ArticleACS chemical biology2013
Evidence for a functionally relevant rocaglamide binding site on the eIF4A-RNA complex.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed.
- Halting translation by the letter with sequence-selective small molecules.Nature chemical biology · 2026Review
- Rocaglates and pateamines target the DEAD-box RNA helicase eIF4A from Schistosoma mansoni and demonstrate anti-schistosomal activity in vitro.Scientific reports · 2026Article
- Activity of Didesmethylrocaglamide in High Grade Serous Ovarian Cancer Using Preclinical In Vitro and In Vivo Models.Journal of natural products · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- Review
- Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis.Antiviral research · 2024Article
- DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs.Nature communications · 2024Article
- Anti-tumor effects of the eIF4A inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas.Scientific reports · 2024Article
- Anti-tumor Effects of the eIF4A Inhibitor Didesmethylrocaglamide and Its Derivatives in Human and Canine Osteosarcomas.Research square · 2024Article
- Protein translation rate determines neocortical neuron fate.Nature communications · 2024Article
- A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.The Journal of clinical investigation · 2023Article
- Post-transcriptional control of antifungal resistance in human fungal pathogens.Critical reviews in microbiology · 2023Review
- Article
- Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates.Scientific reports · 2023Article
- Exploring the targeting spectrum of rocaglates among eIF4A homologs.RNA (New York, N.Y.) · 2023Article
- Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.International journal of molecular sciences · 2023Article
- Enzymatic and Molecular Characterization of Anti-Molecules (Basel, Switzerland) · 2022Article
- In Vitro Safety, Off-Target and Bioavailability Profile of the Antiviral Compound Silvestrol.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Action and function of helicases on RNA G-quadruplexes.Methods (San Diego, Calif.) · 2022Review
12 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors.
Funding
Abstract
Translation initiation is an emerging target in oncology and neurobiology indications. Naturally derived and synthetic rocaglamide scaffolds have been used to interrogate this pathway; however, there is uncertainty regarding their precise mechanism(s) of action. We exploited the genetic tractability of yeast to define the primary effect of both a natural and a synthetic rocaglamide in a cellular context and characterized the molecular target using biochemical studies and in silico modeling. Chemogenomic profiling and mutagenesis in yeast identified the eIF (eukaryotic Initiation Factor) 4A helicase homologue as the primary molecular target of rocaglamides and defined a discrete set of residues near the RNA binding motif that confer resistance to both compounds. Three of the eIF4A mutations were characterized regarding their functional consequences on activity and response to rocaglamide inhibition. These data support a model whereby rocaglamides stabilize an eIF4A-RNA interaction to either alter the level and/or impair the activity of the eIF4F complex. Furthermore, in silico modeling supports the annotation of a binding pocket delineated by the RNA substrate and the residues identified from our mutagenesis screen. As expected from the high degree of conservation of the eukaryotic translation pathway, these observations are consistent with previous observations in mammalian model systems. Importantly, we demonstrate that the chemically distinct silvestrol and synthetic rocaglamides share a common mechanism of action, which will be critical for optimization of physiologically stable derivatives. Finally, these data confirm the value of the rocaglamide scaffold for exploring the impact of translational modulation on disease.
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