FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Cell tracking with caged xenon: using cryptophanes as MRI reporters upon cellular internalization
Klippel, S., Döpfert, J., Jayapaul, J., Kunth, M., Rossella, F., Schnurr, M., Witte, C., Freund, C.; Schröder, L.
Angew Chem Int Ed Engl, 53:493-496
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: Caged xenon has great potential in overcoming sensitivity limitations for solution-state NMR detection of dilute molecules. However, no application of such a system as a magnetic resonance imaging (MRI) contrast agent has yet been performed with live cells. We demonstrate MRI localization of cells labeled with caged xenon in a packed-bed bioreactor working under perfusion with hyperpolarized-xenon-saturated medium. Xenon hosts enable NMR/MRI experiments with switchable contrast and selectivity for cell-associated versus unbound cages. We present MR images with 10(3) -fold sensitivity enhancement for cell-internalized, dual-mode (fluorescence/MRI) xenon hosts at low micromolar concentrations. Our results illustrate the capability of functionalized xenon to act as a highly sensitive cell tracer for MRI detection even without signal averaging. The method will bridge the challenging gap for translation to in vivo studies for the optimization of targeted biosensors and their multiplexing applications.

Ultrafast CEST imaging
Döpfert, J., Zaiss(*), M., Witte, C.; Schröder, L.
J Magn Reson, 243:47-53
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: We describe a new MR imaging method for the rapid characterization or screening of chemical exchange saturation transfer (CEST) contrast agents. It is based on encoding the chemical shift dimension with an additional gradient as proposed in previous ultrafast CEST spectroscopy approaches, but extends these with imaging capabilities. This allows us to investigate multiple compounds simultaneously with an arbitrary sample tube arrangement. The technique requires a fast multislice readout to ensure the saturation is not lost during data acquisition due to T1 relaxation. We therefore employ radial subsampling, acquiring only 10 projections per CEST image with a 128x128 matrix. To recover the images, we use a heuristic reconstruction algorithm that incorporates low rank and limited object support as prior knowledge. This way, we are able to acquire a spectral CEST data set consisting of 15 saturation offsets more than 16 times faster than compared with conventional CEST imaging.

Fast gradient-encoded CEST spectroscopy of hyperpolarized xenon
Döpfert, J., Witte, C.; Schröder, L.
Chemphyschem, 15:261-264
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: Breaking speed limits: The acquisition of xenon-129 Hyper-CEST spectra is drastically accelerated by utilizing gradients to encode the chemical shift dimension. The signal is increased by using repeated spin-echo refocussing. The additional application of a variable flip angle makes the experiment independent from a constant Xe redelivery.

Sensitivity enhancement of (Hyper-)CEST image series by exploiting redundancies in the spectral domain
Döpfert, J., Witte, C., Kunth, M.; Schröder, L.
Contrast media & molecular imaging, 9:100-107
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: CEST has proven to be a valuable technique for the detection of hyperpolarized xenon-based functionalized contrast agents. Additional information can be encoded in the spectral dimension, allowing the simultaneous detection of multiple different biosensors. However, owing to the low concentration of dissolved xenon in biological tissue, the signal-to-noise ratio (SNR) of Hyper-CEST data is still a critical issue. In this work, we present two techniques aiming to increase SNR by exploiting the typically high redundancy in spectral CEST image series: PCA-based post-processing and sub-sampled acquisition with low-rank reconstruction. Each of them yields a significant SNR enhancement, demonstrating the feasibility of the two approaches. While the first method is directly applicable to proton CEST experiments as well, the second one is particularly beneficial when dealing with hyperpolarized nuclei, since it distributes the non-renewable initial polarization more efficiently over the sampling points. The results obtained are a further step towards the detection of xenon biosensors with spectral Hyper-CEST imaging in vivo.

CLCN7 and TCIRG1 Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals
Barvencik(*), F., Kurth(*), I., Koehne(*), T., Stauber, T., Zustin(*), J., Tsiakas, K., Ludwig, C. F., Beil(*), F. T., Pestka(*), J. M., Hahn(*), M., Santer(*), R., Supanchart(*), C., Kornak(*9, U., Del Fattore(*), A., Jentsch, T. J., Teti(*), A., Schulz(*), A., Schinke(*), T.; Amling(*), M.
J Bone Miner Res, 29:982-991
(2014)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Chemical protein synthesis
Becker(*), C. F., Brik(*), A., Dawson(*), P.; Hackenberger, C. P.
J Pept Sci, 20:63
(2014)

Tags: Chemical Biology II (Hackenberger)

Safety, efficacy, and molecular mechanism of claudin-1-specific peptides to enhance blood-nerve-barrier permeability
Sauer(*), R. S., Krug(*), S. M., Hackel(*), D., Staat, C., Konasin(*), N., Yang(*), S., Niedermirtl(*), B., Bosten(*), J., Günther, R., Dabrowski, S., Doppler(*), K., Sommer(*), C., Blasig, I. E., Brack(*), A.; Rittner(*), H. L.
J Control Release, 185:88-98
(2014)

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: The blood-nerve barrier consists of the perineurium and endoneurial vessels. The perineurial barrier is composed of a basal membrane and a layer of perineurial cells sealed by tight junction proteins preventing e.g. application of analgesics for selective regional pain control. One of the barrier-sealing proteins in the blood-nerve barrier is claudin-1. Therefore, the claudin-1-peptidomimetics (C1C2), derived from the first extracellular loop (ECL1) on claudin-1 was developed. In this study, we further evaluated the expression of tight junction proteins in the perineurium in Wistar rats and characterized the specificity, in vivo applicability, mechanism of action as well as the biocompatibility of C1C2. In the perineurium, claudin-19, tricellulin and ZO-1, but no claudin-2, 3, 8 and -11 were expressed. C1C2 specifically bound to the ECL1 of claudin-1 and fluorescent 5,6-carboxytetramethylrhodamine-C1C2 was rapidly internalized. Opening the perineurium with C1C2 reduced the mRNA and protein expression of claudin-1 and increased small and macromolecule permeability into the peripheral nerve. Application of C1C2 facilitated regional analgesia using mu-opioid receptor agonists like DAMGO or morphine without motor impairment in naive rats as well as rats with hind paw inflammation. In contrast the control peptide C2C2 derived from ECL1 on claudin-2 did neither open the barrier nor facilitated opioid-mediated regional analgesia. C1C2 delivery was well tolerated and caused no morphological and functional nerve damage. C1C2 effects could be reversed by interference with the wnt-signal-transduction pathway, specifically the homeobox transcription factor cdx2, using a glycogen-synthase-kinase-3 inhibitor. In summary, we describe the composition of and a pathway to open the perineurial barrier employing a peptide to deliver hydrophilic substances to the peripheral nerve.

Highly conserved cysteines are involved in the oligomerization of occludin-redox dependency of the second extracellular loop
Bellmann, C., Schreivogel, S., Günther, R., Dabrowski, S., Schümann, M., Wolburg(*), H.; Blasig, I. E.
Antioxid Redox Signal, 20:855-867
(2014)

Tags: Molecular Cell Physiology (Blasig, I.E.), Mass Spectrometry (Krause, E.)

Abstract: UNLABELLED: The tight junction (TJ) marker occludin is a 4-transmembrane domain (TMD) protein with unclear physiological and pathological functions, interacting with other TJ proteins. It oligomerizes and is redox sensitive. However, oligomerization sites and mechanisms are unknown. AIMS: To identify hypoxia-sensitive binding sites, we investigated the consequences of amino-acid substitutions of highly conserved cysteines in human occludin, under normal and hypoxic incubations. RESULTS: (i) The extracellular loop 2 (ECL2) showed homophilic trans- and cis-association between opposing cells and along the cell membrane, respectively, caused by a loop properly folded via an intraloop disulfide bridge between the shielded C216 and C237. Hypoxia and reductants prevented the associations. (ii) C82 in TMD1 directly cis-associated without disulfide formation. (iii) C76 in TMD1 and C148 in TMD2 limited the trans-interaction; C76 also limited occludin-related paracellular tightness and changed the strand morphology of claudin-1. (iv) The diminished binding strength found after substituting C82, C216, or C237 was accompanied by increased occludin mobility in the cell membrane. INNOVATION: The data enable the first experimentally proven structural model of occludin and its homophilic interaction sites, in which the ECL2, via intraloop disulfide formation, has a central role in occludin's hypoxia-sensitive oligomerization and to regulate the structure of TJs. CONCLUSION: Our findings support the new concept that occludin acts as a hypoxiasensor and contributes toward regulating the TJ assembly redox dependently. This is of pathogenic relevance for tissue barrier injury with reducing conditions. The ECL2 disulfide might be a model for four TMD proteins in TJs with two conserved cysteines in an ECL.

N-[6-(4-butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methyl piperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide (SAR216471), a novel intravenous and oral, reversible, and directly acting P2Y12 antagonist
Boldron(*), C., Besse(*), A., Bordes(*), M. F., Tissandie(*), S., Yvon(*), X., Gau(*), B., Badorc(*), A., Rousseaux(*), T., Barre(*), G., Meneyrol(*), J., Zech(*), G., Nazare, M., Fossey(*), V., Pflieger(*), A. M., Bonnet-Lignon(*), S., Millet(*), L., Briot(*), C., Dol(*), F., Herault(*), J. P., Savi(*), P., Lassalle(*), G., Delesque(*), N., Herbert(*), J. M.; Bono(*), F.
Journal of medicinal chemistry, 57:7293-7316
(2014)

Tags: Medicinal Chemistry (Nazare)

Abstract: In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.

Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells
Borcherds(*), W., Theillet, F. X., Katzer(*), A., Finzel(*), A., Mishall(*), K. M., Powell(*), A. T., Wu(*), H., Manieri(*), W., Dieterich(*), C., Selenko, P., Loewer(*), A.; Daughdrill(*), G. W.
Nat Chem Biol, 10:1000-1002
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Levels of residual structure in disordered interaction domains determine in vitro binding affinities, but whether they exert similar roles in cells is not known. Here, we show that increasing residual p53 helicity results in stronger Mdm2 binding, altered p53 dynamics, impaired target gene expression and failure to induce cell cycle arrest upon DNA damage. These results establish that residual structure is an important determinant of signaling fidelity in cells.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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