Hans-Dieter Arndt

Friedrich-Schiller-University Jena, Jena, Thuringia, Germany

Are you Hans-Dieter Arndt?

Claim your profile

Publications (49)316.41 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The bacteria ribosome is a major target of naturally occurring thiopeptides antibiotics. Studying thiopeptide (e.g. thiostrepton) binding to the GAR's 23S-L11 ribosomal subunit using docking methods is challenging. Regarding the target, the binding site is composed of a flexible protein-RNA nonbonded interface whose available crystal structure is of medium resolution. Regarding the ligands, the thiopeptides are chemically complex, flexible, and contain macrocycles. In this study we developed a combined MD-Docking-MD workflow that allows us to study thiopeptide--23S-L11 binding. It is shown that docking thiostrepton-like ligands to an MD-refined receptor structure instead of the medium resolution crystal leads to better convergence to the native-like docking pose and a better reproduction of experimental binding affinities. By applying an energy decomposition analysis, we identify key structural binding elements within GAR's rRNA-protein binding site and within the ligand structures.
    Journal of Computer-Aided Molecular Design 10/2014; accepted September 11th:2014. · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We introduce far-red, fluorogenic probes that combine minimal cytotoxicity with excellent brightness and photostability for fluorescence imaging of actin and tubulin in living cells. Applied in stimulated emission depletion (STED) microscopy, they reveal the ninefold symmetry of the centrosome and the spatial organization of actin in the axon of cultured rat neurons with a resolution unprecedented for imaging cytoskeletal structures in living cells.
    Nature Methods 05/2014; · 23.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half-length synthetic peptides. For these compounds, a non-natural motif of alternating D- and L-backbone stereochemistry of the peptide chain predisposed for β-helix formation was explored. Synthetic D-/L-peptides with permuted half-length sequences were delineated from a full-length starter sequence and covalently recombined to create two-dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram-positive and Gram-negative bacteria with low hemolytic activity. Cryo-electron microscopy characterized the membrane-associated mechanism of action of the new D-/L-peptide antibiotics.
    ChemBioChem 10/2013; · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The thiostrepton antibiotic inhibits bacterial protein synthesis by binding to a cleft formed by the ribosomal protein L11 and 23S's rRNA helices 43-44 on the 70S ribosome. It was proposed from crystal structures that the ligand restricts L11's N-terminal movement and thus prevents proper translation factor binding. An exact understanding of thiostrepton's impact on the binding site's dynamics at atomistic resolution is still missing. Here we report an all-atom molecular dynamics simulations of the binary L11·rRNA and the ternary L11·rRNA·thiostrepton complex (rRNA = helices 43-44). We demonstrate that thiostrepton directly impacts the binding site's atomic and biomacromolecular dynamics.
    Bioorganic & medicinal chemistry 09/2012; · 2.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have characterized rationally designed and optimized analogues of the actin-stabilizing natural products jasplakinolide and chondramide C. Efficient actin staining was achieved in fixed permeabilized and non-permeabilized cells using different combinations of dye and linker length, thus highlighting the degree of molecular flexibility of the natural product scaffold. Investigations into synthetically accessible, non-toxic analogues have led to the characterization of a powerful cell-permeable probe to selectively image static, long-lived actin filaments against dynamic F-actin and monomeric G-actin populations in live cells, with negligible disruption of rapid actin dynamics.
    Journal of the American Chemical Society 04/2012; 134(20):8480-6. · 10.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A full account on the synthesis of the antibiotic natural product biphenomycin B and several derivatives is reported, which employs a Suzuki coupling reaction of a free carboxylic acid and macrolactam formation as key transformations. Liberal exchange of the central amino acid was demonstrated. This procedure gave derivatives to study the influence of the polar side chain of the central amino acids on translation inhibition.
    Chemistry - An Asian Journal 06/2011; 6(6):1546-56. · 4.57 Impact Factor
  • Biomimetic Organic Synthesis, 04/2011: pages 317 - 355; , ISBN: 9783527634606
  • Angewandte Chemie International Edition 03/2011; 50(14):3308-12. · 11.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In Biology Oriented Synthesis the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is met by the structurally complex scaffolds of natural products (NPs) selected in evolution. The synthesis of NP-inspired compound collections approaching the complexity of NPs calls for the development of efficient synthetic methods. We have developed a one pot 4-7 step synthesis of mono-, bi-, and tricyclic oxepanes that resemble the core scaffolds of numerous NPs with diverse bioactivities. This sequence entails a ring-closing ene-yne metathesis reaction as key step and makes productive use of polymer-immobilized scavenger reagents. Biological profiling of a corresponding focused compound collection in a reporter gene assay monitoring for Wnt-signaling modulation revealed active Wntepanes. This unique class of small-molecule activators of the Wnt pathway modulates the van-Gogh-like receptor proteins (Vangl), which were previously identified in noncanonical Wnt signaling, and acts in synergy with the canonical activator protein (Wnt-3a).
    Proceedings of the National Academy of Sciences 03/2011; 108(17):6805-10. · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayed-death phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing. We recently demonstrated that thiostrepton and its derivatives interfere with the eukaryotic proteasome, a multimeric protease complex that is important for the degradation of ubiquitinated proteins. Here, we report that the thiostrepton-based compounds are active against chloroquine-sensitive and -resistant Plasmodium falciparum, where they rapidly eliminate parasites before DNA replication. The minor parasite fraction that escapes the fast killing of the first replication cycle is arrested in the schizont stage of the following cycle, displaying a delayed-death phenotype. Thiostrepton further exhibits gametocytocidal activity by eliminating gametocytes, the sexual precursor cells that are crucial for parasite transmission to the mosquito. Compound treatment results in an accumulation of ubiquitinated proteins in the blood stages, indicating an effect on the parasite proteasome. In accordance with these findings, expression profiling revealed that the proteasome is present in the nucleus and cytoplasm of trophozoites, schizonts, and gametocytes. In conclusion, thiostrepton derivatives represent promising candidates for malaria therapy by dually acting on two independent targets, the parasite proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite.
    Antimicrobial Agents and Chemotherapy 01/2011; 55(4):1338-48. · 4.57 Impact Factor
  • Angewandte Chemie 01/2011; 123(14):3366.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ribosomally produced thiopeptide antibiotics are highly promising lead compounds targeting the GTPase-associated region (GAR) of the bacterial ribosome. A representative panel of GAR mutants suspected to confer resistance against thiopeptide antibiotics was reconstituted in vitro and quantitatively studied with fluorescent probes. It was found that single-site mutations of the ribosomal 23S rRNA binding site region directly affect thiopeptide affinity. Quantitative equilibrium binding data clearly identified A1067 as the base contributing most strongly to the binding environment. The P25 residue on the ribosomal protein L11 was essential for binding of the monocyclic thiopeptides micrococcin and promothiocin B, confirming that the mutation of this residue in the producer organism confers self-resistance. For the bicyclic thiopeptides thiostrepton and nosiheptide, all studied single-site resistance mutations on the L11 protein were still fully capable of ligand binding in the upper pM range, both in the RNA-protein complex and in isolated 70S ribosomes. These single-site mutants were then specifically reconstituted in Bacillus subtilis, confirming their efficacy as resistance-conferring. It is thus reasoned that, in contrast to modifications of the 23S rRNA in the GAR, mutations of the L11 protein do not counteract binding of bicyclic thiopeptides, but allow the ribosome to bypass the protein biosynthesis blockade enforced by these antibiotics in the wild type.
    Journal of the American Chemical Society 05/2010; 132(20):6973-81. · 10.68 Impact Factor
  • Angewandte Chemie International Edition 03/2010; 49(19):3317-21. · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The fundamental role played by actin in the regulation of eukaryotic cell maintenance and motility renders it a primary target for small-molecule intervention. In this arena, a class of potent cytotoxic cyclodepsipeptide natural products has emerged over the last quarter-century to stimulate the fields of biology and chemistry with their unique actin-stabilizing properties and complex peptide-polyketide hybrid structures. Despite considerable research effort, a structural basis for the activity of these secondary metabolites remains elusive, not least for the lack of high-resolution structural data and a reliable synthetic route to diverse compound libraries. In response to this, an efficient solid-phase approach has been developed and successfully applied to the total synthesis of jasplakinolide and chondramide C and diverse analogues. The key macrocylization step was realized using ruthenium-catalyzed ring-closing metathesis (RCM) that in the course of a library synthesis produced discernible trends in metathesis reactivity and E/Z-selectivity. After optimization, the RCM step could be operated under mild conditions, a result that promises to facilitate the synthesis of more extensive analogue libraries for structure-function studies. The growth inhibitory effects of the synthesized compounds were quantified and structure-activity correlations established which appear to be in good alignment with relevant biological data from natural products. In this way a number of potent unnatural and simplified analogues have been found. Furthermore, potentially important stereochemical and structural components of a common pharmacophore have been identified and rationalized using molecular modeling. These data will guide in-depth mode-of-action studies, especially into the relationship between the cytotoxicity of these compounds and their actin-perturbing properties, and should inform the future design of simplified and functionalized actin stabilizers as well.
    Journal of the American Chemical Society 02/2010; 132(9):3063-77. · 10.68 Impact Factor
  • Angewandte Chemie, v.122, 3389-3393 (2010). 01/2010;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Semisynthetische Verfahren haben einen großen Beitrag zu der rasanten Entwicklung geleistet, die auf dem noch jungen Feld der Chemischen Biologie in den letzten Jahren stattgefunden haben. Dabei haben beeindruckende Beispiele für die Semisynthese von komplexen modifizierten Proteinen sowie die Derivatisierung von Naturstoffen für biologische Studien nicht nur die Grenzen des Machbaren immer weiter verschoben, sondern auch tatsächlich effiziente Werkzeuge zur Erforschung von Proteinfunktionen etabliert. Gerade für Anwendungen in der Proteomik, das Studium zellulärer Zusammenhänge und ihrer Quantifizierung sind von semisynthetischen Ansätzen weitere Impulse zu erwarten. Dabei zeichnet sie besonders ein interdisziplinärer Charakter aus, der Chemie und Biologie verknüpft. Es ist zu erwarten, dass die wissenschaftliche Bedeutung dieser Verfahren weiter zunehmen wird.Semisynthetic techniques have greatly contributed to the rapid development of Chemical Biology in recent years. In this regard the semisynthesis of complex modified proteins as well as the selective derivatization of natural products has evolved into more than mere proof-of-principle concepts but powerful tools to probe protein functions. This technology provides a solid basis for further investigations on proteomics and qualitative and quantitative cell biology. The interdisciplinary charter bridging chemistry and biology is the hallmark of semisynthesis. It can be expected that its scientific impact will further increase in the future.
    Chemie in unserer Zeit 01/2010; · 0.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In der Semisynthese müssen komplexe Moleküle chemoselektiv, regioselektiv und stereoselektiv manipuliert werden, was pfiffige Schutzgruppenoperationen und innovative Syntheseentwicklung erforderlich macht. Entscheidend sind in jedem Fall leicht zugängliche und geeignete Ausgangsmaterialien, insbesondere biotechnologisch unbegrenzt herstellbare Zwischenstufen. Da eine möglichst weitreichende synthetische Bearbeitung von Wirkstoffkandidaten das größte Innovations- und Patentschutzpotenzial hat, sind auch vielstufige Semi- und sogar Totalsynthesen Bestandteil moderner industrieller Forschung und Wirkstoffentwicklung. Die dabei realisierte Komplexität wäre vor noch gar nicht langer Zeit undenkbar gewesen, was den Fortschritt in der Synthesemethodik eindrucksvoll verdeutlicht. Die Semisynthese zielt vornehmlich auf konkrete Anwendungen ab, wobei der forscherisch-innovative Aspekt in der Klärung molekularer Zusammenhänge besteht. Gerade für das Studium zellulärer Prozesse und ihrer Quantifizierung sind in Zukunft wichtige Impulse zu erwarten. Die Semisynthese wird so auch weiterhin eine tragfähige Brücke zwischen den Zukunftsfeldern Syntheseforschung und Chemischer Biologie bilden.In Semisynthesis complex molecules have to be manipulated in a chemoselective, regioselective, and stereoselective fashion, necessitating smart protective group operations and innovative synthesis development. Key are always easily accessible and suitable starting materials, especially intermediates which can be produced by biotechnological processes. An extensive synthetic construction of drug candidates carries high innovative and intellectual property protection potential, hence multistep semi- and even total syntheses are an integral part of modern industrial research and drug development. Not a long time ago, the complexity such realized would have been inconceivable, which profoundly illustrates the progress synthesis methodology has made. Semisynthesis always aims more toward focussed application, and hence its scientific contribution mostly cater to the elucidation of molecular correlations. Especially the study of cellular processes and their quantification will be stimulated in the future. Thereby semisynthesis will continue to bridge the key future areas of synthesis research and chemical biology.
    Chemie in unserer Zeit 01/2010; · 0.52 Impact Factor
  • Sebastian Schoof, Hans-Dieter Arndt
    [Show abstract] [Hide abstract]
    ABSTRACT: The natural product thiopeptide antibiotic thiostrepton is shown to undergo facile epimerization at its thiazoline residue in favor of the naturally observed D-configuration, suggesting that a classical epimerase enzyme may not be involved in its biosynthesis.
    Chemical Communications 12/2009; · 6.38 Impact Factor
  • Source
    Angewandte Chemie 11/2009;
  • Source
    Angewandte Chemie International Edition 11/2009; 48(49):9211. · 11.34 Impact Factor

Publication Stats

398 Citations
316.41 Total Impact Points

Institutions

  • 2014
    • Friedrich-Schiller-University Jena
      • Institute of Organic Chemistry and Macromolecular Chemistry
      Jena, Thuringia, Germany
  • 2013
    • University of Vienna
      • Department of Biochemistry and Cell Biology
      Wien, Vienna, Austria
  • 2009–2012
    • Max Planck Institute of Molecular Physiology
      • Department of Chemical Biology
      Dortmund, North Rhine-Westphalia, Germany
  • 2011
    • Goethe-Universität Frankfurt am Main
      • Institut für Organische Chemie und Chemische Biologie
      Frankfurt am Main, Hesse, Germany
  • 2006–2011
    • Technische Universität Dortmund
      • Faculty of Chemistry
      Dortmund, North Rhine-Westphalia, Germany
  • 2003–2005
    • California Institute of Technology
      • Division of Chemistry and Chemical Engineering
      Pasadena, CA, United States