ChemInform Abstract: Synthesis and Metal-Templated Assembly of Oxazole and Thiazole-Based Amino Acids. Total Synthesis of Nostocyclamide (Ia) and Related Cyclic Peptides (original) (raw)
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Journal of Peptide Science, 2004
The mucin-2 (MUC2) glycoprotein secreted by the epithelial cells of human colon may be abnormally under-glycosylated in the case of cancer. Monoclonal antibody (mAb) 994 raised against the immunogenic part of the protein core, recognizes malignant human colon tissues as well as pentapeptides with TX 1 TX 2 T motif present in MUC2. Using a combinatorial approach and ELISA experiments it was found that mAb 994 is able to recognize peptides of the sub-library TQTX 2 T very strongly, and to some extent also peptides from TETX 2 T, TLTX 2 T and TVTX 2 T sub-libraries. Binding studies with peptides corresponding to the TQTX 2 T and TETX 2 T sub-libraries showed that mAb 994 recognized only six peptides (IC 50 = 9-208 µmol dm −3 ) from the 19 compounds of the TQTX 2 T sub-library and only three peptides (IC 50 = 3500-16700 µmol dm −3 ) from the 'second-best' TETX 2 T sub-library. The most pronounced mAb binding occurred when Gln was in position X 1 and it was much weaker in the case of Glu, Val or Leu. As for X 2 amino acids, the presence of Pro, Ala can provide a strong, while Tyr, Trp, Phe and Ser a weaker, peptide-antibody interaction. Data from this study suggest that pentapeptide TQTPT, whose sequence is present in the native protein, is bound most strongly. However, almost identical binding properties were observed with peptide TQTAT, whose sequence is not present in the protein. Apart from this, some other 'heteroclitic' peptides were found with a different rank in the binding-hierarchy. Based on these peptides artificial compounds can be prepared as potential candidates for vaccine development. Results of this study also provide a rationale for understanding the molecular background of the heteroclitic nature of the MUC2 protein core specific mAb 994.
Proceedings of the National Academy of Sciences, 2005
The stability of an immunogen against enzymatic degradation is considered an important factor for the design of synthetic vaccines. For our studies, we have selected an epitope from the tandemrepeat unit of the high-molecular-weight MUC2 mucin glycoprotein, which can be underglycosylated in case of colon cancer. In this study, we prepared a MUC2 peptide containing the PTGTQ epitope of a MUC2 protein backbone-specific mAb 996 and its derivatives. In these peptides, the N-and C-terminal flanking regions were systematically substituted by up to three D-amino acids. Peptides prepared by solid-phase synthesis were tested for their mAb 996 binding in competitive ELISA experiments, and their stability was studied in serum and lysosomal preparation. Our data show that the epitope function of peptide 15 TPTPTGTQTPT 25 is retained even in the presence of two D-amino acid residues at its N-terminal flanking region and up to three at its C-terminal flanking region (tpTPTGTQtpt). Also, this partly D peptide shows high resistance against proteolytic degradation in diluted human serum and in lysosomal preparation. These findings suggest that, by appropriate combination of structural modifications (namely, D-amino acid substitution) in the flanks of an Ab epitope, it is feasible to construct a synthetic antigen with preserved recognition properties and high stability against enzymatic degradation. Peptides tPTPTGTQTpt and tpTPTGTQTpt derived from this study can be used for immunization experiments and as potential components of synthetic vaccines for tumor therapy.
Peptide-directed crystal growth modification in the formation of ZnO
J. Mater. Chem. B, 2015
Biomolecule-mediated synthesis is fascinating in terms of the level of control and the intricate hierarchical structures of the materials that can be produced. In this study we compare the behavior of a phage display identified peptide, EAHVMHKVAPRP (EM-12) with that of a mutant peptide EAHVCHKVAPRP (EC-12), having additional complexation capability, on the formation of ZnO from solution. The synthesis conditions (Zn(CH 3 COO) 2 -NH 3 hydrothermal method at 50 1C) were chosen to generate rod-shaped ZnO via layered basic zinc salts (LBZs) as intermediates. Both peptides affected the crystal formation process by moderating the amount of Zn 2+ ions in solution (EC12 having a greater effect than EM12) but only EC12 was shown to interact with the solid phase(s) formed during the reaction. Depending on the peptide concentration used, EM-12 was shown to delay and/or suppress ZnO formation. In contrast, additions of EC-12, although leading to the retention of higher levels of Zn 2+ ions in solution did not similarly delay the transformation of the intermediate phases to ZnO but were found to dramatically modify the morphology of ZnO crystallites with mushroom shaped crystals being formed. From the results of detailed materials characterization and changes in the morphology observed, the interactions between the peptide(s) and solution and solid state species present during the process of ZnO crystal formation in the presence of EM-12 and EC-12 are proposed. † Electronic supplementary information (ESI) available: XPS analysis for the study of the ubiquitous carbonaceous contamination, and XPS data including the relative ratio of Zn/O and BE (eV) for O 1s, C 1s and Zn 2p 3/2 for samples analyzed; calibration curves used for peptide quantification in solution; calculated pK a of peptide side chains using Marvin calculator; Zn 2+ in solution for EC-12-added reactions; XRD and TGA results for 24 hour-precipitates produced in the presence of EC-12; dimension analysis of ZnO crystals obtained from EM-12added reactions (48 hours); lattice strain modification for ZnO planes in the presence of EC-12; and mass spectra for peptides. See
Carrier design: biodistribution of branched polypeptides with a poly(L-lysine) backbone
Bioconjugate Chemistry, 1990
The biodistribution has been examined in mice of a range of synthetic branched polypeptides which are based on a polylysine backbone but which differ in ionic charge, side-chain structure, and molecular size. Polycationic polypeptides, regardless of their size or primary structure at the branches, were cleared rapidly from the circulation, the liver being the major site of clearance. Polypeptides with glutamic acid in the side chain, which would be amphoteric under physiological conditions, showed a significantly prolonged blood survival, and this was seen with polypeptides in the range of molecular weights of 46 000 up to 213 000. Such polypeptides provide a useful system with which to investigate the effect of structural parameters on the pharmacokinetic properties of carrier molecules and would allow the selection of candidate carriers for a variety of uses.
Journal of Peptide Science, 1999
A comparative study has been undertaken between Hmb-protected amino acid and pseudoproline building block analogues for use in the solid phase synthesis of 'difficult' peptides. Both of these derivatives act by blocking inter-and intramolecular hydrogen bonding, which has been shown to be a major cause of poor synthesis/quality/efficiency. While the two were shown to result in substantial improvements in the purity of crude peptides, pseudoproline incoporation was found to be superior to Hmb backbone protection. This was due to slow and incomplete coupling of the amino acid immediately following the Hmb amino acid.
The Journal of Immunology, 2011
Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association. (2009) An investigation into the in vitro and in vivo fate of acyl glucuronides. British Pharmacology Society Winter Meeting; 2009 Dec 15-17; London, UK. British Pharmacology Society; http://www.pA2online.org/abstracts/ Vol7Issue4abst074P.pdf; Hammond TG, Regan SL, Meng X, Maggs JL, Jenkins RE, Kenna GL, Sathish JG, Williams DP, and Park BK (2010) Protein binding and pharmacokinetics of reactive acyl glucuronide drug metabolites, in Toxicology; (2011) In vitro assessment of the interactions between acyl glucuronide drug metabolites and human serum albumin. British Pharmacology Society Winter Meeting; 2010 14-16 Dec; London, UK. British Pharmacology Society; http://www.pA2online.org/abstracts/ Vol8Issue1abst019P.pdf; Hammond TG, Regan SL, Meng X, Maggs JL, Jenkins RE, Kenna JG, Sathish JG, Williams DP, and Park BK (2011) In vitro assessment of the interactions between diclofenac and tolmetin acyl glucuronide drug metabolites and human serum albumin, in Toxicology;
Elucidation of the Role of Nitrogenous Wort Components in Yeast Fermentation
Journal of the Institute of Brewing, 2007
The Free Amino Nitrogen (FAN) content of wort prescribes efficient yeast cell growth and fermentation performance. FAN consists of the individual amino acids, small peptides and ammonia ions formed during malting, the relative amounts of which vary. In this paper, the individual constituents of FAN were dissected and their effect on both ale and lager fermentations determined. The patterns of amino acid and small peptide uptake and the changes in extracellular protease activity revealed the dynamic environment that develops during fermentation. Lysine and methionine, previously identified as key amino acids in wort fermentation, were investigated further.
Biopolymers, 2006
Traditionally, solid-phase synthesis has relied on polystyrene-based resins for the synthesis of all kinds of peptides. However, due to their high hydrophobicity, these resins have certain limitations, particularly in the synthesis of complex peptides, and in such cases, poly(ethylene glycol) (PEG)-based resins are often found to give superior results. Another powerful strategy for expediting the assembly of complex peptides is to employ pseudoproline dipeptides. These derivatives disrupt the interactions among chains that are usually the cause of poor coupling yields in aggregated sequences. Here we report on an efficient stepwise solid-phase synthesis of RANTES (1-68) by combining the advantages of the totally PEG-based ChemMatrix 1 resin and pseudoproline dipeptides. #
Role of VGF-Derived Peptides in the Control of Food Intake, Body Weight and Reproduction
Neuroendocrinology, 2008
selection of this clone from plate V of an NGF-induced PC12 cell cDNA library [1] and should not be confused with VEGF (vascular endothelial growth factor). Unlike other gene products induced by NGF, such as c-fos , VGF is unusual in that it is induced robustly and relatively selectively by neurotropic growth factors, and is synthesized exclusively in neuronal and neuroendocrine cells . VGF is processed into a number of smaller peptides by neuroendocrine specific prohormone convertases PC1/3 and PC2 . VGF mRNA is widely expressed throughout the brain, particularly the arcuate nucleus (ARC) and the paraventricular nucleus (PVN) of the hypothalamus. Immunohistochemical studies have shown that VGF immunoreactive peptides are also produced in peripheral tissues including the pituitary, adrenal, pancreas and gastrointestinal tract. VGF-derived peptides were first implicated in the regulation of energy balance following the development of mice lacking a functional copy of the vgf gene (VGF -/-) [8] . These mice are lean and small, with reduced abdominal fat stores and low leptin levels, and correspondingly high levels of activity and metabolic rate . Subsequently, a number of studies have demonstrated changes in VGF gene expression in states of altered energy balance, and have demonstrated effects of VGF-derived peptides on caloric intake and energy expenditure. Here we review the role of VGF and the processed peptides in the control of food intake and body weight as well as reproduction.