The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Peter B. Dervan - One of the best experts on this subject based on the ideXlab platform.
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α-Diaminobutyric Acid-Linked Hairpin Polyamides
Bioorganic & Medicinal Chemistry, 2007Co-Authors: Michelle E. Farkas, Sherry M. Tsai, Peter B. DervanAbstract:A hairpin Polyamide-chlorambucil conjugate linked by α-diaminobutyric acid (α-DABA) has been shown to have interesting biological properties in cellular and small animal models. Remarkably, this new class of hairpin Polyamides has not been previously characterized with regard to energetics and sequence specificity. Herein we present a series of pyrrole-imidazole hairpin Polyamides linked by α-DABA and compare them to Polyamides containing the standard γ-DABA turn unit. The α-DABA hairpins have overall decreased binding affinities. However, α-DABA Polyamide-chlorambucil conjugates are sequence-specific DNA alkylators with increased specificities. Affinity cleavage studies of α-DABA Polyamide-EDTA conjugates confirmed their preference for binding DNA in a forward hairpin conformation. In contrast, an unsubstituted glycine-linked Polyamide prefers to bind in an extended binding mode. Thus, substitution on the turn unit locks the α-DABA Polyamide into the forward hairpin binding motif.
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Improved nuclear localization of DNA-binding Polyamides
Nucleic Acids Research, 2006Co-Authors: Nicholas G. Nickols, Michelle E. Farkas, Claire S. Jacobs, Peter B. DervanAbstract:Regulation of endogenous genes by DNA-binding Polyamides requires effective nuclear localization. Previous work employing confocal microscopy to study uptake of fluorophore-labeled Polyamides has demonstrated the difficulty of predicting a priori the nuclear uptake of a given Polyamide. The data suggest that dye identity influences uptake sufficiently such that a dye-conjugate cannot be used as a proxy for unlabeled analogs. Polyamides capable of nuclear localization unaided by fluorescent dyes are desirable due to size and other limitations of fluorophores. Recently, a Polyamide-fluorescein conjugate targeted to the hypoxia response element (HRE) was found to inhibit vascular endothelial growth factor (VEGF) expression in cultured HeLa cells. The current study uses inhibition of VEGF expression as a biological read-out for effective nuclear localization of HRE-targeted Polyamides. We synthesized a focused library of non-fluorescent, HRE-targeted Polyamides in which the C-terminus ‘tail’ has been systematically varied. Members of this library bind the HRE with affinities comparable or superior to that of the fluorescein-labeled analog. Although most library members demonstrate modest or no biological activity, two non-fluorescent Polyamides are reported with activity rivaling that of the previously reported fluorescein-labeled Polyamide. We also show evidence that promoter occupancy by HIF-1, the transcription factor that binds the HRE, is inhibited by HRE-targeted Polyamides.
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Accessibility of nuclear chromatin by DNA binding Polyamides.
Chemistry & Biology, 2003Co-Authors: Brigitte Dudouet, Ryan Burnett, Liliane A. Dickinson, Malcolm R. Wood, Christian Melander, Jason M. Belitsky, Benjamin S. Edelson, Nicholas R. Wurtz, Christoph A. Briehn, Peter B. DervanAbstract:Pyrrole-imidazole Polyamides bind DNA with affinities comparable to those of transcriptional regulatory proteins and inhibit the DNA binding activities of components of the transcription apparatus. If Polyamides are to be useful for the regulation of gene expression in cell culture experiments, one pivotal issue is accessibility of specific sites in nuclear chromatin. We first determined the kinetics of uptake and subcellular distribution of Polyamides in lymphoid and myeloid cells using fluorescent Polyamide-bodipy conjugates and deconvolution microscopy. Then cells were incubated with a Polyamide-chlorambucil conjugate, and the sites of specific DNA cleavage in the nuclear chromatin were assayed by ligation-mediated PCR. In addition, DNA microarray analysis revealed that two different Polyamides generated distinct transcription profiles. Remarkably, the Polyamides affected only a limited number of genes.
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Regulation of gene expression by small molecules.
Nature, 1997Co-Authors: Joel M Gottesfeld, E E Baird, John W Trauger, Leslie Neely, Peter B. DervanAbstract:Small molecules that target specific DNA sequences have the potential to control gene expression. Ligands designed for therapeutic application must bind any predetermined DNA sequence with high affinity and permeate living cells. Synthetic Polyamides containing N-methylimidazole and N-methylpyrrole amino acids have an affinity and specificity for DNA comparable to naturally occurring DNA-binding proteins. We report here that an eight-ring Polyamide targeted to a specific region of the transcription factor TFIIIA binding site interferes with 5S RNA gene expression in Xenopus kidney cells. Our results indicate that pyrrole-imidazole Polyamides are cell-permeable and can inhibit the transcription of specific genes.
Klaus Drechsler - One of the best experts on this subject based on the ideXlab platform.
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Evaluating the potential of forming spot-welded layups out of fibre reinforced thermoplastic tape without previous consolidation
International Journal of Material Forming, 2019Co-Authors: Alexander Schug, Dennis Rinker, Roland Hinterhoelzl, Klaus DrechslerAbstract:With an automated tape laying machine like the Fiberforge RELAY2000, spot-welded 2D layups of unidirectional fibre reinforced thermoplastic tape can be produced within short time. The layup process is usually followed by a consolidation step to remove the air of the layup and to fuse the plies. After this, the preforms can be formed into 3D parts. As the consolidation step is very time and energy consuming, methods were investigated within this study to form carbon fibre reinforced Polyamide 6 layups without any previous consolidation. A variety of challenges during pre-heating, handling and forming may occur. To cope with this, a number of different approaches were compared in terms of processability and resulting part quality: 1. Additional ultrasonic spot-welds to improve the heating in an infrared oven. 2. Vacuum setup with polyimide films to remove air and improve the heat transfer between the plies. 3. Vacuum setup with Polyamide 6 films with the same aims as with the polyimide foil plus an improved formability. The quality of the formed parts was examined using thermography, microsections, void content and fibre volume fraction measurements. The reference were formed parts made of consolidated preforms. The evaluation revealed that the vacuum setup with Polyamide 6 films generated the best results that were also comparable to the reference. The additional matrix material caused a reduction of fibre volume fraction and an increase in thickness, but also enabled new possibilities for joining with other parts.
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Evaluating the potential of forming spot-welded layups out of fibre reinforced thermoplastic tape without previous consolidation
International Journal of Material Forming, 2019Co-Authors: Alexander Schug, Dennis Rinker, Roland Hinterhoelzl, Klaus DrechslerAbstract:© 2018 Springer-Verlag France SAS, part of Springer Nature With an automated tape laying machine like the Fiberforge RELAY2000, spot-welded 2D layups of unidirectional fibre reinforced thermoplastic tape can be produced within short time. The layup process is usually followed by a consolidation step to remove the air of the layup and to fuse the plies. After this, the preforms can be formed into 3D parts. As the consolidation step is very time and energy consuming, methods were investigated within this study to form carbon fibre reinforced Polyamide 6 layups without any previous consolidation. A variety of challenges during pre-heating, handling and forming may occur. To cope with this, a number of different approaches were compared in terms of processability and resulting part quality: 1. Additional ultrasonic spot-welds to improve the heating in an infrared oven. 2. Vacuum setup with polyimide films to remove air and improve the heat transfer between the plies. 3. Vacuum setup with Polyamide 6 films with the same aims as with the polyimide foil plus an improved formability. The quality of the formed parts was examined using thermography, microsections, void content and fibre volume fraction measurements. The reference were formed parts made of consolidated preforms. The evaluation revealed that the vacuum setup with Polyamide 6 films generated the best results that were also comparable to the reference. The additional matrix material caused a reduction of fibre volume fraction and an increase in thickness, but also enabled new possibilities for joining with other parts.
Thangavel Vaijayanthi - One of the best experts on this subject based on the ideXlab platform.
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progress and prospects of pyrrole imidazole Polyamide fluorophore conjugates as sequence selective dna probes
ChemBioChem, 2012Co-Authors: Thangavel Vaijayanthi, Toshikazu Bando, Ganesh N Pandian, Hiroshi SugiyamaAbstract:Recently, the versatility of N-methylpyrrole (Py)-N-methylimidazole (Im) Polyamide conjugates, which have been developed from the DNA-binding antibiotics distamycin A and netropsin, has been shown. These synthetic small molecules can permeate cells to bind with duplex DNA in a sequence-specific manner, and hence can influence gene expression in vivo. Accordingly, several reports demonstrating the sequence specificity and biological activity of Py-Im Polyamides have accumulated. However, the benefits of Py-Im Polyamides, in particular those conjugated with fluorophores, has been overlooked. Moreover, clear directions for the employment of these attractive artificial small molecules have not yet been shown. Here, we present a detailed overview of the current and prospective applications of Py-Im Polyamide-fluorophore conjugates, including sequence-specific recognition with fluorescence emission properties, and their potential roles in biological imaging.
Hiroshi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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progress and prospects of pyrrole imidazole Polyamide fluorophore conjugates as sequence selective dna probes
ChemBioChem, 2012Co-Authors: Thangavel Vaijayanthi, Toshikazu Bando, Ganesh N Pandian, Hiroshi SugiyamaAbstract:Recently, the versatility of N-methylpyrrole (Py)-N-methylimidazole (Im) Polyamide conjugates, which have been developed from the DNA-binding antibiotics distamycin A and netropsin, has been shown. These synthetic small molecules can permeate cells to bind with duplex DNA in a sequence-specific manner, and hence can influence gene expression in vivo. Accordingly, several reports demonstrating the sequence specificity and biological activity of Py-Im Polyamides have accumulated. However, the benefits of Py-Im Polyamides, in particular those conjugated with fluorophores, has been overlooked. Moreover, clear directions for the employment of these attractive artificial small molecules have not yet been shown. Here, we present a detailed overview of the current and prospective applications of Py-Im Polyamide-fluorophore conjugates, including sequence-specific recognition with fluorescence emission properties, and their potential roles in biological imaging.
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pharmacokinetic modeling and prediction of plasma pyrrole imidazole Polyamide concentration in rats using simultaneous urinary and biliary excretion data
Biological & Pharmaceutical Bulletin, 2009Co-Authors: Takashi Nagashima, Hiroshi Sugiyama, Takahiko Aoyama, Tsubasa Yokoe, Akiko Fukasawa, Noboru Fukuda, Takahiro Ueno, Hiroki Nagase, Yoshiaki MatsumotoAbstract:The use of urinary and/or biliary excretion data was considered as an alternative approach if the bioanalytical method lacked the appropriate sensitivity to adequately characterize the serum or plasma concentration–time profile. This approach is used for the analysis of plasma concentration–time profile under the lower limit of quantification (LLOQ) of various analytical instruments. The objective of this study was to develop a pharmacokinetic (PK) model that describes the plasma concentration–time profiles under LLOQ of HPLC using urinary and biliary excretion data. As model compounds, pyrrole (Py)-imidazole (Im) Polyamides 1035 (MW, 1035.12) and 1666 (MW, 1665.78) were used. The cumulative urinary excretions of Py-Im Polyamides 1035 and 1666 were 72.4±11.6 and 4.8±0.5% of the administered dose, respectively. The cumulative biliary excretion of Py-Im Polyamide 1035 was 4.3±0.4% of the administered dose, and Py-Im Polyamide 1666 was not detected. The plasma concentration–time profiles of Py-Im Polyamide 1035 were adequately described using linear and non-linear output compartments. The developed PK model could be used to describe the plasma concentration profiles using the linear output compartment interpreted as the urine compartment and the non-linear output compartment interpreted as the bile compartment. This PK model will be able to provide a more accurate prediction of the plasma concentration profiles under LLOQ.
Alexander Schug - One of the best experts on this subject based on the ideXlab platform.
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Evaluating the potential of forming spot-welded layups out of fibre reinforced thermoplastic tape without previous consolidation
International Journal of Material Forming, 2019Co-Authors: Alexander Schug, Dennis Rinker, Roland Hinterhoelzl, Klaus DrechslerAbstract:With an automated tape laying machine like the Fiberforge RELAY2000, spot-welded 2D layups of unidirectional fibre reinforced thermoplastic tape can be produced within short time. The layup process is usually followed by a consolidation step to remove the air of the layup and to fuse the plies. After this, the preforms can be formed into 3D parts. As the consolidation step is very time and energy consuming, methods were investigated within this study to form carbon fibre reinforced Polyamide 6 layups without any previous consolidation. A variety of challenges during pre-heating, handling and forming may occur. To cope with this, a number of different approaches were compared in terms of processability and resulting part quality: 1. Additional ultrasonic spot-welds to improve the heating in an infrared oven. 2. Vacuum setup with polyimide films to remove air and improve the heat transfer between the plies. 3. Vacuum setup with Polyamide 6 films with the same aims as with the polyimide foil plus an improved formability. The quality of the formed parts was examined using thermography, microsections, void content and fibre volume fraction measurements. The reference were formed parts made of consolidated preforms. The evaluation revealed that the vacuum setup with Polyamide 6 films generated the best results that were also comparable to the reference. The additional matrix material caused a reduction of fibre volume fraction and an increase in thickness, but also enabled new possibilities for joining with other parts.
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Evaluating the potential of forming spot-welded layups out of fibre reinforced thermoplastic tape without previous consolidation
International Journal of Material Forming, 2019Co-Authors: Alexander Schug, Dennis Rinker, Roland Hinterhoelzl, Klaus DrechslerAbstract:© 2018 Springer-Verlag France SAS, part of Springer Nature With an automated tape laying machine like the Fiberforge RELAY2000, spot-welded 2D layups of unidirectional fibre reinforced thermoplastic tape can be produced within short time. The layup process is usually followed by a consolidation step to remove the air of the layup and to fuse the plies. After this, the preforms can be formed into 3D parts. As the consolidation step is very time and energy consuming, methods were investigated within this study to form carbon fibre reinforced Polyamide 6 layups without any previous consolidation. A variety of challenges during pre-heating, handling and forming may occur. To cope with this, a number of different approaches were compared in terms of processability and resulting part quality: 1. Additional ultrasonic spot-welds to improve the heating in an infrared oven. 2. Vacuum setup with polyimide films to remove air and improve the heat transfer between the plies. 3. Vacuum setup with Polyamide 6 films with the same aims as with the polyimide foil plus an improved formability. The quality of the formed parts was examined using thermography, microsections, void content and fibre volume fraction measurements. The reference were formed parts made of consolidated preforms. The evaluation revealed that the vacuum setup with Polyamide 6 films generated the best results that were also comparable to the reference. The additional matrix material caused a reduction of fibre volume fraction and an increase in thickness, but also enabled new possibilities for joining with other parts.
