Learning from host-defense peptides: cationic, amphipathic peptoids with potent anticancer activity

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Host defense peptides (HDPs) show promise for anticancer therapies.
• Peptoids are biostable peptidomimetics with tunable sequences.
• Developing effective and selective anticancer agents remains a challenge.

Purpose of the Study:

• To design and synthesize a library of peptoids mimicking cationic, amphipathic HDPs.
• To investigate the structure-activity relationships of these peptoids against cancer cells.
• To evaluate the in vivo efficacy and safety of lead peptoid compounds.

Main Methods:

• Solid-phase synthesis of poly-N-substituted glycines (peptoids).
• In vitro cytotoxicity assays against a broad range of cancer cell lines, including multidrug-resistant (MDR) lines.
• In vivo efficacy study using a human breast cancer xenotransplantation mouse model.

Main Results:

• Several peptoids demonstrated potent, concentration-dependent cytotoxicity against cancer cells at low micromolar concentrations.
• Peptoids effectively targeted cancer cells with multidrug resistance (MDR).
• The most potent peptoid (peptoid 1) significantly inhibited tumor growth in vivo with no observed adverse effects in mice, primarily acting via plasma membrane disruption.

Conclusions:

• Cationic, amphipathic peptoids are effective anticancer agents with potential for clinical development.
• These peptoids exhibit favorable properties like solubility, protease stability, and ability to overcome MDR.
• The study provides valuable structural insights for designing novel HDP mimics for cancer therapy.