Chen Baobao, Li Yinghua, Bai Haohao, Ji Yajing, Cong Wei, Hu Honggang, He Shipeng
Institute of Translational Medicine, Shanghai University, 200444, China.
School of Medicine, Shanghai University, 200444, China.
Bioorg Chem. 2023 Nov;140:106770. doi: 10.1016/j.bioorg.2023.106770. Epub 2023 Aug 16.
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.
鉴定具有革新乳腺癌治疗潜力的新型候选分子具有深远的临床意义。源自野生蜜蜂毒液的巨吞饮（Mac）-1，成为对抗乳腺癌的一种有前景的治疗剂。然而，线性肽长期以来一直面临穿越细胞膜和易受蛋白酶水解的挑战。为应对这一挑战，本研究采用烃钉合修饰来合成一系列钉合的Mac-1肽，并对其化学和生物学性质进行了全面评估。值得注意的是，Mac-1-sp4表现出一系列显著的改进，包括增强的螺旋度、蛋白水解稳定性、细胞膜通透性、诱导细胞凋亡、体内抗肿瘤活性以及抑制微管蛋白聚合。本研究探讨了烃钉合技术对Mac-1二级结构、水解酶稳定性和生物活性的重大影响，揭示了其作为一种革命性强效抗乳腺癌疗法的潜力。这些发现为开发创新且高效的抗肿瘤治疗方法奠定了坚实基础。
