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Dive into the research topics where Bengt Nordén is active.

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Featured researches published by Bengt Nordén.


The FASEB Journal | 2000

Peptide nucleic acid (PNA): its medical and biotechnical applications and promise for the future

Arghya Ray; Bengt Nordén

Synthetic molecules that can bind with high sequence specificity to a chosen target in a gene sequence are of major interest in medicinal and biotechnological contexts. They show promise for the development of gene therapeutic agents, diagnostic devices for genetic analysis, and as molecular tools for nucleic acid manipulations. Peptide nucleic acid (PNA) is a nucleic acid analog in which the sugar phosphate backbone of natural nucleic acid has been replaced by a synthetic peptide backbone usually formed from N‐(2‐amino‐ethyl)‐glycine units, resulting in an achiral and uncharged mimic. It is chemically stable and resistant to hydrolytic (enzymatic) cleavage and thus not expected to be degraded inside a living cell. PNA is capable of sequence‐specific recognition of DNA and RNA obeying the Watson‐Crick hydrogen bonding scheme, and the hybrid complexes exhibit extraordinary thermal stability and unique ionic strength effects. It may also recognize duplex homopurine sequences of DNA to which it binds by strand invasion, forming a stable PNA–DNA–PNA triplex with a looped‐out DNA strand. Since its discovery, PNA has attracted major attention at the interface of chemistry and biology because of its interesting chemical, physical, and biological properties and its potential to act as an active component for diagnostic as well as pharmaceutical applications. In vitro studies indicate that PNA could inhibit both transcription and translation of genes to which it has been targeted, which holds promise for its use for antigene and antisense therapy. However, as with other high molecular mass drugs, the delivery of PNA, involving passage through the cell membrane, appears to be a general problem.—Ray, A., Norden, B. Peptide nucleic acid (PNA): its medical and biotechnical applications and promise for the future. FASEB J. 14, 1041–1060 (2000)


Biochemical and Biophysical Research Communications | 2003

Uptake of analogs of penetratin, Tat(48-60) and oligoarginine in live cells.

Per E. G. Thoren; Daniel Persson; Petter Isakson; Mattias Goksör; Agneta Önfelt; Bengt Nordén

Cell-penetrating peptides are regarded as promising vectors for intracellular delivery of large, hydrophilic molecules, but their mechanism of uptake is poorly understood. Since it has now been demonstrated that the use of cell fixation leads to artifacts in microscopy studies on the cellular uptake of such peptides, much of what has been considered as established facts must be reinvestigated using live (unfixed) cells. In this work, the uptake of analogs of penetratin, Tat(48-60), and heptaarginine in two different cell lines was studied by confocal laser scanning microscopy. For penetratin, an apparently endocytotic uptake was observed, in disagreement with previous studies on fixed cells found in the literature. Substitution of the two tryptophan residues, earlier reported to be essential for cellular uptake, did not alter the uptake characteristics. A heptaarginine peptide, with a tryptophan residue added in the C-terminus, was found to be internalized by cells via an energy-independent, non-endocytotic pathway. Finally, a crucial role for arginine residues in penetratin and Tat(48-60) was demonstrated.


Quarterly Reviews of Biophysics | 1992

Linear dichroism spectroscopy of nucleic acids.

Bengt Nordén; Mikael Kubista; Tomas Kurucsev

This review will consider solution studies of structure and interactions of DNA and DNA complexes using linear dichroism spectroscopy, with emphasis on the technique of orientation by flow. The theoretical and experimental background to be given may serve, in addition, as a general introduction into the state of the art of linear dichroism spectroscopy, particularly as it is applied to biophysical problems.


FEBS Letters | 2000

The antennapedia peptide penetratin translocates across lipid bilayers - the first direct observation.

Per E. G. Thoren; Daniel Persson; Mattias Karlsson; Bengt Nordén

The potential use of polypeptides and oligonucleotides for therapeutical purposes has been questioned because of their inherently poor cellular uptake. However, the 16‐mer oligopeptide penetratin, derived from the homeodomain of Antennapedia, has been reported to enter cells readily via a non‐endocytotic and receptor‐ and transporter‐independent pathway, even when conjugated to large hydrophilic molecules. We here present the first study where penetratin is shown to traverse a pure lipid bilayer. The results support the idea that the uptake mechanism involves only the interaction of the peptide with the membrane lipids. Furthermore, we conclude that the translocation does not involve pore formation.


Applied Spectroscopy Reviews | 1978

Applications of linear Dichroism Spectroscopy

Bengt Nordén

Linear dichroism is the phenomenon of anisotropic absorption of light. It is shown by materials containing oriented molecules for which the absorption varies with the direction. The absorption intensity is proportional to the square of the scalar product between the electric field vector of the light and a molecule-characteristic transition moment vector, the absorption being maximum when the light vector is polarized parallel to the transition moment and zero when perpendicular to it. Linear dichroism can therefore provide (1) directions of transition moments when the molecule orientation is known (spectroscopic applications), or (2) information on molecular orientation when the transition moments are known (structural applications). Both applications are useful in several chemical systems, but so far the use of linear dichroism has been confined to a relatively small number of specialized laboratories, not least because of a lack of appropriate commercial instruments. Plane-polarized spectra have long been measured on crystals and other well-oriented materials, but systems with less complete orientation have usually been studied by birefringence which has allowed greater sensitivity. Birefringence and linear dichroism are related by the dispersion equations and therefore in principle contain the same basic information. However, linear dichroism is better suited for practical use since it is related in a very simple way to more-or-less well-separated quantal transitions, while birefringence is a complicated average over all transitions in the molecule.


Biochemistry | 2012

Effects of tryptophan content and backbone spacing on the uptake efficiency of cell-penetrating peptides.

Hanna Rydberg; Maria Matson; Helene L. Åmand; Elin K. Esbjörner; Bengt Nordén

Cell-penetrating peptides (CPPs) are able to traverse cellular membranes and deliver macromolecular cargo. Uptake occurs through both endocytotic and nonendocytotic pathways, but the molecular requirements for efficient internalization are not fully understood. Here we investigate how the presence of tryptophans and their position within an oligoarginine influence uptake mechanism and efficiency. Flow cytometry and confocal fluorescence imaging are used to estimate uptake efficiency, intracellular distribution and toxicity in Chinese hamster ovarian cells. Further, membrane leakage and lipid membrane affinity are investigated. The peptides contain eight arginine residues and one to four tryptophans, the tryptophans positioned either at the N-terminus, in the middle, or evenly distributed along the amino acid sequence. Our data show that the intracellular distribution varies among peptides with different tryptophan content and backbone spacing. Uptake efficiency is higher for the peptides with four tryptophans in the middle, or evenly distributed along the peptide sequence, than for the peptide with four tryptophans at the N-terminus. All peptides display low cytotoxicity except for the one with four tryptophans at the N-terminus, which was moderately toxic. This finding is consistent with their inability to induce efficient leakage of dye from lipid vesicles. All peptides have comparable affinities for lipid vesicles, showing that lipid binding is not a decisive parameter for uptake. Our results indicate that tryptophan content and backbone spacing can affect both the CPP uptake efficiency and the CPP uptake mechanism. The low cytotoxicity of these peptides and the possibilities of tuning their uptake mechanism are interesting from a therapeutic point of view.


Biopolymers | 1991

The CD of ligand‐DNA systems. 2. Poly(dA‐dT) B‐DNA

Reidar Lyng; Alison Rodger; Bengt Nordén

A systematic theoretical study of the CD of [poly(dA‐dT)]2 and its complexes with achiral small molecules is presented. The CD spectra of [poly(dA‐dT)]2 and of poly(dA):poly(dT) are calculated for various DNA structures using the matrix method. The calculated and experimental spectra agree reasonably well for [poly(dA‐dT)]2 but less well for poly (dA):poly (dT). The calculated CD spectrum of [poly (dA‐dT)]2 fails to reproduce the wavelength region of 205–245 nm of the experimental spectrum. This discrepancy can be explained by a magnetic dipole allowed transition contributing significantly to the CD spectrum in this region. The induced CD of a transition moment of a molecule bound to [poly (dA‐dT)]2 is also calculated. As was the case for [poly(dG‐dC)]2, the induced CD of a groove bound molecule is one order of magnitude stronger than that of an intercalated molecule. The calculations also show considerable differences between pyrimidine‐purine sites and purine‐pyrimidine sites. Both signs and magnitudes of the CD induced into ligands bound in the minor groove agree with experimental observations.


FEBS Letters | 1995

Phospholipid membrane permeability of peptide nucleic acid.

Pernilla Wittung; Johan Kajanus; Katarina Edwards; Peter E. Nielsen; Bengt Nordén; Bo G. Malmström

Phospholipid vesicles (liposomes) as membrane models have been used to study the penetration properties of peptide nucleic acid (PNA), a new DNA analog in which the nucleobases are attached to a pseudo‐peptide backbone. The liposomes were characterised by carboxyfluorescein efflux, light‐scattering and cryogenic transmission electron microscopy. The liposome structure was found not to be affected by the incorporation of PNA or an oligonucleotide. Two 10‐mer fluorescein‐labelled PNAs were found to have low efflux rates (half‐times of 5.5 and 11 days), comparable to a 10‐mer oligonucleotide (half‐time of 7 days). We conclude that passive diffusion of unmodified PNA is not an effective way of transport into biological cells.


Methods in Enzymology | 2001

Linear and circular dichroism of drug-nucleic acid complexes

Magdalena Eriksson; Bengt Nordén

Publisher Summary Polarized light spectroscopy offers possibilities to quickly characterize nucleic acids and their complexes with bound proteins or drug molecules, using a relatively small amount of sample. Linear dichroism (LD) provides structure information in terms of relative orientation between the bound drug molecule and the DNA molecular long axis, and also about the effects of ligand binding on the host. Circular dichroism (CD) may contribute additional structural details about such complexes. LD and CD, like other optical techniques, offer possibilities for rapid characterization of nucleic acid complexes using relatively small amounts of sample. The information that may be gained varies with the level of sophistication at which the measurements are carried out and interpreted. The presence of detectable LD thus, means that the ligand is bound to the oriented DNA, while the sign and amplitude of the LD signal contain information about the nature of the predominant binding mode. Use of complementary techniques, such as CD and fluorescence spectroscopy, may allow further conclusions regarding the structure and dynamics of DNA-ligand complexes. Nonchiral drug molecules (molecules that lack handedness and thereby optical activity) have no CD signal.


Molecular Pharmaceutics | 2010

Effects of PEGylation and acetylation of PAMAM dendrimers on DNA Binding, cytotoxicity and in vitro transfection efficiency

Kristina Fant; Elin K. Esbjörner; Alan Jenkins; Martin C. Grossel; Per Lincoln; Bengt Nordén

Poly(amidoamine) (PAMAM) dendrimers are promising multipotent gene delivery vectors, providing favorable DNA condensation properties also in combination with the possibility of conjugation of different targeting ligands to their surface. They have been used for transfection both in vitro and in vivo, but their application is currently somewhat limited due to inherent cytotoxicity. In this work we investigate how two types of surface modification, acetylation and PEGylation, affect the DNA binding characteristics, the cytotoxicity and the in vitro transfection efficiency of generation 4 and 5 PAMAM dendrimers. Particularly, we address how the morphology of DNA-dendrimer complexes, formed under low salt conditions, changes upon dilution in cell growth medium, an event that inevitably occurs before the complexes reach the cell surface in any transfection experiment. We find that acetylation and PEGylation essentially eliminates the inherent dendrimer cytotoxicity. However, the transfection efficiency of the modified dendrimers is lower than that of the corresponding unmodified dendrimers, which can be rationally understood by our observations that DNA is less condensed when complexed with these modified dendrimers. Although small DNA-dendrimer particles are formed, the availability for ethidium intercalation and nuclease degradation is significantly higher in the modified DNA-dendrimer complexes than in unmodified ones. Dilution in cell growth medium has a drastic effect on these electrostatically assembled complexes, resulting in increase in size and DNA availability. Our results strongly add to the notion that it is of importance to perform a biophysical characterization under conditions as close to the transfection situation as possible, to enable conclusions regarding structure-activity relations of gene delivery vectors.

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Per Lincoln

Chalmers University of Technology

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Mikael Kubista

Academy of Sciences of the Czech Republic

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Bo Albinsson

Chalmers University of Technology

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L. Marcus Wilhelmsson

Chalmers University of Technology

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