Efficient synthesis, stability-guided optimization and anticancer evaluation of bee venom peptide Melittin

Area of Science:

• Biochemistry
• Pharmacology
• Peptide Chemistry

Background:

• Natural cytotoxic peptides (NCPs) are promising anticancer agents.
• Melittin, a key NCP from bee venom, faces challenges like poor stability and hemolysis.
• Melittin's potential as an anticancer scaffold is limited by its susceptibility to degradation.

Purpose of the Study:

• To design and synthesize Melittin-based derivatives with improved anticancer efficacy and stability.
• To investigate the in vitro anticancer activity, stability, and mechanism of action of these derivatives.
• To explore terminal modification and hybridization strategies for Melittin optimization.

Main Methods:

• Synthesis of ten Melittin-based derivatives using terminal modification and hybridization.
• Evaluation of in vitro cytotoxicity, time-kill kinetics, and serum stability.
• Assessment of anti-migration activity, hemolysis effects, and anticancer mechanisms.

Main Results:

• Melittin derivatives demonstrated potent cytotoxicity against six cancer cell lines.
• LJ-5 (N-terminal acetylation, C-terminal hydrazidation) and LJ-6 (methotrexate conjugate) showed enhanced proteolytic stability and durability.
• LJ-5 and LJ-6 exhibited reduced hemolysis and effectively disrupted cancer cell membrane integrity and mitochondrial function.

Conclusions:

• Stability-guided optimization of Melittin yielded hydrolysis-resistant derivatives LJ-5 and LJ-6.
• These derivatives possess significant potential as anticancer candidates.
• The study provides a valuable reference for further optimization of cytotoxic peptides.