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Weak Affinity (weak + affinity)
Selected AbstractsImproved 2,4-Diarylthiazole-Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in PotencyCHEMMEDCHEM, Issue 9 2010Abstract Amide derivatives of 2,4-diarylthiazole-5-carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4-diphenyl-5-aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5-diaryl-1,2,4-thiadiazoles isolated as by-products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrPC) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrPC. [source] Glyconanomaterials: Synthesis, Characterization, and Ligand PresentationADVANCED MATERIALS, Issue 17 2010Xin Wang Abstract Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins. [source] Transient complexes of redox proteins: structural and dynamic details from NMR studiesJOURNAL OF MOLECULAR RECOGNITION, Issue 6 2004Miguel Prudêncio Abstract Redox proteins participate in many metabolic routes, in particular those related to energy conversion. Protein,protein complexes of redox proteins are characterized by a weak affinity and a short lifetime. Two-dimensional NMR spectroscopy has been applied to many redox protein complexes, providing a wealth of information about the process of complex formation, the nature of the interface and the dynamic properties of the complex. These studies have shown that some complexes are non-specific and exist as a dynamic ensemble of orientations while in other complexes the proteins assume a single orientation. The binding interface in these complexes consists of a small hydrophobic patch for specificity, surrounded by polar, uncharged residues that may enhance dissociation, and, in most complexes, a ring or patch of charged residues that enhances the association by electrostatic interactions. The entry and exit port of the electrons is located within the hydrophobic interaction site, ensuring rapid electron transfer from one redox centre to the next. Copyright © 2004 John Wiley & Sons, Ltd. [source] Immediate Posttransplantation Cotrimoxazole-Induced Immune ThrombocytopeniaAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010R. Caluwé Drug-induced immune thrombocytopenia (DITP) can be caused by numerous drugs. When this condition develops, platelet destruction results from binding of antibodies to normal platelets only in the presence of a sensitizing drug. A recently proposed model suggests that these drug-dependent antibodies are derived from a pool of naturally occurring antibodies with weak affinity for specific epitopes on certain platelet membrane glycoproteins. We describe here a case of DITP secondary to cotrimoxazole exposure in the immediate posttransplantation phase in a renal transplant recipient. Apart from heparin-induced thrombocytopenia, DITP posttransplantation has to the best of our knowledge never been described, perhaps because of its immune-mediated origin. Our case demonstrates that DITP can occur posttransplantation, that cotrimoxazole due to its intensive use in the transplanted population is one of the most likely causative agents and that a timely recognition and treatment might have important consequences for both graft and patient. [source] Pharmacological characterization of F-180: a selective human V1a vasopressin receptor agonist of high affinityBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2002Miriam Andrés The pharmacological properties of F-180, a vasopressin (VP) structural analogue, were determined on CHO cells expressing the different human vasopressin and oxytocin (OT) receptor subtypes. Binding experiments revealed that F-180 exhibited a high affinity for the human V1a receptor subtype (Ki=11 nM) and was selective for this receptor subtype. Functional studies performed on CHO cells expressing human V1a receptors indicate that similarly to AVP, F-180 can stimulate the accumulation of inositol phosphate. The activation constant (Kact) for both F-180 and AVP was 1.7 nM. F-180 was also an agonist for the human V2 and V1b receptor subtypes and an antagonist for the human OT receptor. Since marked species pharmacological differences for vasopressin receptors have been described, we studied the properties of F-180 on various mammalian species. F-180 showed high affinity and good selectivity for human and bovine V1a receptors, but weak affinity and non selective properties for rat V1a receptors. To assess the functional properties of F-180 on a native biological model, we performed studies on primary cultures of cells from bovine zona fasciculata (ZF). As AVP, F-180 stimulated inositol phosphate accumulation and cortisol secretion with similar efficiency. In conclusion, we demonstrate that F-180 is the first selective V1a agonist described for human and bovine vasopressin receptors. Therefore F-180 can be used as a powerful pharmacological tool to characterize the actions of vasopressin that are mediated by V1a receptor subtypes. British Journal of Pharmacology (2002) 135, 1828,1836; doi:10.1038/sj.bjp.0704634 [source] Glycochips from Polyanionic Glycopolymers as Tools for Detecting Shiga ToxinsCHEMBIOCHEM, Issue 17 2007Hirotaka Uzawa Dr. Abstract An alternating layer-by-layer adsorption methodology was applied to the assembly of glycochips by using synthetic polyanionic glycopolymers. Three glycochips carrying globobioside (Gb2), ,-lactoside (, -Lac), or , - D -mannoside (, -Man) residues were prepared, and used for the detection of Shiga toxins, Stx-1 and Stx-2, by using surface plasmon resonance (SPR). Using this method, we could confirm that both Stx-1 and Stx-2 show binding specificity for the Gb2 glycochip as well as a weak affinity for the , -Lac glycochip. The affinity constants of these toxins depended strongly on the sugar content of the Gb2 polymer used to prepare the glycochip. Greater affinity was observed for chips with a higher sugar content (up to 43,%) in the Gb2 glycopolymer. The maximal affinity constants of Stx-1 and Stx-2 (Ka=108,109,M,1) enabled highly sensitive and facile analysis (10 ng,mL,1, 30 min). When Gb2 glycopolymers were used as competitors, Stx-1 and Stx-2 behaved differently from one another in terms of their SPR response; this allowed us to perform discriminative analysis between the two toxins. [source] | |||||||||||||