A5071271596- Adipose Tissue and Metabolism
- RNA and protein synthesis mechanisms
- Viral Infectious Diseases and Gene Expression in Insects
- PI3K/AKT/mTOR signaling in cancer
- Phytochemical compounds biological activities
- Microbial Metabolic Engineering and Bioproduction
- RNA Research and Splicing
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Plant biochemistry and biosynthesis
- Animal Disease Management and Epidemiology
- RNA modifications and cancer
- Advanced Breast Cancer Therapies
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Polyamine Metabolism and Applications
- RNA regulation and disease
- Fungal Plant Pathogen Control
- Cancer Mechanisms and Therapy
- Diet and metabolism studies
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Traditional and Medicinal Uses of Annonaceae
- RNA Interference and Gene Delivery
- Cocoa and Sweet Potato Agronomy
McGill University
2015-2025
McGill University Health Centre
2010-2024
Medical University of Vienna
2004-2014
Max Perutz Labs
2004-2008
Laboratoire de Biochimie
2008
Boston University
2008
Vienna Biocenter
2001-2005
University of Vienna
2001
Background Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and vivo inhibit translation initiation. They have been shown to modulate eIF4A, DEAD-box RNA helicase subunit eukaryotic initiation factor (eIF) 4F complex, complex stimulates ribosome recruitment during One flavagline, silvestrol, is capable modulating chemosensitivity mechanism-based mouse model. Methodology/Principal Findings Among number flavagline members tested...
Despite the growing number of examples small-molecule inhibitors that disrupt protein–protein interactions (PPIs), origin druggability such targets is poorly understood. To identify druggable sites in interfaces we combine computational solvent mapping, which explores protein surface using a variety small “probe” molecules, with conformer generator to account for side-chain flexibility. Applications unliganded structures 15 PPI target proteins show comprise cluster binding hot spots,...
Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step protein synthesis the loading ribosomes onto mRNA templates stimulated by heterotrimeric complex, eukaryotic factor (eIF)4F. This represents an attractive target for anticancer drug discovery because it resides at nexus TOR signaling pathway. We have undertaken ultra-high-throughput screen to identify inhibitors that prevent assembly eIF4F complex. One identified compounds...
Abstract The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (eIF4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, oncogenic transformation. eIF4F is involved recruitment ribosomes to mRNAs thought generally be rate-limiting phase translation. Here, we show that c-Myc directly activates three subunits (eIF4E, eIF4AI, eIF4GI). These transcriptional effects are mediated through canonical E-boxes (5′CACGTG3′)...
RNAi combined with next-generation sequencing has proven to be a powerful and cost-effective genetic screening platform in mammalian cells. Still, this technology its limitations is incompatible situ mutagenesis screens on genome-wide scale. Using p53 as proof-of-principle target, we readapted the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated 9) genome-editing system demonstrate feasibility of methodology for targeted gene disruption positive...
Significance IFIT1 is an antiviral effector of host innate-immunity that selectively recognizes the 5′-end viral mRNAs, which are often capped to mimic mRNA, and blocks their translation. Our X-ray structural analysis reveals cap four additional nucleotides encircled by through a central tunnel in adaptable manner, gives it flexibility required defend against many different viruses, deter ability rapidly evolve. Host normally ribose methylated at first second following cap, avoids...
The recruitment of ribosomes to eukaryotic cellular mRNAs requires the activity two prototypic RNA helicases, initiation factor (eIF) 4AI and eIF4AII. eIF4A isoforms are highly conserved, thought be functionally interchangeable, directed 5' m(7)GpppN cap structure during translation by virtue their assembly into eIF4F, a heterotrimeric complex that also harbors eIF4E binding protein eIF4G scaffolding unit. During course interference experiments aimed at investigating respective roles eIF4AI...
The clustered regularly interspaced short palindromic repeat (CRISPR)-associated enzyme Cas9 is an RNA-guided nuclease that has been widely adapted for genome editing in eukaryotic cells. However, the vivo target specificity of poorly understood and most studies rely on silico predictions to define potential off-target spectrum. Using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we delineate genome-wide binding panorama catalytically inactive directed two different single...
Abstract Inactivating mutations in SMARCA4 ( BRG1 ), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to inhibition cyclin-dependent kinase 4/6 (CDK4/6). loss causes profound downregulation cyclin D1, which limits CDK4/6 activity leads vitro vivo susceptibility inhibitors. patient...
Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of controls ribosome recruitment flux eukaryotic factor (eIF) 4F, a hetero-trimeric complex composed the cap binding protein eIF4E, scaffolding eIF4G, RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising activity preclinical settings. Among these are some rocaglate family members well...
In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes high degree heterogeneity associated with disease. Specifically, focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as potential vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment...
RNA helicases represent a large family of proteins implicated in many biological processes including ribosome biogenesis, splicing, translation and mRNA degradation. However, these have little substrate specificity, making inhibition selected challenging problem. The prototypical DEAD box helicase, eIF4A, works conjunction with other factors to prepare templates for recruitment during initiation. Herein, we provide insight into the selectivity small molecule inhibitor hippuristanol. This...
The total synthesis of the natural product (−)-silvestrol (1) has been accomplished and features enantioselective [3+2] photocycloaddition a substituted 3-hydroxyflavone methyl cinnamate promoted by chiral Brønsted acid. Initial biological studies indicate 5–10-fold greater activity silvestrol as an inhibitor protein in HeLa cells than its 1′′′′ diastereomer.
The rocaglates/rocaglamides are a class of natural products known to display potent anticancer activity. One such derivative, silvestrol, has shown activity comparable taxol in certain settings. Here, we report the synthesis various rocaglamide analogues and identification hydroxamate derivative (-)-9 having similar silvestrol vitro ex vivo for inhibition protein synthesis. We also show that synergizes with doxorubicin reduce Eμ-Myc driven lymphomas.
Coronaviruses are a family of enveloped single-stranded positive-sense RNA viruses causing respiratory, enteric, and neurologic diseases in mammals fowl. Human coronaviruses recognized to cause up third common colds suspected be involved enteric diseases. Coronavirus replication involves the generation nested subgenomic mRNAs (sgmRNAs) with capped 5' leader sequence. The translation most sgmRNAs is thought cap dependent displays requirement for eukaryotic initiation factor 4F (eIF4F),...
Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities pre-clinical cancer studies. As result, this compounds has been significantly expanded through the development efficient synthetic schemes. However, it is unknown whether all members rocaglate act similar mechanisms action. Here, we present comprehensive study comparing biological >200 rocaglates better understand how presence different...
Shedding light on translation: A light-driven, biomimetic [3+2] cycloaddition has been achieved with the synthesis of a series rocaglate derivatives. Mechanistic data suggest possibility for donor–acceptor interactions and involvement triplet biradicaloids in photoexcited state. Several new derivatives approach potency anticancer agent silvestrol.
Translation is regulated predominantly at the initiation phase by several signal transduction pathways that are often usurped in human cancers, including PI3K/Akt/mTOR axis. mTOR exerts unique administration over translation regulating assembly of eukaryotic factor (eIF) 4F, a heterotrimeric complex responsible for recruiting 40S ribosomes (and associated factors) to mRNA 5′ cap structures. Hence, there much interest targeted therapies block eIF4F activity assess consequences on tumor cell...
p53 is a central mediator of cellular stress responses, and its precise regulation essential for the normal progression hematopoiesis. MYSM1 an epigenetic regulator maintenance hematopoietic stem cell (HSC) function, progenitor survival, lymphocyte development. We recently demonstrated that all developmental phenotypes Mysm1 deficiency are p53-mediated rescued in Mysm1−/−p53−/− mouse model. However, mechanisms triggering activation Mysm1−/− HSPCs, pathways downstream driving different...
Uncompetitive inhibition is an effective strategy for suppressing dysregulated enzymes and their substrates, but discovery of suitable ligands depends on often-unavailable structural knowledge serendipity. Hence, despite surging interest in mass spectrometry-based target identification, proteomic studies substrate-dependent engagement remain sparse. Herein, we describe a the ligand binding. Using proteome integral solubility alteration (PISA) assays, show that simple biochemical additives...