The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH2) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC50=2.5±0.2μM), breast adenocarcinoma MDA-MB-231 cells (LC50=9.0±0.3μM), colorectal adenocarcinoma HT-29 cells (LC50=9.7±0.2μM), and hepatocarcinoma HepG2 cells (LC50=22.5±1.4μM) with appreciably less hemolytic activity against human erythrocytes (LC50=213±18μM). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro5, Glu6 and Asp9on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6fold) but hemolytic activity also increases (LC50=174±12μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC50 in the range 2.1-21μM) but show reduced hemolytic activity (LC50>300μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.
Bibliographical noteFunding Information:
This work was supported by a Faculty Support Grant and a University/National Research Foundation Grant from U.A.E. University and an award from the Terry Fox Fund for Cancer Research . The authors thank Dr. Katarina Hostanska, Department of Internal Medicine, Institute for Complementary Medicine, University Hospital of Zurich for providing the A549 cell line, Prof. Joan Massague, Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center for providing the MDA-MB-231 cell line, and Prof. Nico Nagelkerke, Institute of Public Health, U.A.E. University for help with data analysis.
- Frog skin
- Host-defense peptide