Transformation of the naturally occurring frog skin peptide, alyteserin-2a into a potent, non-toxic anti-cancer agent

J. Michael Conlon, Milena Mechkarska, Manju Prajeep, Kholoud Arafat, Milan Zaric, Miodrag L. Lukic, Samir Attoub

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


Alyteserin-2a (ILGKLLSTAAGLLSNL.NH2) is a cationic, amphipathic α-helical cell-penetrating peptide, first isolated from skin secretions of the midwife toad Alytes obstetricans. Structure-activity relationships were investigated by synthesizing analogs of alyteserin-2a in which amino acids on the hydrophobic face of the helix were replaced by l-tryptophan and amino acids on the hydrophilic face were replaced by one or more l-lysine or d-lysine residues. The Trp-containing peptides display increased cytotoxic activity against non-small cell lung adenocarcinoma A549 cells (up to 11-fold), but hemolytic activity against human erythrocytes increases in parallel. The potency of the N15K analog against A549 cells (LC50 = 13 μM) increases sixfold relative to alyteserin-2a and the therapeutic index (ratio of LC 50 for erythrocytes and tumor cells) increases twofold. Incorporation of a d-Lys11 residue into the N15K analog generates a peptide that retains potency against A549 cells (LC50 = 15 μM) but whose therapeutic index is 13-fold elevated relative to the native peptide. [G11k, N15K] alyteserin-2a is also active against human hepatocarcinoma HepG2 cells (LC50 = 26 μM), breast adenocarcinoma MDA-MB-231 cells (LC 50 = 20 μM), and colorectal adenocarcinoma HT-29 cells (LC 50 = 28 μM). [G11k, N15K] alyteserin-2a, in concentrations as low as 1 μg/mL, significantly (P < 0.05) inhibits the release of the immune-suppressive cytokines IL-10 and TGF-β from unstimulated and concanavalin A-stimulated peripheral blood mononuclear cells. The data suggest a strategy of increasing the cationicity while reducing the helicity of naturally occurring amphipathic α-helical peptides to generate analogs with improved cytotoxicity against tumor cells but decreased activity against non-neoplastic cells.

Original languageEnglish
Pages (from-to)715-723
Number of pages9
JournalAmino Acids
Issue number2
Publication statusPublished - Feb 2013


  • Alyteserin-2a
  • Anticancer
  • Cell-penetrating peptide
  • Structure-activity

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry


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