Promiscuous antibodies characterised by their physico-chemical properties: From sequence to structure and back.
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ABSTRACT:
SUBMITTER: Laffy JMJ
PROVIDER: S-EPMC6167913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The present work is a concrete example of how physico-chemical studies, if performed in depth, are crucial to understand the behavior of pharmaceutical solids and constitute a solid basis for the control of the reproducibility of the industrial batches. In particular, a deep study of the thermal behavior of glipizide, a hypoglycemic drug, was carried out with the aim of clarifying whether the recognition of its polymorphic forms can really be done on the basis of the endothermic peak that the literature studies attribute to the melting of the compound. A number of analytical techniques were used: thermal techniques (DSC, TGA), X-ray powder diffraction (XRPD), FT-IR spectroscopy and scanning electron microscopy (SEM). Great attention was paid to the experimental design and to the interpretation of the combined results obtained by all these techniques. We proved that the attribution of the endothermic peak shown by glipizide to its melting was actually wrong. The DSC peak is no doubt triggered by a decomposition process that involves gas evolution (cyclohexanamine and carbon dioxide) and formation of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which remains as decomposition residue. Thermal treatments properly designed and the combined use of DSC with FT-IR and XRPD led to identifying a new polymorphic form of 5-methyl-N-[2-(4-sulphamoylphenyl) ethyl] pyrazine-2-carboxamide, which is obtained by crystallization from the melt. Hence, our results put into evidence that the check of the polymorphic form of glipizide cannot be based on the temperature values of the DSC peak, since such a peak is due to a decomposition process whose Tonset value is strongly affected by the particle size. Kinetic studies of the decomposition process show the high stability of solid glipizide at room temperature.
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Project description:CyanoPhyChe is a user friendly database that one can browse through for physico-chemical properties, structure and biochemical pathway information of cyanobacterial proteins. We downloaded all the protein sequences from the cyanobacterial genome database for calculating the physico-chemical properties, such as molecular weight, net charge of protein, isoelectric point, molar extinction coefficient, canonical variable for solubility, grand average hydropathy, aliphatic index, and number of charged residues. Based on the physico-chemical properties, we provide the polarity, structural stability and probability of a protein entering in to an inclusion body (PEPIB). We used the data generated on physico-chemical properties, structure and biochemical pathway information of all cyanobacterial proteins to construct CyanoPhyChe. The data can be used for optimizing methods of expression and characterization of cyanobacterial proteins. Moreover, the 'Search' and data export options provided will be useful for proteome analysis. Secondary structure was predicted for all the cyanobacterial proteins using PSIPRED tool and the data generated is made accessible to researchers working on cyanobacteria. In addition, external links are provided to biological databases such as PDB and KEGG for molecular structure and biochemical pathway information, respectively. External links are also provided to different cyanobacterial databases. CyanoPhyChe can be accessed from the following URL: http://bif.uohyd.ac.in/cpc.
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Project description:Protein-peptide interactions are a common occurrence and essential for numerous cellular processes, and frequently explored in broad applications within biology, medicine, and proteomics. Therefore, understanding the molecular mechanism(s) of protein-peptide recognition, specificity, and binding interactions will be essential. In this study, we report the first detailed analysis of antibody-peptide interaction characteristics, by combining large-scale experimental peptide binding data with the structural analysis of eight human recombinant antibodies and numerous peptides, targeting tryptic mammalian and eukaryote proteomes. The results consistently revealed that promiscuous peptide-binding interactions, that is, both specific and degenerate binding, were exhibited by all antibodies, and the discovery was corroborated by orthogonal data, indicating that this might be a general phenomenon for low-affinity antibody-peptide interactions. The molecular mechanism for the degenerate peptide-binding specificity appeared to be executed through the use of 2-3 semi-conserved anchor residues in the C-terminal part of the peptides, in analogue to the mechanism utilized by the major histocompatibility complex-peptide complexes. In the long-term, this knowledge will be instrumental for advancing our fundamental understanding of protein-peptide interactions, as well as for designing, generating, and applying peptide specific antibodies, or peptide-binding proteins in general, in various biotechnical and medical applications.
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Project description:A group of four selected non-ionic surfactants based on carbohydrates, namely octyl d-xyloside (C8X), nonyl d-xyloside (C9X), decyl d-xyloside (C10X) and dodecyl d-xyloside (C12X), have been investigated to accomplish a better understanding of their physico-chemical properties as well as biological activities. The surface-active properties, such as critical micelle concentration (CMC), emulsion and foam stability, the impact of the compounds on cell surface hydrophobicity and cell membrane permeability together with their toxicity on the selected bacterial strains have been determined as well. The studied group of surfactants showed high surface-active properties allowing a decrease in the surface tension to values below 25 mN m-1 for dodecyl d-xyloside at the CMC. The investigated compounds did not have any toxic influence on two Pseudomonas bacterial strains at concentrations below 25 mg L-1. The studied long-chain alkyl xylosides influenced both the cell inner membrane permeability and the cell surface hydrophobicity. Furthermore, the alkyl chain length, as well as the surfactant concentration, had a significant impact on the modifications of the cell surface properties. The tested non-ionic surfactants exhibited strong surface-active properties accompanied by the significant influence on growth and properties of Pseudomonas bacteria cells.
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Project description:A series of dicationic ionic liquids (ILs) including [C4(MIM)2][PF6]2, [C5(MIM)2][PF6]2, [C6(MIM)2][PF6]2 and [C4(PYR)2][PF6]2 were synthesized. Their thermal stability and melting points were analysed. It was found that dicationic ILs presented important implications in the design of homogeneous and heterogeneous system with water. A homogeneous system of dicationic ILs with water could be formed at a relatively high temperature and then a heterogeneous system was formed when the solution was cooled to a low temperature. The ILs recovered by altering the temperature were obtained in high percentage yields of [C4(MIM)2][PF6]2 (97.6%), [C5(MIM)2][PF6]2 (97.3%), [C6(MIM)2][PF6]2 (98.0%) and [C4(PYR)2][PF6]2 (94.2%). On the other hand, [C4(MIM)2][PF6]2 and [C5(MIM)2][PF6]2 exhibited good solubility in acetonitrile and acetone. A homogeneous system could be achieved with imidazolium-based ILs with a relatively low amount of water and acetonitrile at room temperature. All of the properties of dicationic ILs have a strong correlation with the nature of dications, the linkage chain and the symmetry of dications. Dicationic ILs may provide a new opportunity for some specific applications in order to enable the effective separation and isolation of products.
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Project description:Betulin-3,28-diphosphate (BDP) obtained by phosphorylation of betulin using POCl? has two main structural forms-BDP-1 and BDP-2-which differ in ethanol solubility, melting point, FTIR spectra, thermoanalytical characteristics and biological activity. Betulin-3,28-diphosphate and its sodium salt (Na-BDP) were characterized using 13C and 31P-NMR spectra, powder XRD experiments, as well as differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) methods. The exo-effects at 193 ± 8 °C for ethanol soluble BDP-1 samples (-19.7 ± 0.2 kJ?mol-1) were about three times less than for ethanol insoluble BDP-2 samples f (-70.5 ± 0.7 kJ?mol-1). The DSC curves of Na-BDP-1 and Na-BDP-2 characterized the endo-effects having a maximum at 95?112 °C. Water-soluble Na-BDP-1 was obtained as needle-like crystals, unlike poorly crystalline Na-BDP-2, whereas BDP-1 and BDP-2 aged with time and were isolated as amorphous substances. In vitro experiments on rats showed that compared to the control, Na-BDP-1 increased catalase and SOD activity and improved energy metabolism more effectively than Na-BDP-2.
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Project description:PurposeIt is hypothesized that sodium acetate (SA) can be used for in situ coating of drug loaded chitosan NPs for improved physico-chemical properties.MethodsTenofovir (TFV) is used as a model drug. Uncoated chitosan NPs are prepared by ionic gelation. SA is generated in situ from half neutralization of acetic acid with sodium hydroxide, and coats chitosan NPs during freeze-drying. The NPs' physico-chemical properties [e.g., particle mean diameters (PMD) zeta potential (ζ), EE%, drug release profile, morphology] are characterized by dynamic light scattering, spectrophotometry, Korsmeyer-Peppas model, transmission electron microscopy (TEM), respectively. Melting point (MP), non-aqueous titration, Fourier transform infrared (FTIR) analysis, and powder X-ray diffractometry (XRD) pattern evaluate the SA coated chitosan NPs. The NPs' cytotoxicity on macrophages Raw 264.7 is assessed by neutral red, resazurin, nitrite oxide (NO) and cytokines assays.ResultsCollectively, FTIR, ζ, XRD, MP, and TEM data confirm that SA coats chitosan NPs. The PMD range is 136-348 nm (uncoated) and 171-379 nm (coated NPs). The ζ values range is +24.3-28.5 mV (uncoated) and 0.1-3.1 mV (coated NPs). The EE% ranges from 5.5 to 11.7% (uncoated NPs) and increased up to 86.3-92.7%(8-17-fold) after coating. The SA also prevents NPs aggregation during the freeze-drying and aqueous dispersion. The core-shell NPs exhibited a sustain release of TFV following anomalous transport mechanism (R(2) ~ 0.99). The coated NPs are non-cytotoxic (cell viability ~100%) and without any proinflammatory response.ConclusionsThis SA coating chitosan NPs mechanism may be useful for (i) efficient encapsulation, (ii) stabilizing colloidal dispersions, (iii) controlling the release and solubility of bioactive agents.
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Project description:In this paper, the results on the fabrication of ferroelectric membranes as vascular patches with modified surfaces are presented. For the modification of a membrane surface contacting blood, DLC coating was deposited using the pulsed vacuum arc deposition technique. The physico-chemical properties and cytotoxicity of the membranes modified under various conditions were studied. It was found that DLC coatings do not affect membrane microstructure, preserving its crystal structure as well as its high strength and elongation. It was revealed that an increase in the capacitor storage voltage results in the rise in sp2- and sp-hybridized carbon concentration, which makes it possible to control the chemical structure and surface energy of the modified surface. The experiments with 3T3L1 fibroblasts showed no toxic effects of the materials extracts.
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Project description:Interaction of serum proteins and nanoparticles leads to a nanoparticle-protein complex formation that defines the rational strategy for a clinically relevant formulation for drug delivery, hyperthermia, and magnetic resonance imaging (MRI) applications in cancer nanomedicine. Given this perspective, we have examined the pattern of human serum protein corona formation with our recently engineered magnetic nanoparticles (MNPs). The alteration in particle size, zeta potential, hemotoxicity, cellular uptake/cancer cells targeting potential, and MRI properties of the MNPs after formation of human serum (HS) protein corona were studied. Our results indicated no significant change in particle size of our MNPs upon incubation with 0.5-50 wt/v% human serum, while zeta potential of MNPs turned negative due to human serum adsorption. When incubated with an increased serum and particle concentration, apolipoprotein E was adsorbed on the surface of MNPs apart from serum albumin and transferrin. However, there was no significant primary or secondary structural alterations observed in serum proteins through Fourier transform infrared spectroscopy, X-ray diffraction, and circular dichroism. Hemolysis assay suggests almost no hemolysis at the tested concentrations (up to 1 mg/mL) for MNPs compared to the sodium dodecyl sulfate (positive control). Additionally, improved internalization and uptake of MNPs by C4-2B and Panc-1 cancer cells were observed upon incubation with human serum (HS). After serum protein adsorption to the surface of MNPs, the close vicinity within T1 (?1.33-1.73 s) and T2 (?12.35-13.43 ms) relaxation times suggest our MNPs retained inherent MRI potential even after biomolecular protein adsorption. All these superior clinical parameters potentially enable clinical translation and use of this formulation for next generation nanomedicine for drug delivery, cancer-targeting, imaging and theranostic applications.
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Project description:Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration.
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