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Dive into the research topics where Ivan Cornella-Taracido is active.

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Featured researches published by Ivan Cornella-Taracido.


Journal of Virology | 2009

Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication

Jason Borawski; Philip Troke; Xiaoling Puyang; Veronica Gibaja; ShanChaun Zhao; Craig Mickanin; Juliet Leighton-Davies; C. Wilson; Vic E. Myer; Ivan Cornella-Taracido; Jeremy Baryza; John A. Tallarico; Gerard Joberty; Marcus Bantscheff; Markus Schirle; Tewis Bouwmeester; Joanna E. Mathy; Kai Lin; Teresa Compton; Mark Labow; Brigitte Wiedmann; L. Alex Gaither

ABSTRACT Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.


Nature Cell Biology | 2014

Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo

William E. Dowdle; Beat Nyfeler; Jane Nagel; Robert Elling; Shanming Liu; Ellen Triantafellow; Suchithra Menon; Zuncai Wang; Ayako Honda; Gwynn Pardee; John Cantwell; Catherine Luu; Ivan Cornella-Taracido; Edmund Harrington; Peter Fekkes; Hong Lei; Qing Fang; Mary Ellen Digan; Debra Burdick; Andrew F. Powers; Stephen B. Helliwell; Simon D’Aquin; Julie Bastien; Henry Wang; Dmitri Wiederschain; Jenny Kuerth; Philip Bergman; David Schwalb; Jason R. Thomas; Savuth Ugwonali

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4−/− mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo.


Nature Chemical Biology | 2011

Natural products reveal cancer cell dependence on oxysterol-binding proteins

Anthony W G Burgett; Thomas B Poulsen; Kittikhun Wangkanont; D. Ryan Anderson; Chikako Kikuchi; Kousei Shimada; Shuichi Okubo; Kevin C. Fortner; Yoshihiro Mimaki; Minpei Kuroda; Jason Murphy; David Schwalb; Eugene C. Petrella; Ivan Cornella-Taracido; Markus Schirle; John A. Tallarico; Matthew D. Shair

Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Aurelio Bonavia; Michael Franti; Erin P. Keaney; Kelli Kuhen; Mohindra Seepersaud; Branko Radetich; Jian Shao; Ayako Honda; Janetta M. Dewhurst; Kara Balabanis; James Monroe; Karen Wolff; Colin P. Osborne; Leanne Lanieri; Keith Hoffmaster; Jakal Amin; Judit Markovits; Michelle Broome; Elizabeth Skuba; Ivan Cornella-Taracido; Gerard Joberty; Tewis Bouwmeester; Lawrence G. Hamann; John A. Tallarico; Ruben Tommasi; Teresa Compton; Simon Bushell

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.


Blood | 2011

Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells

Carla Russo; Ivan Cornella-Taracido; Luisa Galli-Stampino; Rishi K. Jain; Edmund Harrington; Yuko Isome; Simona Tavarini; Chiara Sammicheli; Sandra Nuti; M. Lamine Mbow; Nicholas M. Valiante; John A. Tallarico; Ennio De Gregorio; Elisabetta Soldaini

TLR7 and TLR8 are intracellular sensors activated by single-stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 or TLR8 or both through an unknown mechanism. Notably, direct interaction between small molecules and TLR7 or TLR8 has never been shown. To shed light on how small molecule agonists target TLRs, we labeled 2 imidazoquinolines, resiquimod and imiquimod, and one adenine-based compound, SM360320, with 2 different fluorophores [5(6) carboxytetramethylrhodamine and Alexa Fluor 488] and monitored their intracellular localization in human plasmacytoid dendritic cells (pDCs). All fluorescent compounds induced the production of IFN-α, TNF-α, and IL-6 and the up-regulation of CD80 and CD86 by pDCs showing they retained TLR7-stimulating activity. Confocal imaging of pDCs showed that, similar to CpG-B, all compounds concentrated in the MHC class II loading compartment (MIIC), identified as lysosome-associated membrane protein 1(+), CD63, and HLA-DR(+) endosomes. Treatment of pDCs with bafilomycin A, an antagonist of the vacuolar-type proton ATPase controlling endosomal acidification, prevented the accumulation of small molecule TLR7 agonists, but not of CpG-B, in the MIIC. These results indicate that a pH-driven concentration of small molecule TLR7 agonists in the MIIC is required for pDC activation.


Methods of Molecular Biology | 2012

Kinase Inhibitor Profiling Using Chemoproteomics

Markus Schirle; Eugene C. Petrella; Scott M. Brittain; David Schwalb; Edmund Harrington; Ivan Cornella-Taracido; John A. Tallarico

Quantitative chemoproteomics has recently emerged as an experimental approach to determine protein interaction profiles of small molecules in a given cell line or tissue. In contrast to standard biochemical and biophysical kinase assays, application of this method to kinase inhibitors determines compound binding to endogenously expressed kinases under conditions approximating the physiological situation with regard to the molecular state of the kinase and presence of required cofactors and regulatory proteins. Using a dose-dependent, competition-based experimental design in combination with quantitative mass spectrometry approaches, such as the use of tandem mass tags (TMT) for isobaric labeling described here, allows to rank-order interactions of inhibitors to kinase by binding affinity.


ACS Medicinal Chemistry Letters | 2016

Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo

Ayako Honda; Edmund Harrington; Ivan Cornella-Taracido; Pascal Furet; Mark Knapp; Meir Glick; Ellen Triantafellow; William E. Dowdle; Dmitri Wiedershain; Wieslawa Maniara; Christine Moore; Peter Finan; Lawrence G. Hamann; Brant Firestone; Leon O. Murphy; Erin P. Keaney

Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.


ACS Chemical Biology | 2016

Conversion of a Single Polypharmacological Agent into Selective Bivalent Inhibitors of Intracellular Kinase Activity

Carrie M. Gower; Jason R. Thomas; Edmund Harrington; Jason Murphy; Matthew E. K. Chang; Ivan Cornella-Taracido; Rishi K. Jain; Markus Schirle; Dustin J. Maly

Loss-of-function studies are valuable for elucidating kinase function and the validation of new drug targets. While genetic techniques, such as RNAi and genetic knockouts, are highly specific and easy to implement, in many cases post-translational perturbation of kinase activity, specifically pharmacological inhibition, is preferable. However, due to the high degree of structural similarity between kinase active sites and the large size of the kinome, identification of pharmacological agents that are sufficiently selective to probe the function of a specific kinase of interest is challenging, and there is currently no systematic method for accomplishing this goal. Here, we present a modular chemical genetic strategy that uses antibody mimetics as highly selective targeting components of bivalent kinase inhibitors. We demonstrate that it is possible to confer high kinase selectivity to a promiscuous ATP-competitive inhibitor by tethering it to an antibody mimetic fused to the self-labeling protein SNAPtag. With this approach, a potent bivalent inhibitor of the tyrosine kinase Abl was generated. Profiling in complex cell lysates, with competition-based quantitative chemical proteomics, revealed that this bivalent inhibitor possesses greatly enhanced selectivity for its target, BCR-Abl, in K562 cells. Importantly, we show that both components of the bivalent inhibitor can be assembled in K562 cells to block the ability of BCR-Abl to phosphorylate a direct cellular substrate. Finally, we demonstrate the generality of using antibody mimetics as components of bivalent inhibitors by generating a reagent that is selective for the activated state of the serine/threonine kinase ERK2.


Journal of Proteome Research | 2009

Use of ligand based models for protein domains to predict novel molecular targets and applications to triage affinity chromatography data.

Andreas Bender; Dmitri Mikhailov; Meir Glick; Josef Scheiber; John W. Davies; Stephen Cleaver; Stephen Marshall; John A. Tallarico; Edmund Harrington; Ivan Cornella-Taracido; Jeremy L. Jenkins


Proceedings of the National Academy of Sciences of the United States of America | 2011

Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature: Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Aurelio Bonavia; Michael Franti; E. Pusateri Keaney; Kelli Kuhen; Mohindra Seepersaud; Branko Radetich; Jian Shao; Akio Honda; John K. Dewhurst; Kara Balabanis; Jocelyn Rebecca Monroe; Karl Erich Wolff; Colin P. Osborne; Leanne Lanieri; Keith Hoffmaster; J. Amin; Judit Markovits; Matthew R. Broome; Elizabeth Skuba; Ivan Cornella-Taracido; G. Joberty; Tewis Bouwmeester; Lawrence G. Hamann; John A. Tallarico; Ruben Tommasi; Todd Compton; Simon Bushell

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Kelli Kuhen

Genomics Institute of the Novartis Research Foundation

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Teresa Compton

University of Wisconsin-Madison

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