Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives

ACS Chem Biol. 2021 Aug 20;16(8):1354-1364. doi: 10.1021/acschembio.1c00094. Epub 2021 Jul 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Molecular Structure
  • Peptide Elongation Factor 1 / antagonists & inhibitors*
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / pharmacology*
  • Protein Biosynthesis / drug effects
  • Protein Synthesis Inhibitors / chemical synthesis
  • Protein Synthesis Inhibitors / pharmacology*
  • Solid-Phase Synthesis Techniques
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Peptide Elongation Factor 1
  • Peptides, Cyclic
  • Protein Synthesis Inhibitors
  • cordyheptapeptide A