FMP Publications

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

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References
Small-molecule inhibitors of AF6 PDZ-mediated protein-protein interactions
Vargas, C., Radziwill(*), G., Krause, G., Diehl, A., Keller, S., Kamdem, N., Czekelius(*), C., Kreuchwig, A., Schmieder, P., Doyle(*), D., Moelling(*), K., Hagen, V., Schade(*), M.; Oschkinat, H.
Chemmedchem, 9:1458-1462
(2014)

Tags: NMR-Supported Structural Biology (Oschkinat), Solution NMR (Schmieder), Synthetic Organic Biochemistry (Hagen), Structural Bioinformatics and Protein Design (Krause, G.), Biophysics of Membrane Proteins (Keller), Synthetic Organic Biochemistry (Hagen)

Abstract: PDZ (PSD-95, Dlg, ZO-1) domains are ubiquitous interaction modules that are involved in many cellular signal transduction pathways. Interference with PDZ-mediated protein-protein interactions has important implications in disease-related signaling processes. For this reason, PDZ domains have gained attention as potential targets for inhibitor design and, in the long run, drug development. Herein we report the development of small molecules to probe the function of the PDZ domain from human AF6 (ALL1-fused gene from chromosome 6), which is an essential component of cell-cell junctions. These compounds bind to AF6 PDZ with substantially higher affinity than the peptide (Ile-Gln-Ser-Val-Glu-Val) derived from its natural ligand, EphB2. In intact cells, the compounds inhibit the AF6-Bcr interaction and interfere with epidermal growth factor (EGF)-dependent signaling.

AhR sensing of bacterial pigments regulates antibacterial defence
Moura-Alves(*), P., Fae(*), K., Houthuys(*), E., Dorhoi(*), A., Kreuchwig, A., Furkert, J., Barison(*), N., Diehl, A., Munder(*), A., Constant, P., Skrahina(*), T., Guhlich-Bornhof(*), U., Klemm(*), M., Koehler(*), A. B., Bandermann(*), S., Goosmann(*), C., Mollenkopf(*), H. J., Hurwitz(*), R., Brinkmann(*), V., Fillatreau(*), S., Daffe(*), M., Tummler, B., Kolbe(*), M., Oschkinat, H., Krause, G.; Kaufmann(*), S. H.
Nature, 512:387-392
(2014)

Tags: Structural Bioinformatics and Protein Design (Krause, G.), NMR-Supported Structural Biology (Oschkinat), Protein Trafficking (Schülein)

Abstract: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.

BAR domain scaffolds in dynamin-mediated membrane fission
Daumke(*), O., Roux(*), A.; Haucke, V.
Cell, 156:882-892
(2014)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Biological membranes undergo constant remodeling by membrane fission and fusion to change their shape and to exchange material between subcellular compartments. During clathrin-mediated endocytosis, the dynamic assembly and disassembly of protein scaffolds comprising members of the bin-amphiphysin-rvs (BAR) domain protein superfamily constrain the membrane into distinct shapes as the pathway progresses toward fission by the GTPase dynamin. In this Review, we discuss how BAR domain protein assembly and disassembly are controlled in space and time and which structural and biochemical features allow the tight regulation of their shape and function to enable dynamin-mediated membrane fission.

Activation of Ligand Binding Domains of an AMPA-Type Glutamate Receptor
Baranovic, J., Chebli, M., Salazar, H. P., Faelber(*), K., Ghisi, V., Lau(*), A. Y., Daumke(*), O.; Plested, A. J. R.
Biophys. J., 106:29a-29a
(2014)

Tags: Molecular Neuroscience and Biophysics (Plested)

Synergistic activity of the tyrocidines, antimicrobial cyclodecapeptides from Bacillus aneurinolyticus, with amphotericin B and caspofungin against Candida albicans biofilms
Troskie(*), A. M., Rautenbach(*), M., Delattin(*), N., Vosloo(*), J. A., Dathe, M., Cammue(*), B. P.; Thevissen(*), K.
Antimicrob Agents Chemother, 58:3697-3707
(2014)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Tyrocidines are cationic cyclodecapeptides from Bacillus aneurinolyticus that are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonic Candida albicans in the low-micromolar range. These tyrocidines also prevented C. albicans biofilm formation in vitro. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of mature C. albicans biofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using a Caenorhabditis elegans infection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment.

Lipopeptide-modified PEG-PE-based pharmaceutical nanocarriers for enhanced uptake in blood–brain barrier cells and improved cytotoxicity against glioma cells
Sydow, K., Torchilin, V. P.; Dathe, M.
European Journal of Lipid Science and Technology, 116:1174-1183
(2014)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Surface modification of nanoparticles is a promising approach for enhancing the delivery of drugs into the brain and cancer cells. Recently cationic lipopeptide micelles showed selective uptake into endothelial cells of brain microvessels. Here, we show that lipopeptides are promising tools to deliver an anticancer drug incorporated into PEGylated lipid (PEG-PE) micelles to brain endothelial cells and into glioblastoma cells. PEG-PE micelles containing PCL were stably modified with different arginine (R-) and lysine (K)-rich lipopeptides. The size and surface charge of the micelles did not change after modification with lipopeptides. Flow cytometry (FACS) and confocal laser scanning microscopy (CLSM) revealed pronounced interaction of lipopeptide-modified micelles with brain endothelial cells. Furthermore, the co-localisation of both the fluorescent lipopeptides and a marker lipid of micelles within human glioblastoma cells (U87MG) confirmed the integrity of the carrier after internalisation. FACS studies showed that the arginine-rich lipopeptide caused most efficient uptake into the cancer cells. The pronounced uptake correlated with higher a cytotoxic effect of PCL incorporated into peptide-tagged micelles compared to the unmodified carriers. As a conclusion, arginine-rich lipopeptides known to enhance the uptake of different NP into blood–brain barrier endothelial cells seem to be also encouraging candidates for targeting brain-located tumors. Practical applications: The surface modification of existing carrier systems with lipopeptides to improve their applicability has been proven by this work. Furthermore, the findings in this study are the basis for further improvement of lipopeptide modified PEG-PE micelles and their possible in vivo application in animal models of glioblastoma. The incorporation of anti-cancer drugs as well as diagnostic agents and their delivery to and beyond the BBB can be a tool for a broad number of further investigations. Lipopeptide (P2Rn)-modified PEG-PE micelles show enhanced uptake into human glioma cells (nuclei stained cyan). This improved uptake correlates with higher cytotoxicity of incorporated anti-cancer drug paclitaxel (PCL).

Cationic synthetic peptides: assessment of their antimicrobial potency in liquid preserved boar semen
Speck(*), S., Courtiol(*), A., Junkes, C., Dathe, M., Müller(*), K.; Schulze(*), M.
Plos One, 9:e105949
(2014)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Various semen extender formulas are in use to maintain sperm longevity and quality whilst acting against bacterial contamination in liquid sperm preservation. Aminoglycosides are commonly supplemented to aid in the control of bacteria. As bacterial resistance is increasing worldwide, antimicrobial peptides (AMPs) received lively interest as alternatives to overcome multi-drug resistant bacteria. We investigated, whether synthetic cationic AMPs might be a suitable alternative for conventional antibiotics in liquid boar sperm preservation. The antibacterial activity of two cyclic AMPs (c-WWW, c-WFW) and a helical magainin II amide analog (MK5E) was studied in vitro against two Gram-positive and eleven Gram-negative bacteria. Isolates included ATCC reference strains, multi-resistant E. coli and bacteria cultured from boar semen. Using broth microdilution, minimum inhibitory concentrations were determined for all AMPs. All AMPs revealed activity towards the majority of bacteria but not against Proteus spp. (all AMPs) and Staphylococcus aureus ATCC 29213 (MK5E). We could also demonstrate that c-WWW and c-WFW were effective against bacterial growth in liquid preserved boar semen in situ, especially when combined with a small amount of gentamicin. Our results suggest that albeit not offering a complete alternative to traditional antibiotics, the use of AMPs offers a promising solution to decrease the use of conventional antibiotics and thereby limit the selection of multi-resistant strains.

Effects of cationic antimicrobial peptides on liquid-preserved boar spermatozoa
Schulze(*), M., Junkes, C., Mueller(*), P., Speck(*), S., Ruediger(*), K., Dathe, M.; Mueller(*), K.
Plos One, 9:e100490
(2014)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Antibiotics are mandatory additives in semen extenders to control bacterial contamination. The worldwide increase in resistance to conventional antibiotics requires the search for alternatives not only for animal artificial insemination industries, but also for veterinary and human medicine. Cationic antimicrobial peptides are of interest as a novel class of antimicrobial additives for boar semen preservation. The present study investigated effects of two synthetic cyclic hexapeptides (c-WFW, c-WWW) and a synthetic helical magainin II amide derivative (MK5E) on boar sperm during semen storage at 16 degrees C for 4 days. The standard extender, Beltsville Thawing Solution (BTS) containing 250 microg/mL gentamicin (standard), was compared to combinations of BTS with each of the peptides in a split-sample procedure. Examination revealed peptide- and concentration-dependent effects on sperm integrity and motility. Negative effects were more pronounced for MK5E than in hexapeptide-supplemented samples. The cyclic hexapeptides were partly able to stimulate a linear progressive sperm movement. When using low concentrations of cyclic hexapeptides (4 microM c-WFW, 2 microM c-WWW) sperm quality was comparable to the standard extender over the course of preservation. C-WFW-supplemented boar semen resulted in normal fertility rates after AI. In order to investigate the interaction of peptides with the membrane, electron spin resonance spectroscopic measurements were performed using spin-labeled lipids. C-WWW and c-WFW reversibly immobilized an analog of phosphatidylcholine (PC), whereas MK5E caused an irreversible increase of PC mobility. These results suggest testing the antimicrobial efficiency of non-toxic concentrations of selected cyclic hexapeptides as potential candidates to supplement/replace common antibiotics in semen preservation.

Kinetics and efficiency of a methyl-carboxylated 5-Fluorouracil-bovine serum albumin adduct for targeted delivery
Koziol(*), M. J., Sievers(*), T. K., Smuda(*), K., Xiong(*), Y., Müller(*), A., Wojcik(*), F., Steffen(*), A., Dathe, M., Georgieva(*), R.; Bäumler(*), H.
Macromolecular bioscience, 14:428-439
(2014)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: 5-Fluorouracil (5-FU) is a clinically well-established anti-cancer drug effectively applied in chemotherapy, mainly for the treatment of breast and colorectal cancer. Substantial disadvantages are adverse effects, arising from serious damage of healthy tissues, and shortcoming pharmacokinetics due to its low molecular weight. A promising approach for improvement of such drugs is their coupling to suitable carriers. Here, a 5-FU adduct, 5-fluorouracil acetate (FUAc) is synthesized and covalently coupled to bovine serum albumin (BSA) as model carrier molecule. On average, 12 molecules FUAc are bound to one BSA. Circular dichriosm (CD)-spectra of BSA and FUAc-BSA are identical, suggesting no significant conformational differences. FUAc-BSA is tested on T-47D and MDA-MB-231 breast cancer cells. Proliferation inhibition of membrane albumin-binding protein (mABP)-expressing T-47D cells by FUAc-BSA is similar to that of 5-FU and only moderate for MDA-MB-231 cells that lack such expression. Therefore, a crucial role of mABP expression in effective cell growth inhibition by FUAc-BSA is assumed.

Site-specific analysis of heteronuclear Overhauser effects in microcrystalline proteins
del Amo, J. M. L., Agarwal, V., Sarkar(*), R., Porter(*), J., Asami(*), S., Rubbelke(*), M., Fink, U., Xue(*), Y., Lange(*), O. F.; Reif, B.
J. Biomol. NMR, 59:241-249
(2014)

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Relaxation parameters such as longitudinal relaxation are susceptible to artifacts such as spin diffusion, and can be affected by paramagnetic impurities as e.g. oxygen, which make a quantitative interpretation difficult. We present here the site-specific measurement of [H-1]C-13 and [H-1]N-15 heteronuclear rates in an immobilized protein. For methyls, a strong effect is expected due to the three-fold rotation of the methyl group. Quantification of the [H-1]C-13 heteronuclear NOE in combination with C-13-R (1) can yield a more accurate analysis of side chain motional parameters. The observation of significant [H-1]N-15 heteronuclear NOEs for certain backbone amides, as well as for specific asparagine/glutamine sidechain amides is consistent with MD simulations. The measurement of site-specific heteronuclear NOEs is enabled by the use of highly deuterated microcrystalline protein samples in which spin diffusion is reduced in comparison to protonated samples.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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