Isolation and Identification of Eukaryotic Initiation Factor 4A as a Molecular Target for the Marine Natural Product Pateamine A

Low, Woon Kai; Dang, Yongjun; Schneider‐Poetsch, Tilman; Shi, Zonggao; Choi, Nam Song; Rzasa, Robert M.; Shea, Hélène A.; Li, Shukun; Park, Kaapjoo; Ma, Gil; Romo, Daniel; Liu, Jun O.

doi:10.1016/s0076-6879(07)31014-8

Cited by 29 publications

(24 citation statements)

References 47 publications

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“…Previous work by others has identified eIF4A RNA helicase, a component of protein translation initiation machinery, as a cellular target of natural pateamine A (7–9, 11). A natural product extract containing pateamine A was identified as a positive hit in a screen for chemical inhibitors of translation, and the inhibitory activity of pateamine A on Cap-dependent protein translation in cells was subsequently shown by pulse labeling using radiolabeled amino acid.…”

Section: Discussionmentioning

confidence: 99%

“…The eukaryotic initiation factor 4A (eIF4A) family of RNA helicases was identified as the molecular target of pateamine A using affinity chromatography by attaching pateamine A directly to a resin (7). In parallel, Lowet al also identified the translation initiation factor eIF4A as a molecular target for pateamine A by using an affinity purification approach with a biotin-pateamine A conjugate (8, 9). In addition, the precise effect of pateamine A on eIF4A, which includes increasing its ATPase and helicase activities, was proposed to involve binding of pateamine A to eIF4A and as a result stabilizing the interaction between eIF4A and mRNA.…”

Section: Introductionmentioning

confidence: 99%

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Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

Kuznetsov

Rudolph-Owen

et al. 2009

Molecular Cancer Therapeutics

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We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDAPatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

Kuznetsov

Rudolph-Owen

et al. 2009

Molecular Cancer Therapeutics

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115

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“…We therefore reasoned that an inhibitor of all three eIF4A family members might significantly impair virus growth. One such inhibitor is the natural product pateamine A (Bordeleau et al, 2006; Hood et al, 2001; Low et al, 2007b), which specifically binds and inhibits all three eIF4A helicases (Bordeleau et al, 2005; Korneeva, 2007; Kuznetsov et al, 2009; Low et al, 2007a). Importantly, pateamine A is minimally toxic to quiescent cells, bioavailable and well-tolerated in vivo for extended periods (Di Marco et al, 2012; Kuznetsov et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

The eIF4AIII RNA helicase is a critical determinant of human cytomegalovirus replication

et al. 2016

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Human cytomegalovirus (HCMV) was recently shown to encode a large number of spliced mRNAs. While the nuclear export of unspliced viral transcripts has been extensively studied, the role of host mRNA export factors in HCMV mRNA trafficking remains poorly defined. We found that the eIF4AIII RNA helicase, a component of the exon junction complex, was necessary for efficient virus replication. Depletion of eIF4AIII limited viral DNA accumulation, export of viral mRNAs from the nucleus, and the production of progeny virus. However eIF4AIII was dispensable for the association of viral transcripts with ribosomes. We found that pateamine A, a natural compound that inhibits both eIF4AI/II and eIF4AIII, has potent antiviral activity and inhibits HCMV replication throughout the virus lytic cycle. Our results demonstrate that eIF4AIII is required for efficient HCMV replication, and suggest that eIF4A family helicases may be a new class of targets for the development of host-directed antiviral therapeutics.

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“…Biotinylated probes can be utilized in various ways in target identification strategies. They can be pre-complexed with a streptavidin resin to create a non-covalent affinity matrix [29][30][31][32][33][34][35][36], or incubated with live cells for desired time and then fished out of the solution with streptavidin resin after cell lysis [37][38][39][40]. The biotinylated probes and their attached proteins may be eluted from avidin resins by 8 M guanidineHCl, pH 1.5, or by boiling in a typical denaturing SDS-PAGE loading dye.…”

Section: Activity-based Probes Tagged With Biotin Tagmentioning

confidence: 99%

Identifying the Cellular Targets of Bioactive Small Molecules with Activity-Based Probes

Li¹,

2010

CMC

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The renaissance of cell- or organism-based phenotypic assays has made subsequent target identification for bioactive small organic molecules an important aspect of current drug discovery. Among the many strategies available for target identification, derivatizing bioactive small molecules into activity-based probes has the main advantage of determining small molecule-protein interactions directly in the native environment where the target proteins maintain their three-dimensional structures, including all the post-translational modifications, as the discrete small molecular probes usually have better access to intracellular compartments. Thus this chemical platform will not only afford a more precise means of understanding the mechanisms of action for bioactive molecules, but shed light onto the specificity of the bioactive small molecules. Here we will provide an overview of the strategies for the design of activity-based small molecular probes and review their applications for target identification using case studies. Special emphasis is placed on logistic concerns for probe's design as well as recent developments in this field.

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Isolation and Identification of Eukaryotic Initiation Factor 4A as a Molecular Target for the Marine Natural Product Pateamine A

Cited by 29 publications

References 47 publications

Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

The eIF4AIII RNA helicase is a critical determinant of human cytomegalovirus replication

Identifying the Cellular Targets of Bioactive Small Molecules with Activity-Based Probes

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