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Nihon Ronen Igakkai Zasshi. Japanese... Nov 1992The serum protein-binding of 12 representative cephems (CET, CEZ, CZX, CPZ, CZON, CPM, CDZM, CFX, CMZ, CTT, LMOX, FMOX) was assessed, using sera from young healthy...
The serum protein-binding of 12 representative cephems (CET, CEZ, CZX, CPZ, CZON, CPM, CDZM, CFX, CMZ, CTT, LMOX, FMOX) was assessed, using sera from young healthy subjects (mean age, 28.6 years old) and elderly healthy subjects (mean age, 69.7 years old), applying equilibrium dialysis under the same conditions in vitro. The protein-binding capacity of 12 cephems in elderly subjects was significantly less than that in young subjects, and marked increase in free drug concentration was observed in elderly subjects. This decrease in the protein binding capacity of cephems in elderly subjects was possibly caused by decreased serum albumin and change in non-esterified fatty acid constitution related to aging. As free-drug concentration participates in the appearance of effects and adverse reactions, the possibility of an enhanced pharmacological effects and increased adverse reactions of cephems due to decrease of protein binding in elderly subjects should be considered.
Topics: Adult; Aged; Blood Proteins; Cephalosporins; Fatty Acids, Nonesterified; Humans; Male; Protein Binding
PubMed: 1491484
DOI: 10.3143/geriatrics.29.874 -
Journal of Cellular Physiology Sep 2005Protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and in the replication of pathogen organisms in host cells.... (Review)
Review
Protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and in the replication of pathogen organisms in host cells. Thus, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and microbial targets. In the past few years, attempts to inhibit protein-protein interactions using antibodies, peptides, and synthetic or natural small molecules have met with varying degrees of success, and these will be the focus of this review.
Topics: Animals; Apoptosis; Drug Design; Humans; Ligands; Protein Binding; Proteins
PubMed: 15880642
DOI: 10.1002/jcp.20356 -
Journal of Pharmaceutical Sciences Nov 2019Significant advances have been made over the years to accurately measure plasma protein binding (PPB) of highly bound compounds. However, because of perceived...
Significant advances have been made over the years to accurately measure plasma protein binding (PPB) of highly bound compounds. However, because of perceived uncertainty based on historical suboptimal methods and limitation of radiochemical purity of radiolabeled materials, current regulatory guidelines recommend using an arbitrary cutoff fraction unbound (f) of 0.01 as the lower limit for drug-drug interaction (DDI) prediction. This can result in significant overprediction of DDI for highly bound compounds, unnecessary DDI clinical trials and more restrictive drug product labels. To build confidence in the accuracy of PPB measurement for highly bound compounds, 2 orthogonal methods, equilibrium dialysis and ultracentrifugation, are assessed in this study to measure PPB of 10 highly bound drugs (f < 0.01). The results show that the 2 very different methods yield comparable f values, generally within 2-fold of each other. The data suggest that PPB of highly bound compounds can be measured accurately using current state-of-art methods, and the experimental f should be used for DDI prediction to provide a more realistic evaluation of DDI risk in the clinic.
Topics: Blood Proteins; Drug Interactions; Humans; Male; Plasma; Protein Binding; Ultracentrifugation
PubMed: 31419399
DOI: 10.1016/j.xphs.2019.08.004 -
BMC Genomics Dec 2015Francisella tularensis is a select bio-threat agent and one of the most virulent intracellular pathogens known, requiring just a few organisms to establish an infection....
BACKGROUND
Francisella tularensis is a select bio-threat agent and one of the most virulent intracellular pathogens known, requiring just a few organisms to establish an infection. Although several virulence factors are known, we lack an understanding of virulence factors that act through host-pathogen protein interactions to promote infection. To address these issues in the highly infectious F. tularensis subsp. tularensis Schu S4 strain, we deployed a combined in silico, in vitro, and in vivo analysis to identify virulence factors and their interactions with host proteins to characterize bacterial infection mechanisms.
RESULTS
We initially used comparative genomics and literature to identify and select a set of 49 putative and known virulence factors for analysis. Each protein was then subjected to proteome-scale yeast two-hybrid (Y2H) screens with human and murine cDNA libraries to identify potential host-pathogen protein-protein interactions. Based on the bacterial protein interaction profile with both hosts, we selected seven novel putative virulence factors for mutant construction and animal validation experiments. We were able to create five transposon insertion mutants and used them in an intranasal BALB/c mouse challenge model to establish 50 % lethal dose estimates. Three of these, ΔFTT0482c, ΔFTT1538c, and ΔFTT1597, showed attenuation in lethality and can thus be considered novel F. tularensis virulence factors. The analysis of the accompanying Y2H data identified intracellular protein trafficking between the early endosome to the late endosome as an important component in virulence attenuation for these virulence factors. Furthermore, we also used the Y2H data to investigate host protein binding of two known virulence factors, showing that direct protein binding was a component in the modulation of the inflammatory response via activation of mitogen-activated protein kinases and in the oxidative stress response.
CONCLUSIONS
Direct interactions with specific host proteins and the ability to influence interactions among host proteins are important components for F. tularensis to avoid host-cell defense mechanisms and successfully establish an infection. Although direct host-pathogen protein-protein binding is only one aspect of Francisella virulence, it is a critical component in directly manipulating and interfering with cellular processes in the host cell.
Topics: Animals; Female; Francisella tularensis; Host-Pathogen Interactions; Mice; Mice, Inbred BALB C; Protein Binding; Virulence; Virulence Factors
PubMed: 26714771
DOI: 10.1186/s12864-015-2351-1 -
Current Topics in Medicinal Chemistry 2006
Topics: Cell Nucleus; Cytoplasm; Protein Binding; Protein Transport; Receptors, Calcitriol; Transcription, Genetic; Vitamin D
PubMed: 16848736
DOI: 10.2174/156802606777864944 -
Masui. the Japanese Journal of... Nov 2006
Review
[Description of anesthesia through the xenon binding response in a protein model under a pressure-of 2,000-anesthetic binding with low specificity produces resistance to pressure with the volume increase].
Topics: Anesthetics; Atmospheric Pressure; Models, Chemical; Protein Binding; Xenon
PubMed: 17458133
DOI: No ID Found -
Drug Discovery Today Mar 2010Protein-protein interactions (PPIs) are one of the next major classes of therapeutic targets, although they are too intricate to tackle with standard approaches. This is... (Review)
Review
Protein-protein interactions (PPIs) are one of the next major classes of therapeutic targets, although they are too intricate to tackle with standard approaches. This is due, in part, to the inadequacy of today's chemical libraries. However, the emergence of a growing number of experimentally validated inhibitors of PPIs (i-PPIs) allows drug designers to use chemoinformatics and machine learning technologies to unravel the nature of the chemical space covered by the reported compounds. Key characteristics of i-PPIs can then be revealed and highlight the importance of specific shapes and/or aromatic bonds, enabling the design of i-PPI-enriched focused libraries and, therefore, of cost-effective screening strategies.
Topics: Animals; Humans; Pharmaceutical Preparations; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping
PubMed: 19969101
DOI: 10.1016/j.drudis.2009.11.007 -
Current Pharmaceutical Design 2004In recent years, new strategies in cancer therapy have been developed targeting key signaling molecules in the receptor tyrosine kinase signal transduction pathway. In... (Review)
Review
In recent years, new strategies in cancer therapy have been developed targeting key signaling molecules in the receptor tyrosine kinase signal transduction pathway. In contrast, most therapeutical concepts to manipulate G protein-coupled receptors (GPCR)-mediated disorders are still limited to the use of receptor-specific agonists or antagonists. Visible progress in the understanding of GPCR signaling complexity, especially the detection of several families of highly target- and cell-specific regulator proteins of GPCRs, G proteins, and effector components may open new horizons to develop novel therapeutical concepts targeting GPCR signaling elements. Thus, this review will focus on different molecular levels that may be of particular interest in terms of new drug development such as: (i) GPCR subtypes, allosteric binding sites, dimerization and constitutive activity, the use of RAMPs (receptor-activity-modifying proteins) and RASSLs (receptor activated solely by synthetic ligands); (ii) AGS (activators of G protein signaling) and RGS (regulators of G protein signaling) proteins which modify G protein activity; (iii) the high diversity of isozymes involved in the generation, signal transmission, and degradation of second messenger molecules.
Topics: Animals; Drug Delivery Systems; GTP-Binding Proteins; Humans; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 15180530
DOI: 10.2174/1381612043384367 -
Physical Review. E Jul 2021Vesicle budding induced by protein binding that generates an isotropic spontaneous curvature is studied using a mean-field theory. Many spherical buds are formed via...
Vesicle budding induced by protein binding that generates an isotropic spontaneous curvature is studied using a mean-field theory. Many spherical buds are formed via protein binding. As the binding chemical potential increases, the proteins first bind to the buds and then to the remainder of the vesicle. For a high spontaneous curvature and/or high bending rigidity of the bound membrane, it is found that a first-order transition occurs between a small number of large buds and a large number of small buds. These two states coexist around the transition point. The proposed scheme is simple and easily applicable to many interaction types, so we investigate the effects of interprotein interactions, the protein-insertion-induced changes in area, the variation of the saddle-splay modulus, and the area-difference-elasticity energy. The differences in the preferred curvatures for curvature sensing and generation are also clarified.
Topics: Biophysical Phenomena; Elasticity; Protein Binding; Proteins
PubMed: 34412221
DOI: 10.1103/PhysRevE.104.014410 -
Archives of Pharmacal Research Sep 2004The effects of glycyrrhizic acid (GLZ) on protein binding of diltiazem, verapamil, and nifedipine were investigated. Protein binding studies (human serum, human serum... (Comparative Study)
Comparative Study
The effects of glycyrrhizic acid (GLZ) on protein binding of diltiazem, verapamil, and nifedipine were investigated. Protein binding studies (human serum, human serum albumin (HSA) and alpha1-acid glycoprotein (AAG)) were conducted using the equilibrium dialysis method with and without addition of GLZ. The binding parameters, such as the number of moles of bound drug per mole of protein, the number of binding sites per protein molecule, and the association constant, were estimated using the Scatchard plot. The serum binding of nifedipine, verapamil, and diltiazem was displaced with addition of GLZ, and the decreases of Ks for serum were observed. GLZ decreased the association constants of three drugs for HSA and AAG, while the binding capacity remained similar with addition of GLZ. Although the characteristics of interaction were not clear, GLZ seemed to mainly affect HSA binding of nifedipine rather than AAG binding, while GLZ seemed to affect both AAG- and HSA-bindings of verapamil and diltiazem resulting in a serum binding displacement.
Topics: Diltiazem; Glycyrrhizic Acid; Humans; Male; Nifedipine; Protein Binding; Serum Albumin; Verapamil
PubMed: 15473671
DOI: 10.1007/BF02975854