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....