Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives,ACS Chemical Biology

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Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-07-12 , DOI: 10.1021/acschembio.1c00094
Victoria G Klein ₁ , Walter M Bray ₁ , Hao-Yuan Wang ₂ , Quinn Edmondson ₁ , Joshua Schwochert ₁ , Satoshi Ono ₃ , Matthew R Naylor ₁ , Alexandra C Turmon ₁ , Justin H Faris ₁ , Okimasa Okada ₃ , Jack Taunton ₂ , R Scott Lokey ₁

Affiliation

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.

中文翻译：

鉴定 Cordyheptapeptide A 和合成衍生物的细胞靶点

Cordyheptapeptide A 是一种亲脂性环肽，来自珍贵的冬虫夏草真菌属，在多种癌细胞系中显示出有效的细胞毒性。为了更好地了解虫七肽 A 的生物活性和理化特性，最终目标是确定其细胞靶点，我们开发了这种多N-甲基化环状七肽的固相合成方法，可以快速获得侧链和骨架修饰的衍生物. 去除主链酰胺N 之一-甲基（N-Me）基团保持生物活性，同时由于在低介电溶剂中形成新的分子内氢键，膜渗透性也得以保持。基于其在 NCI-60 细胞系面板中的细胞毒性特征，以及其在基于显微镜的细胞学测定中的表型，我们假设虫七肽作为蛋白质合成抑制剂作用于细胞。进一步的研究揭示了虫七肽 A 的分子靶标是真核翻译延伸因子 1A (eEF1A)，这是其他亲脂性环肽天然产物共有的靶标。这项工作提供了一种研究和改进环肽天然产物的策略，同时强调了这些亲脂性化合物有效抑制细胞内疾病靶标的能力。

更新日期：2021-08-20

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