Cover image for ChemBioChem

July 4, 2005

Volume 6, Issue 7

Pages 1137–1294

    1. Cover Picture: 1,2,3-Triazole as a Peptide Surrogate in the Rapid Synthesis of HIV-1 Protease Inhibitors (ChemBioChem 7/2005) (page 1137)

      Ashraf Brik, Jerry Alexandratos, Ying-Chuan Lin, John H. Elder, Arthur J. Olson, Alexander Wlodawer, David S. Goodsell and Chi-Huey Wong

      Version of Record online: 24 JUN 2005 | DOI: 10.1002/cbic.200590021

      The cover picture shows a close up of the substrate-bindng site of HIV protease (shown as a blue ribbon), with the NC[BOND]P1 substrate (shown as a thin black backbone and transparent solvent-excluded surface) and the backbone of the click chemistry-based triazole inhibitor (shown as ball and stick, atoms colored). The structural water (red sphere) hydrogen bonds to a triazole nitrogen of the inhibitor and to the substrate peptide backbone. For further details, see the article by C.-H. Wong, A. Wlodawer, D. S. Goodsell et al. on p. 1167 ff.

    2. Evolutions in Science Triggered by Green Fluorescent Protein (GFP) (pages 1149–1156)

      Johannes A. Schmid and Hannah Neumeier

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200500029

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      Painting by proteins: Based on green fluorescent protein (GFP), other fluorescent proteins were developed, which differ from normal GFP by their fluorescence characteristics, stability, maturation, or pH sensitivity (the 3D structure of enhanced GFP (EGFP) is shown). These proteins opened up a vast field of potential applications, including live-cell fluorescence microscopy, visualization of protein interactions, and investigation of a great variety of cellular parameters.

    3. Cisplatin Damage: Are DNA Repair Proteins Saviors or Traitors to the Cell? (pages 1157–1166)

      Haralabos Zorbas and Bernhard K. Keppler

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400427

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      Help or hindrance? Two recent publications corroborated the involvement of poly(adenosine diphosphate–ribose)polymerase (PARP) and DNA-dependent protein kinase (DNA-PK) in the cellular response to cisplatin treatment. However, the obtained data and their interpretation reveal a more complex outcome than is perhaps intuitively expected, in that these mammalian DNA repair proteins may harm rather than help the cells (see schematic representation).

    4. 1,2,3-Triazole as a Peptide Surrogate in the Rapid Synthesis of HIV-1 Protease Inhibitors (pages 1167–1169)

      Ashraf Brik, Jerry Alexandratos, Ying-Chuan Lin, John H. Elder, Arthur J. Olson, Alexander Wlodawer, David S. Goodsell and Chi-Huey Wong

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200500101

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      Substitute for another bond. Docking simulations of two potent inhibitors that bear the 1,2,3-triazole moiety produced two conformations of approximately equal energy. Further analysis of the protease by X-ray crystallography solved the ambiguity of the binding mode and revealed that the triazole ring is an effective amide surrogate and retains all the hydrogen bonds in the active site (see figure).

    5. Carbohydrate-Encapsulated Gold Nanoparticles for Rapid Target-Protein Identification and Binding-Epitope Mapping (pages 1169–1173)

      Yu-Ju Chen, Shu-Hua Chen, Yuh-Yih Chien, Yu-Wan Chang, Hsin-Kai Liao, Chih-Yang Chang, Mi-Dan Jan, Ken-Tseng Wang and Chun-Cheng Lin

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200500023

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      Carbohydrate–lectin recognition plays important roles in cell–cell communication, proliferation, and differentiation. We report here a new approach of using a carbohydrate-encapsulated gold nanoparticle (shown in purple) as an affinity probe for the efficient separation and enrichment of target proteins, and then protein identification and epitope mapping by MALDI-TOF MS.

    6. Development and Biological Evaluation of Potent and Specific Inhibitors of Mitotic Kinesin Eg5 (pages 1173–1177)

      Michael Gartner, Nils Sunder-Plassmann, Jeanette Seiler, Mathias Utz, Isabelle Vernos, Thomas Surrey and Athanassios Giannis

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200500005

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      Monastrol was the first specific but moderate inhibitor of the mitotic kinesin Eg5 to be identified. It proved to be useful for studies of cell division and is thought to have anticancer potential. We have synthesized a small chemical library of monastrol analogues and tested them for Eg5 inhibition in vitro and for arresting mitosis of cultured cells. We found that dimethylenastron (1) is more than 100-times more potent than monastrol in both cases.

    7. Histidine Residue at Position 234 of Oxidosqualene-Lanosterol Cyclase from Saccharomyces cerevisiae Simultaneously Influences Cyclization, Rearrangement, and Deprotonation Reactions (pages 1177–1181)

      Tung-Kung Wu, Yuan-Ting Liu and Cheng-Hsian Chang

      Version of Record online: 25 MAY 2005 | DOI: 10.1002/cbic.200500084

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      Multiple triterpenes, including achilleol A (1), protosta-12,24-dien-3β-ol (2), lanosterol (3), and parkeol (4; 14:26:51:9) were isolated from an ERG7 oxidosqualene-lanosterol cyclase-deficient Saccharomyces cerevisiae TKW14 strain that expresses the ERG7H234Y mutation. The results indicate a role for H234 in modulating multiple aspects of the oxidosqualene cyclization/rearrangement reaction, including cyclization, rearrangement, and deprotonation.

    8. Enhanced Inhibition of Transcription Start by Targeting with 2′-OMe Pentaribonucleotides Comprising Locked Nucleic Acids and Intercalating Nucleic Acids (pages 1181–1184)

      Vyacheslav V. Filichev, Birte Vester, Lykke H. Hansen, Mohammed T. Abdel Aal, B. Ravindra Babu, Jesper Wengel and Erik B. Pedersen

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200400457

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      Inhibition assay. Pentaribonucleotides can bind to a DNA template strand near the transcription start site of an open complex (−4 to +1). 2′-OMe-Pentamers encompassing locked nucleic acids (TL, GL and AL) and intercalating nucleic acids (INA monomer P) exhibited enhanced inhibition compared to the unmodified pentamer.

    9. Unexpected Puckering of Hydroxyproline in the Guest Triplets, Hyp-Pro-Gly and Pro-alloHyp-Gly Sandwiched between Pro-Pro-Gly Sequence (pages 1184–1187)

      Nattha Jiravanichanun, Chizuru Hongo, Guanghan Wu, Keiichi Noguchi, Kenji Okuyama, Norikazu Nishino and Teresita Silva

      Version of Record online: 1 JUN 2005 | DOI: 10.1002/cbic.200500055

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      The ups and downs. High-resolution X-ray data revealed interesting proline ring puckering of hydroxyproline diastereoisomers, which could be in an atypical state depending on position selectivity. AlloHyp at the Y position in one sequence showed up-puckering (left), while Hyp at the X position in another showed down-puckering (right). On the other hand, Hyp at the Y position showed up-puckering as expected.

    10. Acceleration of Short Helical Peptide Conformational Dynamics by Trifluoroethanol in an Organic Solvent (pages 1187–1190)

      Matthew Kubasik and Adam Blom

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400198

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      Solvent dependency. The influence of the cosolvent trifluorethanol on the rate of enantiomerization of an octameric peptide (see figure) in CD2Cl2 solution is described. Kinetic data have been taken over a range of temperatures, thus allowing for a discussion of the enthalpic and entropic origins of the catalytic effect.

    11. Effect of PbII on the Secondary Structure and Biological Activity of Trypsin (pages 1191–1195)

      Lin Yang, Zhiyong Gao, Ying Cao, Ruimin Xing and Xiuying Zhang

      Version of Record online: 24 JUN 2005 | DOI: 10.1002/cbic.200400267

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      Lead toxicity. It is well known that lead and its compounds are major environmental pollutants. This work investigates the effect of PbII on the secondary structure and biological activity of trypsin by measuring its conductivity and IR and CD (see figure) spectra. The results are of significance for understanding the mechanisms of diseases caused by lead.

    12. SPR Studies of Carbohydrate–Protein Interactions: Signal Enhancement of Low-Molecular-Mass Analytes by Organoplatinum(II)-Labeling (pages 1196–1203)

      Daniela Beccati, Koen M. Halkes, Guido D. Batema, Gabriela Guillena, Adriana Carvalho de Souza, Gerard van Koten and Johannis P. Kamerling

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200400402

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      Getting more for less. Labeling of low-molecular-mass carbohydrates with an organoplatinum(II) complex of the type [PtCl(NCN[BOND]R)] ensures facile SPR detection, even at very low analyte concentrations (4 μM; top trace: organoplati-num(II)-labeled lactose, bottom: lactose) The labeling did not influence the specificity of the interaction, and the platinum atom was confirmed to be responsible for the SPR signal enhancement.

    13. Structure and Redox Properties of the Haem Centre in the C357M Mutant of Cytochrome P450cam (pages 1204–1211)

      Rajamanickam Murugan and Shyamalava Mazumdar

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200400399

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      Tuning redox potentials by mutation. Site-specific mutation of the axial cysteine residue of cytochrome P450cam with methionine led to the formation of a “cytochrome c-type” coordination geometry of the haem centre in the enzyme. The steric effect due to the methyl group in methionine possibly causes the haem to tilt, and one of the histidines from the proximal β-loop binds at the sixth coordination site of the metal ion in the mutant cytochrome P450cam.

    14. Synthesis and Application of Integrin Targeting Lipopeptides in Targeted Gene Delivery (pages 1212–1223)

      Jodie E. Waterhouse, Richard P. Harbottle, Michael Keller, Kostas Kostarelos, Charles Coutelle, Michael R. Jorgensen and Andrew D. Miller

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400408

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      Two novel lipopeptides (X=CO2CH2CH2 or CH2CH2) displaying a tenascin peptide sequence known to bind the α9β1-integrin proteins predominant on upper-airway epithelial cells have been synthesised. Low positively charged cationic liposome/DNA complexes incorporating these lipopeptides exhibit some specific targeting effects in in vitro transfection studies.

    15. Chemical Synthesis of a Dual Branched Malto-Decaose: A Potential Substrate for α-Amylases (pages 1224–1233)

      Iben Damager, Morten T. Jensen, Carl E. Olsen, Andreas Blennow, Birger L. Møller, Birte Svensson and Mohammed S. Motawia

      Version of Record online: 24 JUN 2005 | DOI: 10.1002/cbic.200400449

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      The cleavage pattern of seven different α-amylases were investigated by using complex malto-oligosaccharides. A block synthetic strategy has been developed to chemically synthesize the first well-defined dual branched malto-decaose with a defined spacing. All of the tested α-amylases were able to cleave the substrate; some could cleave specifically at one site while others could cleave at two sites shown in the scheme.

    16. High-Throughput Evaluation of Antioxidant and Pro-oxidant Activities of Polyphenols with Thymidine Protection Assays (pages 1234–1241)

      Stéphane Meunier, Mikaël Hanédanian, Marine Desage-El Murr, Stéphanie Nowaczyk, Thierry Le Gall, Serge Pin, Jean-Philippe Renault, Didier Boquet, Christophe Créminon, Charles Mioskowski and Frédéric Taran

      Version of Record online: 24 JUN 2005 | DOI: 10.1002/cbic.200400421

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      Pulvinic acid derivatives were found to display remarkable protective properties against different types of oxidative stress. These compounds (see figure) present similar reactive-oxygen-species scavenging activities to the mushroom pigment Norbadione A, but are devoid of pro-oxidant deleterious effects. These findings were highlighted by using a triple high-throughput screening based on immunoassay techniques.

    17. A New Ligand for Immunoglobulin G Subdomains by Screening of a Synthetic Peptide Library (pages 1242–1253)

      Antonio Verdoliva, Daniela Marasco, Antonia De Capua, Angela Saporito, Piero Bellofiore, Vincenzo Manfredi, Roberto Fattorusso, Carlo Pedone and Menotti Ruvo

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400368

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      A ring that binds: A cyclic dimeric tripeptide (1) has been selected from a synthetic combinatorial library as an affinity ligand for G-type immunoglobulins of different animal species. A preliminary chromatographic characterization is provided, along with an indication of one of the potential binding sites on immunoglobulin G.

    18. Highly Stable DNA Triplexes Formed with Cationic Phosphoramidate Pyrimidine α-Oligonucleotides (pages 1254–1262)

      Thibaut Michel, Françoise Debart, Frédéric Heitz and Jean-Jacques Vasseur

      Version of Record online: 24 MAY 2005 | DOI: 10.1002/cbic.200400436

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      At physiological pH and in the absence of magnesium ions, cationic phosphoramidate α-oligonucleotides in the pyrimidine motif (see scheme) form highly stable and sequence-specific triplexes with DNA duplexes.

    19. Engineering Substrate Specificity of O6-Alkylguanine-DNA Alkyltransferase for Specific Protein Labeling in Living Cells (pages 1263–1269)

      Alexandre Juillerat, Christian Heinis, India Sielaff, Jan Barnikow, Hugues Jaccard, Beatrice Kunz, Alexey Terskikh and Kai Johnsson

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400431

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      Welcomed resistance. Protein engineering was used to generate a mutant of human O6-alkylguanine-DNA alkyltransferase (AGT) that is resistant to an inhibitor of the wild-type protein. This allowed for the specific fluorescence labeling of AGT mutant fusion proteins in living cells (see figure).

    20. The RNA-Bound Conformation of Neamine as Determined by Transferred NOE Experiments (pages 1270–1276)

      Richard Szilaghi, Syed Shahzad-ul-Hussan and Thomas Weimar

      Version of Record online: 3 JUN 2005 | DOI: 10.1002/cbic.200400363

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      The design of new drugs targeting RNA structures benefits greatly from knowledge of the molecular details of RNA-bound ligand effectors. Aminoglycosides are a class of compounds known to modify the biological activity of RNA structures, and are therefore interesting lead structures for the development of new anti-RNA agents. In this report, transferred NOE experiments have been used for the first time to define the RNA-bound conformation of an aminoglycoside.

    21. Production of the Tubulin Destabilizer Disorazol in Sorangium cellulosum: Biosynthetic Machinery and Regulatory Genes (pages 1277–1286)

      Maren Kopp, Herbert Irschik, Silke Pradella and Rolf Müller

      Version of Record online: 13 MAY 2005 | DOI: 10.1002/cbic.200400459

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      Road map to disorazol. Disorazols are immensely cytotoxic tubulin destabilizers with a reported IC50 value of 3 pM (see left: control microtubules, right: after incubation with disorazol). Identification of the core biosynthetic genes of the natural producer, myxobacterium Sorangium cellulosum So ce12, reveals a hybrid between nonribosomal peptide synthetase and bacterial trans-AT type polyketide synthase. Additional genes found elsewhere in the chromosome are required for disorazol biosynthesis.

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      Version of Record online: 24 JUN 2005 | DOI: 10.1002/cbic.200590023