Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives
| العنوان: | Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives |
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| المؤلفون: | Alexandra C Turmon, Matthew R. Naylor, R. Scott Lokey, Okimasa Okada, Hao-Yuan Wang, Walter M. Bray, Joshua Schwochert, Quinn Edmondson, Satoshi Ono, Jack Taunton, Victoria G. Klein, Justin H Faris |
| المصدر: | ACS Chem Biol |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Protein Synthesis Inhibitors, chemistry.chemical_classification, Molecular Structure, Membrane permeability, Chemistry, Antineoplastic Agents, General Medicine, Peptides, Cyclic, Biochemistry, Article, Cyclic peptide, Elongation factor, Structure-Activity Relationship, Peptide Elongation Factor 1, Eukaryotic translation, Cell culture, Cell Line, Tumor, Protein Biosynthesis, Side chain, Humans, Molecular Medicine, Cytotoxicity, Solid-Phase Synthesis Techniques, Intracellular |
| الوصف: | Cordyheptapeptide A is a lipophilic cyclic peptide from the prized Cordyceps fungal genus that shows potent cytotoxicity in multiple cancer cell lines. To better understand the bioactivity and physicochemical properties of cordyheptapeptide A with the ultimate goal of identifying its cellular target, we developed a solid-phase synthesis of this multiply N-methylated cyclic heptapeptide which enabled rapid access to both side chain- and backbone-modified derivatives. Removal of one of the backbone amide N-methyl (N-Me) groups maintained bioactivity, while membrane permeability was also preserved due to the formation of a new intramolecular hydrogen bond in a low dielectric solvent. Based on its cytotoxicity profile in the NCI-60 cell line panel, as well as its phenotype in a microscopy-based cytological assay, we hypothesized that cordyheptapeptide was acting on cells as a protein synthesis inhibitor. Further studies revealed the molecular target of cordyheptapeptide A to be the eukaryotic translation elongation factor 1A (eEF1A), a target shared by other lipophilic cyclic peptide natural products. This work offers a strategy to study and improve cyclic peptide natural products while highlighting the ability of these lipophilic compounds to effectively inhibit intracellular disease targets. |
| تدمد: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.1c00094 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::06ef22094d2527c9d53b0e48af95ef1d https://doi.org/10.1021/acschembio.1c00094 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....06ef22094d2527c9d53b0e48af95ef1d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548937 15548929 |
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| DOI: | 10.1021/acschembio.1c00094 |