Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.1c00094 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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