Affiliation: Merck Research Laboratories
- Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culturePetra Neddermann
IRBM, Via Pontina Km 30, 600, 00040 Pomezia, Rome, Italy
J Virol 78:13306-14. 2004..This is the first direct demonstration that the presence of high amounts of NS5A-p58 causes inhibition of HCV RNA replication in cell culture and that this inhibition can be relieved by kinase inhibitors...
- A novel, inducible, eukaryotic gene expression system based on the quorum-sensing transcription factor TraRPetra Neddermann
Istituto di Ricerche di Biologia Molecolare P Angeletti, Via Pontina Km 30 600, 00040 Pomezia Roma, Italy
EMBO Rep 4:159-65. 2003..The basal level of transcription was low in the absence of 3-oxo-C(8)-HSL, and gene expression was stimulated up to 1,000-fold at a saturating concentration of 3-oxo-C(8)-HSL...
- The crystal structure of the quorum sensing protein TraR bound to its autoinducer and target DNAAlessandro Vannini
IRBM P Angeletti, Via Pontina Km 30 600, I 00040 Pomezia, Rome, Italy
EMBO J 21:4393-401. 2002..In TraR, the gene fusion is between a GAF/PAS domain and a DNA-binding domain, resulting in a specific transcriptional regulator involved in quorum sensing...
- Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domainMatthew J Bottomley
Istituto di Ricerche di Biologia Molecolare P Angeletti, Merck Research Laboratories, Via Pontina Km 30 600, 00040 Pomezia Roma, Italy
J Biol Chem 283:26694-704. 2008..HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions...
- Hepatitis C virus NS5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitorsManuela Quintavalle
Istituto di Ricerche di Biologia Molecolare P Angeletti, Via Pontina Km 30 6, 00040 Pomezia, Rome, Italy
J Biol Chem 282:5536-44. 2007..In vitro kinase reactions performed with NS5A peptides show that Ser-2204 is a preferred substrate residue for CKI-alpha after pre-phosphorylation of Ser-2201...
- Synthesis and SAR of piperazinyl-N-phenylbenzamides as inhibitors of hepatitis C virus RNA replication in cell cultureImmacolata Conte
Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P Angeletti S p A, Merck Research Laboratories Rome, 00040 Pomezia, Rome, Italy
Bioorg Med Chem Lett 19:1779-83. 2009..We report here substituted piperazinyl-N-(aryl)benzamides as potent inhibitors of HCV replication exerted via modulation of the dimerization of NS5A...
- Determination of the stoichiometry of noncovalent complexes using reverse-phase high-performance liquid chromatography coupled with electrospray ion trap mass spectrometryLaura Orsatti
Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare P. Angeletti, IRBM, Via Pontina Km 30.600, Pomezia (Rome, Italy
Anal Biochem 309:11-8. 2002..Both TraR/AAI and NS3/NS4A complexes have 1:1 stoichiometries, in line with those already reported in the literature...
- The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylationManuela Quintavalle
Istituto di Ricerche di Biologia Molecolare P Angeletti, 00040 Pomezia Roma, Italy
J Virol 80:11305-12. 2006..Finally, we showed that down-regulation of CKI-alpha attenuates HCV RNA replication...
- NS5A phosphorylation and hyperphosphorylationPetra Neddermann
Istituto di Ricerche di Biologia Molecolare P Angeletti, Pomezia Rome, Italy
Methods Mol Biol 510:95-110. 2009..The problem with this approach is that purified components, like the purified NS5A substrate and the kinase of interest, are not always available...
- Crystallization and preliminary X-ray diffraction studies of the transcriptional regulator TraR bound to its cofactor and to a specific DNA sequenceAlessandro Vannini
Department of Biochemistry, IRBM P. Angeletti, 00040 Pomezia, Rome, Italy
Acta Crystallogr D Biol Crystallogr 58:1362-4. 2002..A three-wavelength MAD data set for the seleno-L-methionine-substituted form has been collected to a resolution of 3 A. 20 of the 24 crystallographically independent selenium sites were located as part of the MAD-phasing process...
- Probing the elusive catalytic activity of vertebrate class IIa histone deacetylasesPhilip Jones
IRBM Merck Research Laboratories, Via Pontina Km 30, 600, 00040 Pomezia, Italy
Bioorg Med Chem Lett 18:1814-9. 2008..The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors...
- High-throughput screening of the yeast kinome: identification of human serine/threonine protein kinases that phosphorylate the hepatitis C virus NS5A proteinCarlos Coito
Department of Microbiology, Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA
J Virol 78:3502-13. 2004..Our results suggest that this novel approach may be generally applicable to the screening of other protein biochemical activities by mechanistic class...
- Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinaseYupeng He
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195, USA
J Virol 76:9207-17. 2002....