Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3

Wang, Hao‐Yuan; Yang, Haojun; Holm, Mikael; Tom, Harrison; Oltion, Keely; Al-Khdhairawi, Amjad Ayad Qatran; Weber, Jean Frederic; Blanchard, Scott C.; Ruggero, Davide; Taunton, Jack

doi:10.1038/s41557-022-01039-3

Cited by 14 publications

(10 citation statements)

References 37 publications

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“…Given the rapid response of some cell lines to eEF1A inhibitors, there is a possibility for achieving efficacy against rapidly proliferating cells in vivo with a ternatin-like inhibitor, while sparing the broad toxicity of irreversible translation inhibition. Indeed, we have recently found that a hydroxylated variant of ternatin-4 is efficacious in a mouse model of MYC-dependent B cell lymphoma ( Wang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes

Juette

Carelli

Rundlet

et al. 2022

eLife

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Rapid and accurate mRNA translation requires efficient codon-dependent delivery of the correct aminoacyl-tRNA (aa-tRNA) to the ribosomal A site. In mammals, this fidelity-determining reaction is facilitated by the GTPase elongation factor-1 alpha (eEF1A), which escorts aa-tRNA as an eEF1A(GTP)-aa-tRNA ternary complex into the ribosome. The structurally unrelated cyclic peptides didemnin B and ternatin-4 bind to the eEF1A(GTP)-aa-tRNA ternary complex and inhibit translation but have different effects on protein synthesis in vitro and in vivo. Here, we employ single-molecule fluorescence imaging and cryogenic electron microscopy to determine how these natural products inhibit translational elongation on mammalian ribosomes. By binding to a common site on eEF1A, didemnin B and ternatin-4 trap eEF1A in an intermediate state of aa-tRNA selection, preventing eEF1A release and aa-tRNA accommodation on the ribosome. We also show that didemnin B and ternatin-4 exhibit distinct effects on the dynamics of aa-tRNA selection that inform on observed disparities in their inhibition efficacies and physiological impacts. These integrated findings underscore the value of dynamics measurements in assessing the mechanism of small-molecule inhibition and highlight potential of single-molecule methods to reveal how distinct natural products differentially impact the human translation mechanism.

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Section: Discussionmentioning

confidence: 99%

Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes

Juette

Carelli

Rundlet

et al. 2022

eLife

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“…Thus far fluorescence microscopy has become an indispensable tool to investigate the mechanism of diverse eEF1A-targeting macrocycles. 65,70,[77][78][79] A FLIM-phasor FRET (fluorescence resonance energy transfer) approach provided concrete evidence for direct binding of coumarin-labeled plitidepsin to eEF1A2-GFP (green fluorescent protein) fusion protein. 65 Recently, single-molecule FRET (smFRET) imaging was applied to characterize the binding kinetics of ternatin derivative SR-A3 in detail for the first time.…”

Section: Rsc Medicinal Chemistry Research Articlementioning

confidence: 99%

“…65 Recently, single-molecule FRET (smFRET) imaging was applied to characterize the binding kinetics of ternatin derivative SR-A3 in detail for the first time. 77 Another elegant work utilized immunofluorescence analysis to establish colocalization of a rhodamine-linked fluorescence probe of BE-43547A 2 and eEF1A1 in the cytoplasm. 78 Nevertheless, subcellular localization of this class of targeted agents remains underexplored.…”

Section: Rsc Medicinal Chemistry Research Articlementioning

confidence: 99%

Site-directed late-stage diversification of macrocyclic nannocystins facilitating anticancer SAR and mode of action studies

et al. 2023

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“…Based on the verified structure of ternatin-4 ( 7 ), a β-hydroxyl group was introduced at its residue 3 to obtain two epimers of A3 , namely SR-A3 ( 8 ) and SS-A3 ( 9 ). An improved second-generation total synthesis allowed quick access to both compounds [ 68 ]. Hence, the identity of natural product A3 was established as SR-A3 ( 8 ).…”

Section: Recent Advances In Anticancer Eef1a-targeting Agentsmentioning

confidence: 99%

“…Finally, preclinical evaluation of 8 vis-a-vis 7 was carried out in an aggressive Myc-driven mouse lymphoma model. Compared with its des-hydroxyl variant ternatin-4 ( 7 ), SR-A3 ( 8 ) significantly reduced tumor burden while extending the survival of the treated Eμ-Myc mice [ 68 ]. This work highlights the importance of side-chain modification in macrocyclic drug discovery and also makes a good case that the drug–target interaction can be more precisely characterized using the drug–target residence time model [ 69 ].…”

Section: Recent Advances In Anticancer Eef1a-targeting Agentsmentioning

confidence: 99%

Anticancer Small-Molecule Agents Targeting Eukaryotic Elongation Factor 1A: State of the Art

Zhang

Cai

et al. 2023

IJMS

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Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet paradoxically, the oncogenic nature of this instrumental protein has long been recognized. Consistently, eEF1A has proven to be targeted by a wide assortment of small molecules with excellent anticancer activity, among which plitidepsin has been granted approval for the treatment of multiple myeloma. Meanwhile, metarrestin is currently under clinical development for metastatic cancers. Bearing these exciting advances in mind, it would be desirable to present a systematic up-to-date account of the title topic, which, to the best of our knowledge, has thus far been unavailable in the literature. The present review summarizes recent advances in eEF1A-targeting anticancer agents, both naturally occurring and synthetically crafted, with regard to their discovery or design, target identification, structure–activity relationship, and mode of action. Their structural diversity and differential eEF1A-targeting mechanisms warrant continuing research in pursuit of curing eEF1A-driven malignancy.

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Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3

Cited by 14 publications

References 37 publications

Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes

Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes

Site-directed late-stage diversification of macrocyclic nannocystins facilitating anticancer SAR and mode of action studies

Anticancer Small-Molecule Agents Targeting Eukaryotic Elongation Factor 1A: State of the Art

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