Cover image for ChemBioChem

January 3, 2003

Volume 4, Issue 1

Pages 1–122

    1. Cover Picture: ChemBioChem 1/2003 (page 1)

      Sachdev S. Sidhu, Wayne J. Fairbrother and Kurt Deshayes

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390000

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      Editorial: A Golden Future (pages 3–4)

      Kathryn Wright

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390010

    3. Graphical Abstract: ChemBioChem 1/2003 (pages 5–10)

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390013

    4. Exploring Protein–Protein Interactions with Phage Display (pages 14–25)

      Sachdev S. Sidhu, Wayne J. Fairbrother and Kurt Deshayes

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390008

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      Peptides on show: Phage-display libraries present diverse populations of polypeptides on phage particles that also contain the encoding DNA. Selections with immobilized target proteins can be used to isolate ligands with particular binding characteristics (see schematic representation), and the polypeptide sequences can be decoded subsequently from the DNA. By permitting the combinatorial sampling of billions of ligands en masse, phage-display technology provides a powerful approach to the rapid exploration of protein–protein interactions.

    5. Total Enantioselective Synthesis and In Vivo Biological Evaluation of a Novel Fluorescent BODIPY α-Galactosylceramide (pages 27–33)

      Yen Vo-Hoang, Laurent Micouin, Catherine Ronet, Gabriel Gachelin and Martine Bonin

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390009

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      Probing immunoregulatory potential: NKT cells play a pivotal role in the homeostasis of the immune system. Their activation by α-GalCer analogues like KRN7000 (1) induces immediate release of IL-4 and IFNγ, molecules which initiate antitumour immunity and the remission of autoimmune symptoms. The biologically active fluorescent probe 2 was prepared by a convergent synthetic approach. In vivo studies show that different specialised cells capture the probe depending on the method of administration. This information could potentially lead to new immunoregulatory drugs.

    6. Assembly of Designed Oligonucleotides as an Efficient Method for Gene Recombination: A New Tool in Directed Evolution (pages 34–39)

      Dongxing Zha, Andreas Eipper and Manfred T. Reetz

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390011

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      Bringing genes together: A new method for gene recombination and production of a library of mutant genes is described. The approach involves the assembly of synthetic oligonucleotides whose design is based on sequence alignment of the parent genes (see figure). A major advantage over conventional family shuffling methods is the minimization or elimination of self-hybridization of the parent genes. The method was applied to two lipase genes but could be extended to more than two genes and should be an attractive approach for application to the directed evolution of functional proteins and to metabolic engineering.

    7. Solution Structure and Stability of Tryptophan-Containing Nucleopeptide Duplexes (pages 40–49)

      Irene Gómez-Pinto, Vicente Marchán, Federico Gago, Anna Grandas and Carlos González

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390012

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      A stable stack: Insight into the stacking interactions between aromatic amino acids and nucleobases can be gained from the study of covalently linked peptide–oligonucleotide hybrids. The solution structures of several tryptophan-containing nucleopeptide duplexes show that the peptide chain adopts a folded structure that allows the tryptophan ring to stack against the 3′-terminal guanine base (see figure) to form a cap at the end of the duplex. This stacking interaction contributes to the stability of the duplex and resembles other tryptophan–nucleobase interactions observed in larger protein–DNA complexes.

    8. Design of a Composite Ethidium–Netropsin–Anilinoacridine Molecule for DNA Recognition (pages 50–61)

      Carolina Carrasco, Philippe Helissey, Michelyne Haroun, Brigitte Baldeyrou, Amélie Lansiaux, Pierre Colson, Claude Houssier, Sylviane Giorgi-Renault and Christian Bailly

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390014

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      Ganging up on tumors: The new trifunctional DNA ligand R-132 (shown in the picture) combines a central bispyrrole unit, which mimics the antibiotic netropsin, with two intercalating chromophores, ethidium and anilinoacridine, positioned at both ends. The three moieties of the combilexin molecule interact with DNA through a concerted intercalation and minor groove-binding mode. R-132 is a potent poison of DNA topoisomerase II and displays cytotoxic activities. It therefore provides a lead for the design of gene-targeted antitumor agents.

    9. Synthesis and Biological Activity of a Platinum(II) 6-Phenyl-2,2′-bipyridine Complex and Its Dimeric Analogue (pages 62–68)

      Hing-Leung Chan, Dik-Lung Ma, Mengsu Yang and Chi-Ming Che

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390015

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      Apoptosis activators: The intercalating PtII complex (pyridyl)-(6-phenyl-2,2′-bipyridine)platinum(II) hexafluorophosphate (1) and its corresponding dimer μ-N,N′-bis(isonicotinyl)-1,6-hexanediamino-bis-[6-phenyl-2,2′-bipyridine-platinum(II)] dichloride (2) were synthesized. The DNA binding constants of 1 and 2 at 20 °C were determined by absorption titration to be 2.25×104M−1 and 3.07×106M−1, respectively. Compound 2 exhibited cytotoxicity comparable to that of cisplatin, and was more toxic than 1 by an order of magnitude. Both 1 and 2 were shown to induce apoptosis.

    10. Synthesis and Biological Evaluation of Pyrazolylnaphthoquinones as New Potential Antiprotozoal and Cytotoxic Agents (pages 69–72)

      Norma R. Sperandeo and Reto Brun

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390016

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      New drugs against American trypanosomiasis (Chagas' disease) and malaria may result from novel pyrazolylnaphthoquinones (13) and their 5-aminoisoxazole analogues, which were evaluated against the etiological agents of these diseases. The studied compounds showed significant antitrypanosomal and antimalarial activities and results suggest that trypanocidal and cytotoxic activities may be separated by molecular modification.

    11. Conformational Features of Human Melanin-Concentrating Hormone: An NMR and Computational Analysis (pages 73–81)

      Rosa Maria Vitale, Laura Zaccaro, Benedetto Di Blasio, Roberto Fattorusso, Carla Isernia, Pietro Amodeo, Carlo Pedone and Michele Saviano

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390017

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      Shaping up: The conformational features of human melanin-concentrating hormone (hMCH) [Asp1-Phe2-Asp3-Met4-Leu5-Arg6-cyclo(S[BOND]S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14- Pro15-Cys16)-Trp17-Gln18-Val19] in water and in a CD3CN/H2O mixture at 298 K have been determined by NMR spectroscopy followed by simulated annealing and molecular dynamics analyses. From our structural data, we conclude that the resulting structures (see figure) are substantially different from that reported in the literature for the cyclic MCH(5–14) subunit of salmon MCH, which was later used to perform a molecular characterization of the MCH/receptor complex. Our conformational data call for a critical revision of the proposed MCH/receptor complex model.

    12. Optimization of Electrochemical and Peroxide-Driven Oxidation of Styrene with Ultrathin Polyion Films Containing Cytochrome P450cam and Myoglobin (pages 82–89)

      Bernard Munge, Carmelita Estavillo, John B. Schenkman and James F. Rusling

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390018

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      Getting between the sheets with proteins: Ultrathin films of myoglobin and cytochrome P450cam grown layer-by-layer with polyions were optimized for electrochemical and hydrogen peroxide driven epoxidation of styrene (see figure). Very thin films (approximately 12–25 nm) containing nanomolar amounts of protein gave the best rates for the catalytic epoxidation. Classical bell-shaped activity/pH profiles and turnover rates similar to those in solution were obtained.

    13. Novel Trifluoromethyl Ketones as Potent Gastric Lipase Inhibitors (pages 90–95)

      George Kokotos, Stavroula Kotsovolou and Robert Verger

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390019

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      An ester bond surrogate: A novel class of human digestive lipase inhibitors, lipophilic trifluoromethyl ketones (see scheme), was developed. The inhibition of human pancreatic and gastric lipases by trifluoromethyl ketone derivatives was studied by the monolayer technique. One of these derivatives has the best inhibition constant reported for any synthetic human gastric lipase inhibitor, equal to that of the antiobesity drug tetrahydrolipstatin. The trifluoromethyl keto group is a valuable ester bond surrogate for use in the design of inhibitors of lipolytic enzymes.

    14. Evaluation of Lipopolysaccharide Aggregation by Light Scattering Spectroscopy (pages 96–100)

      Nuno C. Santos, Ana C. Silva, Miguel A. R. B. Castanho, J. Martins-Silva and Carlota Saldanha

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390020

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      Endotoxins gang up: Lipopolysaccharides (LPS; see figure, A=O-specific chain, B=core region, C=Lipid A) may behave as bacterial endotoxins and their self-aggregation may affect their toxicity. Light scattering spectroscopy was used to characterize the LPS aggregation process. Premicelle structures were observed below the apparent critical micelle concentration and larger aggregates were found above this concentration. The search for drugs that interfere with aggregation is a possible therapeutic strategy.

    15. Analysis of Protein Tyrosine Kinase Inhibitors in Recombinant Yeast Lacking the ERG6 Gene (pages 101–107)

      Daniel D. Clark and Blake R. Peterson

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390001

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      Getting through to yeast: Studies of small-molecule–protein interactions in yeast are often hindered by the limited permeability of yeast to small molecules. We deleted the ERG6 gene in yeast to ablate biosynthesis of the membrane steroid ergosterol and enhance membrane permeability. This gene deletion enabled detection of typically impermeable protein tyrosine kinase inhibitors such as herbimycin A (see formula) in recombinant yeast genetic systems, which should facilitate the analysis and screening of small-molecule–protein interactions in yeast.

    16. Urdamycin L: A Novel Metabolic Shunt Product that Provides Evidence for the Role of the urdM Gene in the Urdamycin A Biosynthetic Pathway of Streptomyces fradiae TÜ 2717 (pages 109–111)

      Uwe Rix, Lily L. Remsing, Dirk Hoffmeister, Andreas Bechthold and Jürgen Rohr

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390002

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      Sixes and sevens: The isolation and structure elucidation of urdamycin L, a novel shunt product from the Sreptomyces fradiae TÜ 2717 urdM mutant, gives new insight into the mechanism of 12b-hydroxylation during urdamycin biosynthesis (see scheme). The lactone structure of urdamycin L suggests an initial Baeyer–Villiger oxygenation followed by a rearrangement of the seven-membered lactone ring to a six-membered carbocycle, a step that is probably base assisted.

    17. Site-Specific Cleavage of the HIV-1 TAR RNA by a Hydroxysalen–Copper(III) Complex (pages 112–114)

      Christian Bailly, Valérie Guerniou, Eric Lamour, Jean-Luc Bernier, Françoise Villain and Hervé Vezin

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390003

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      A copper cutter: XANES and EXAFS measurements show that a para-hydroxysalen compound binds CuIII in solution (see scheme). The complex induces cleavage of the HIV-1 TAR RNA at a specific U40 residue near the trinucleotide bulge and thus provides the first example of a salen-based ribonuclease. The findings may be used for the design of ribonucleases to probe RNA structure.

    18. The Biosynthesis of Indolocarbazoles in a Heterologous E. coli Host (pages 114–117)

      Chang-Gu Hyun, Tsion Bililign, Jianchun Liao and Jon S. Thorson

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390004

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      The antitumor antibiotic rebeccamycin (1), produced by the bacterium Saccharothrix aerocolonigenes, is a prototype of a class of complex natural products called indolocarbazoles. The cloning and characterization of the rebeccamcyin (reb) gene locus from S. aerocolonigenes is reported. The heterologous expression of this intact gene cluster in Escherichia coli led to the production of 1 and two putative biosynthetic intermediates. This work represents the first production of indolocarbazole analogues in the heterologous host E. coli.

    19. Preview: ChemBioChem 1/2003 (page 122)

      Version of Record online: 3 JAN 2003 | DOI: 10.1002/cbic.200390007