鉴定出具有潜力彻底改变乳腺癌治疗的新型候选分子具有重要的临床意义。源自野蜂毒液的大蜜蜂素（Mac-1）作为一种有望用于对抗乳腺癌的治疗药物崭露头角。然而，线性肽长期以来一直难以穿越细胞膜并易于受到蛋白酶水解的挑战。为了解决这一难题，本研究采用碳氢键钉扎修饰合成了一系列钉扎Mac-1肽，对它们的化学和生物学性质进行了全面评估。显著的是，Mac-1-sp4表现出了一系列显著的改进，包括增强的螺旋结构、蛋白酶稳定性、细胞膜通透性、诱导细胞凋亡、体内抗肿瘤活性和抑制微管聚合作用。本研究探讨了碳氢键钉扎技术对Mac-1的二级结构、水解酶稳定性和生物活性的重要影响，为其作为一种革命性和强效的抗乳腺癌疗法提供了线索。研究结果为开发创新和高效的抗肿瘤治疗奠定了坚实基础。版权所有 © 2023 Elsevier Inc. 保留所有权利。

The identification of novel candidate molecules with the potential to revolutionize the treatment of breast cancer holds profound clinical significance. Macropin (Mac)-1, derived from the venom of wild bees, emerges as an auspicious therapeutic agent for combating breast cancers. Nevertheless, linear peptides have long grappled with the challenges of traversing cell membranes and succumbing to protease hydrolysis. To address this challenge, the present study employed hydrocarbon stapling modification to synthesize a range of stapled Mac-1 peptides, which were comprehensively evaluated for their chemical and biological properties. Significantly, Mac-1-sp4 exhibited a remarkable set of improvements, including enhanced helicity, proteolytic stability, cell membrane permeability, induction of cell apoptosis, in vivo antitumor activity, and inhibition of tubulin polymerization. This study explores the significant impact of the hydrocarbon stapling technique on the secondary structure, hydrolase stability, and biological activity of Mac-1, shedding light on its potential as a revolutionary and potent anti-breast cancer therapy. The findings establish a strong basis for the development of innovative and highly effective anti-tumor treatments.Copyright © 2023 Elsevier Inc. All rights reserved.