TY - JOUR
T1 - Transformation of the naturally occurring frog skin peptide, alyteserin-2a into a potent, non-toxic anti-cancer agent
AU - Conlon, J. Michael
AU - Mechkarska, Milena
AU - Prajeep, Manju
AU - Arafat, Kholoud
AU - Zaric, Milan
AU - Lukic, Miodrag L.
AU - Attoub, Samir
N1 - Funding Information:
This work was supported by a University Grant (G00000900) and a Faculty Support Grant (NP-10-12/103) from the United Arab Emirates University and by a grant from the Terry Fox for Cancer Research.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Alyteserin-2a
KW - Anticancer
KW - Cell-penetrating peptide
KW - Structure-activity
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U2 - 10.1007/s00726-012-1395-7
DO - 10.1007/s00726-012-1395-7
M3 - Article
C2 - 22965637
AN - SCOPUS:84878355317
SN - 0939-4451
VL - 44
SP - 715
EP - 723
JO - Amino Acids
JF - Amino Acids
IS - 2
ER -