Aβ and tau pathology infused intraperitoneally for 2 months showed IgMκp in the soluble brain homogenate, peaking at 24 h postinoculation. Treated mice exhibited significant cognitive rescue on radial arm maze testing compared with vehicle control-infused mice. Immunohistochemically, treatment resulted in a significant decrease of extracellular pathology. Biochemically, treatment resulted in significant reductions of oligomeric forms of Aβ and tau.ConclusionsThese results suggest that GW-23B7, an anti-β-sheet conformational mAb humanized for clinical trials, may be an effective therapeutic agent for human AD.
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Project description:In 1953, Pauling and Corey predicted that enantiomeric β-sheet peptides would coassemble into so-called "rippled" β-sheets, in which the β-sheets would consist of alternating l- and d-peptides. To date, this phenomenon has been investigated primarily with amphipathic peptide sequences composed of alternating hydrophilic and hydrophobic amino acid residues. Here, we show that enantiomers of a fragment of the amyloid-β (Aβ) peptide that does not follow this sequence pattern, amyloid-β (16-22), readily coassembles into rippled β-sheets. Equimolar mixtures of enantiomeric amyloid-β (16-22) peptides assemble into supramolecular structures that exhibit distinct morphologies from those observed by self-assembly of the single enantiomer pleated β-sheet fibrils. Formation of rippled β-sheets composed of alternating l- and d-amyloid-β (16-22) is confirmed by isotope-edited infrared spectroscopy and solid-state NMR spectroscopy. Sedimentation analysis reveals that rippled β-sheet formation by l- and d-amyloid-β (16-22) is energetically favorable relative to self-assembly into corresponding pleated β-sheets. This work illustrates that coassembly of enantiomeric β-sheet peptides into rippled β-sheets is not limited to peptides with alternating hydrophobic/hydrophilic sequence patterns, but that a broader range of sequence space is available for the design and preparation of rippled β-sheet materials.
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Project description:Amyloid oligomers represent the primary pathological species for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Toxic oligomers are formed by many different proteins and peptides, but their polydispersity makes them highly dynamic and heterogeneous. One way to stabilize these structures is to prepare constrained peptides that can be used to study amyloid intermediates, to identify oligomer-specific drugs, and to generate conformational antibodies. These conformational antibodies have demonstrated that oligomers share a common epitope. In this research, we used a 40-amino acid unstructured segment of prion protein (Prp) 109-148 with substitutions of methionine for glycine (Prp-G) residues to prepare a stable and homogeneous population of β-sheet oligomer mimics. These structures were characterized by multiple biophysical and biochemical techniques that show characteristic features of oligomers. Finally, this preparation was not detected by three different sequence dependent prion antibodies.
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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:CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 protein, has been identified, the mechanism by which CIGB-552 exerts such effects remains elusive. In the present study, we show the role of COMMD1 in CIGB-552 mechanism of action by generating the COMMD1 knock-out from the human lung cancer cell line NCI-H460. A microarray was performed to analyze both wild-type and KO cell lines with regard to CIGB-552 treatment. Additionally, different signaling pathways were studied in both cell lines to validate the results. Furthermore, the interaction between CIGB-552 and COMMD1 was analyzed by confocal microscopy. By signaling pathway analysis we found that genes involved in cell proliferation and apoptosis, oncogenic transformation, angiogenesis and inflammatory response are potentially regulated by the treatment with CIGB-552. We then demonstrated that CIGB-552 is capable of modulating NF-kB in both 2D and 3D cell culture models. Finally, we show that the ability of CIGB-552 to negatively modulate NF-kB and HIF-1 pathways is impaired in the COMMD1 knock-out NCI-H460 cell line, confirming that COMMD1 is essential for the peptide mechanism of action.
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