K Klumpp

Summary

Affiliation: F. Hoffmann-La Roche Ltd

Publications

  1. ncbi Variation in ATP requirement during influenza virus transcription
    K Klumpp
    EMBL Grenoble Outstation, France
    J Gen Virol 79:1033-45. 1998
  2. ncbi Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside
    Plinio Perrone
    Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK
    J Med Chem 50:1840-9. 2007
  3. ncbi Influenza virus endoribonuclease
    K Klumpp
    Roche Products Ltd, Welwyn Garden City, Hertfordshire AL7 3AY, United Kingdom
    Methods Enzymol 342:451-66. 2001
  4. doi Essential role of the N-terminal domain in the regulation of RIG-I ATPase activity
    Peter Gee
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    J Biol Chem 283:9488-96. 2008
  5. ncbi 2'-deoxy-4'-azido nucleoside analogs are highly potent inhibitors of hepatitis C virus replication despite the lack of 2'-alpha-hydroxyl groups
    Klaus Klumpp
    Roche Palo Alto LLC, Palo Alto, California 94304, USA
    J Biol Chem 283:2167-75. 2008
  6. ncbi Recent progress in the design of small molecule inhibitors of HIV RNase H
    Klaus Klumpp
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Curr Pharm Des 12:1909-22. 2006
  7. ncbi Optimization of small molecule drugs binding to highly polar target sites: lessons from the discovery and development of neuraminidase inhibitors
    Klaus Klumpp
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Curr Top Med Chem 6:423-34. 2006
  8. ncbi The novel nucleoside analog R1479 (4'-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture
    Klaus Klumpp
    Roche Palo Alto LLC, CA 94304, USA
    J Biol Chem 281:3793-9. 2006
  9. pmc Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors
    Klaus Klumpp
    Roche Discovery Welwyn, Welwyn Garden City, UK
    Nucleic Acids Res 31:6852-9. 2003
  10. ncbi RNA and DNA hydrolysis are catalyzed by the influenza virus endonuclease
    K Klumpp
    Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Herts AL7 3AY, United Kingdom
    J Biol Chem 275:6181-8. 2000

Collaborators

Detail Information

Publications28

  1. ncbi Variation in ATP requirement during influenza virus transcription
    K Klumpp
    EMBL Grenoble Outstation, France
    J Gen Virol 79:1033-45. 1998
    ....
  2. ncbi Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside
    Plinio Perrone
    Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK
    J Med Chem 50:1840-9. 2007
    ..The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy...
  3. ncbi Influenza virus endoribonuclease
    K Klumpp
    Roche Products Ltd, Welwyn Garden City, Hertfordshire AL7 3AY, United Kingdom
    Methods Enzymol 342:451-66. 2001
    ..Low concentrations of the detergent DOC inhibit the activity and also disrupt the trimeric polymerase complex, whereas other detergents do not have a significant effect on the activity...
  4. doi Essential role of the N-terminal domain in the regulation of RIG-I ATPase activity
    Peter Gee
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    J Biol Chem 283:9488-96. 2008
    ....
  5. ncbi 2'-deoxy-4'-azido nucleoside analogs are highly potent inhibitors of hepatitis C virus replication despite the lack of 2'-alpha-hydroxyl groups
    Klaus Klumpp
    Roche Palo Alto LLC, Palo Alto, California 94304, USA
    J Biol Chem 283:2167-75. 2008
    ..Therefore, 2'-alpha-deoxy-4'-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection...
  6. ncbi Recent progress in the design of small molecule inhibitors of HIV RNase H
    Klaus Klumpp
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Curr Pharm Des 12:1909-22. 2006
    ..Together, these developments provide promising new starting points for the rational design of selective HIV RH inhibitors...
  7. ncbi Optimization of small molecule drugs binding to highly polar target sites: lessons from the discovery and development of neuraminidase inhibitors
    Klaus Klumpp
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Curr Top Med Chem 6:423-34. 2006
    ....
  8. ncbi The novel nucleoside analog R1479 (4'-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture
    Klaus Klumpp
    Roche Palo Alto LLC, CA 94304, USA
    J Biol Chem 281:3793-9. 2006
    ..The S282T point mutation in the coding sequence of NS5B confers resistance to inhibition by 2'-C-MeATP and other 2'-methyl-nucleotides. In contrast, the S282T mutation did not confer cross-resistance to R1479...
  9. pmc Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors
    Klaus Klumpp
    Roche Discovery Welwyn, Welwyn Garden City, UK
    Nucleic Acids Res 31:6852-9. 2003
    ..Based on this difference in active site structure, a series of small molecule N-hydroxyimides was identified with significant enzyme inhibitory potency and selectivity for HIV RNase H...
  10. ncbi RNA and DNA hydrolysis are catalyzed by the influenza virus endonuclease
    K Klumpp
    Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Herts AL7 3AY, United Kingdom
    J Biol Chem 275:6181-8. 2000
    ..The observed relative cleavage rates with DNA and RNA substrates argue against a direct interaction of a catalytic metal ion with a 2'-hydroxy group in the endonuclease active site...
  11. pmc A sensitive, single-tube assay to measure the enzymatic activities of influenza RNA polymerase and other poly(A) polymerases: application to kinetic and inhibitor analysis
    L Hooker
    Department of Biology and Department of Chemistry, Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK
    Nucleic Acids Res 29:2691-8. 2001
    ..4-0.6 microM) is approximately 100-fold lower than the K(m) value for ATP (50 microM) in the case of yeast PAP...
  12. doi In vitro resistance development for RO-0335, a novel diphenylether nonnucleoside reverse transcriptase inhibitor
    H Javanbakht
    Virology Disease Biology Area, Roche Palo Alto, Palo Alto, CA 94304 1396, USA
    Antiviral Res 86:212-9. 2010
    ..Patterns containing F227C or quadruple mutations selected by RO-0335 showed a low relative fitness value when compared to wild-type HXB2D...
  13. doi Robust antiviral activity of R1626, a novel nucleoside analog: a randomized, placebo-controlled study in patients with chronic hepatitis C
    Stuart K Roberts
    The Alfred Hospital, Melbourne, Australia
    Hepatology 48:398-406. 2008
    ..Conclusion: These data support further studies of R1626 in combination with peginterferon alfa-2a and ribavirin for the treatment of patients with chronic HCV infection...
  14. ncbi Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data
    Zachary K Sweeney
    Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Curr Opin Drug Discov Devel 11:458-70. 2008
    ..In this review, the desirable features of a next-generation NNRTI for treatment-naïve patients are discussed, as well as the properties of the NNRTIs that are currently in development...
  15. doi Discovery of triazolinone non-nucleoside inhibitors of HIV reverse transcriptase
    Zachary K Sweeney
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Bioorg Med Chem Lett 18:4348-51. 2008
    ..Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats. Several fragments of inhibitor 7c were prepared, and the binding of these compounds to HIV-RT was analyzed by surface plasmon resonance spectroscopy...
  16. doi Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase
    Zachary K Sweeney
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Bioorg Med Chem Lett 18:4352-4. 2008
    ..Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described...
  17. ncbi First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus
    Plinio Perrone
    Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK
    J Med Chem 50:5463-70. 2007
    ..The benzyl ester and the l-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18-21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity...
  18. ncbi Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) and identification of a novel active 5'-triphosphate species
    Han Ma
    Roche Palo Alto LLC, Palo Alto, California 94304, USA
    J Biol Chem 282:29812-20. 2007
    ..These results demonstrate that PSI-6130 is metabolized to two pharmacologically active species in primary human hepatocytes...
  19. ncbi Design, synthesis, and antiviral properties of 4'-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479
    David B Smith
    Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Bioorg Med Chem Lett 17:2570-6. 2007
    ..Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides...
  20. ncbi Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors
    Kevin E B Parkes
    Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Herts, AL7 3AY, UK
    J Med Chem 46:1153-64. 2003
    ..The pharmacophore was used to design a novel structural class of inhibitors, some of which were found to have activities similar to that of known influenza endonuclease inhibitors and were also antiviral in cell culture...
  21. ncbi Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides
    Julie Qi Hang
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Biochem Biophys Res Commun 317:321-9. 2004
    ..Specific binding of N-hydroxyimide compounds to the isolated RNase H domain was observed by protein fluorescence quenching...
  22. ncbi Inhibition of native hepatitis C virus replicase by nucleotide and non-nucleoside inhibitors
    Han Ma
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Virology 332:8-15. 2005
    ..The allosteric non-nucleoside NS5B polymerase inhibitors are inactive against established HCV replicase but may function antagonistically with the formation of a productive enzyme-template complex...
  23. ncbi Structure of the unphosphorylated STAT5a dimer
    Dante Neculai
    Department for NMR based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany
    J Biol Chem 280:40782-7. 2005
    ..The separation of the dimeric arrangement, taking place upon activation and nuclear translocation of STAT5a, is demonstrated by fluorescence resonance energy transfer experiments in living cells...
  24. pmc Activation of influenza virus RNA polymerase by the 5' and 3' terminal duplex of genomic RNA
    M T Michael Lee
    Centre for Veterinary Science, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK
    Nucleic Acids Res 31:1624-32. 2003
    ..This suggests a mechanism by which the virus couples transcription initiation and termination during mRNA transcription...
  25. ncbi In vitro selected Con1 subgenomic replicons resistant to 2'-C-methyl-cytidine or to R1479 show lack of cross resistance
    Sophie Le Pogam
    Roche Palo Alto LLC, S3 1, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Virology 351:349-59. 2006
    ..These data will allow the optimization of new polymerase inhibitors and their use in combination therapy...
  26. pmc Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus
    Sophie Le Pogam
    Roche Palo Alto LLC, Palo Alto, CA 94304, USA
    J Virol 80:6146-54. 2006
    ..Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants...
  27. ncbi Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs)
    Julie Q Hang
    Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
    Biochem Biophys Res Commun 352:341-50. 2007
    ....
  28. ncbi Quantitative analysis of influenza virus RNP interaction with RNA cap structures and comparison to human cap binding protein eIF4E
    Lisa Hooker
    Roche Discovery Welwyn, Welwyn Garden City, UK
    Biochemistry 42:6234-40. 2003
    ..Due to this difference in cap subsite interaction, it was possible to identify novel cap analogues, which selectively interact with influenza virus, but not human cap binding protein...