Systematic Review Details Melittin Modifications to Overcome Toxicity, Improve Stability, and Enable Targeted Delivery

Melittin, a 26-residue peptide from bee venom, holds significant therapeutic promise due to its broad-spectrum antibacterial, antitumor, and anti-inflammatory activities. However, its clinical translation is severely hampered by critical limitations such as severe hemolysis, poor cell selectivity, rapid plasma degradation, and high immunogenicity. Current research focuses on structural modifications to overcome these druggability issues, aiming to transform this potent natural toxin into a safe and effective therapeutic agent by mitigating its inherent toxicity while preserving its beneficial effects.

This systematic review comprehensively analyzed three primary modification approaches for melittin: sequence remodeling, chemical derivatization, and conjugate engineering. Researchers synthesized how these strategies specifically tune melittin's conformation, charge, and amphiphilicity to enhance its therapeutic profile. The review systematically summarized the impact of these modifications on lowering toxicity and immunogenicity, improving in vivo stability, and enabling targeted, stimulus-responsive delivery. It also aimed to unravel melittin's core functional sites and mechanisms, identifying current research gaps and future directions for developing safer and more effective melittin-based therapeutics.

The review highlighted that structural modifications successfully mitigate melittin's severe toxicity and immunogenicity. Sequence remodeling, for example, precisely adjusts melittin's amphiphilicity and charge, leading to improved cell selectivity and reduced off-target effects. Chemical derivatization further enhances its stability and bioavailability, making it more suitable for systemic administration. Conjugate engineering emerged as a powerful strategy, enabling melittin to be delivered in a stimulus-responsive and targeted manner, significantly improving its therapeutic index. This approach allows for controlled release at disease sites, minimizing systemic exposure. The review also elucidated the core functional sites responsible for melittin's potent membrane-disrupting and immunomodulatory activities, providing a blueprint for rational design. These combined strategies transform melittin from a natural toxic peptide into a highly programmable therapeutic module. > Modifications successfully reduce melittin's severe hemolysis and immunogenicity while preserving its broad-spectrum antibacterial, antitumor, and anti-inflammatory activities.