Cyclic Analogues of Horseshoe Crab Peptide Tachyplesin I With Anticancer and Cell Penetrating Properties

ACS Chem Biol. 2019 Dec 20;14(12):2895-2908. doi: 10.1021/acschembio.9b00782. Epub 2019 Nov 27.


Tachyplesin-I (TI) is a host defense peptide from the horseshoe crab Tachypleus tridentatus that has outstanding potential as an anticancer therapeutic lead. Backbone cyclized TI (cTI) has similar anticancer properties to TI but has higher stability and lower hemolytic activity. We designed and synthesized cTI analogues to further improve anticancer potential and investigated structure-activity relationships based on peptide-membrane interactions, cellular uptake, and anticancer activity. The membrane-binding affinity and cytotoxic activity of cTI were found to be highly dependent on peptide hydrophobicity and charge. We describe two analogues with increased selectivity toward melanoma cells and one analogue with the ability to enter cells with high efficacy and low toxicity. Overall, the structure-activity relationship study shows that cTI can be developed as a membrane-active antimelanoma lead, or be employed as a cell penetrating peptide scaffold that can target and enter cells without damaging their integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / pharmacology*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / pharmacology*
  • Horseshoe Crabs / chemistry*
  • Humans
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*


  • Antimicrobial Cationic Peptides
  • Antineoplastic Agents
  • Cell-Penetrating Peptides
  • DNA-Binding Proteins
  • Peptides, Cyclic
  • tachyplesin peptide, Tachypleus tridentatus