Rationally designed short cationic α-helical peptides with selective anticancer activity

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Naturally derived or synthetic anticancer peptides (ACPs) are a promising class of anticancer agents.
• ACPs exhibit higher selectivity for cancer cells and reduced drug resistance compared to conventional therapies.
• The α-helix is the predominant secondary structure in many ACPs.

Purpose of the Study:

• To develop and characterize a novel library of short cationic amphiphilic α-helical ACPs.
• To evaluate the selective cytotoxicity of these ACPs against colorectal and cervical cancer cell lines.
• To investigate the structure-activity relationships and mechanisms underlying ACP selectivity and efficacy.

Main Methods:

• Peptide synthesis with a general formula C(XXYY)3, where X and Y represent hydrophobic and cationic amino acids, respectively.
• Structural and physicochemical characterization using RP-HPLC, LC-MS, and CD spectroscopy.
• Cytotoxicity assessment via MTT assay, cell proliferation, and mitochondrial damage assays; mechanism investigation using Langmuir trough.

Main Results:

• Peptides with lysine (K) in hydrophilic domains showed selective anticancer activity, while arginine (R) analogs were toxic to normal cells.
• Anticancer activity correlated with helical content and hydrophobicity; C-terminal modifications enhanced these properties.
• Variants demonstrated potent activity against colorectal cancer multicellular tumor spheroids (MCTS) by penetrating negatively charged cancer cell membranes and inducing apoptosis via mitochondrial damage.

Conclusions:

• Short cationic amphiphilic α-helical peptides can be rationally designed for selective cancer therapy.
• Lysine-based peptides offer improved selectivity and efficacy against colorectal and cervical cancers.
• The findings provide a foundation for developing next-generation ACPs with enhanced anticancer properties.