Hydrocarbon stapling strategy and antitumor activity of antimicrobial peptide Lasioglossum III.

The identification of novel candidate molecules with breakthrough potential is critical for advancing breast cancer therapy. Lasioglossum-III (LL-III), a linear peptide isolated from wild bee venom, has emerged as a promising lead compound for breast cancer treatment. However, its therapeutic potential is limited by poor membrane permeability and low stability, which are common limitations of linear peptides. To overcome these challenges, we applied an all-hydrocarbon stapling strategy to design and synthesize a series of LL-III stapled peptides and systematically evaluated their physicochemical properties and antitumor activities. Among the derivatives, LL-III-4 exhibited the most pronounced overall improvements, including enhanced α-helicity, increased protease resistance, improved membrane permeability, strengthened apoptosis induction, elevated in intro antitumor efficacy, and augmented inhibition of tubulin polymerization. Collectively, this study demonstrates that all-hydrocarbon stapling effectively optimizes the secondary structure, stability, and biological activity of LL-III, providing a novel drug candidate for breast cancer therapy.