Luo Daoxin, Jia Chunyan, Zhu Xinghan, Zhou Jin, Li Pengzhe, Wan Juncheng, Yang Qing, Ding Rong, Gao Xiang, Zeng Zhiping, Ren Changliang
Fujian Provincial Key Laboratory of Innovative Drug Target Research, State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China.
JACS Au. 2025 May 23;5(6):2580-2592. doi: 10.1021/jacsau.5c00204. eCollection 2025 Jun 23.
Peptide transporters are integral membrane proteins responsible for the cellular uptake of dipeptides and tripeptides from the extracellular environment, which play pivotal roles in nutrient absorption, antigen presentation, and cellular signaling. Despite their essential biological functions, the development of artificial peptide transporters capable of efficiently transporting charge-neutral peptides, which are highly polar and prone to aggregation, remains a significant challenge. Herein, we introduce a novel class of peptide transporters involving the integration of anion and cation transport functionalities. Notably, , which functions as a molecular tweezer, forms a stable 1:1 complex with the charge-neutral peptide tyroserleutidean anticancer agent currently in Phase III clinical trialsand actively facilitates its transmembrane transport by shielding it from the membrane's hydrophobic core, achieving an EC value of 7.5 μM. For the first time, could remarkably enhance the peptide's bioavailability and exhibit a pronounced enhanced anticancer effect against MCF-7 breast cancer cells both and .
肽转运体是整合膜蛋白，负责从细胞外环境中摄取二肽和三肽，它们在营养吸收、抗原呈递和细胞信号传导中发挥关键作用。尽管它们具有重要的生物学功能，但开发能够有效转运电荷中性肽（高度极性且易于聚集）的人工肽转运体仍然是一项重大挑战。在此，我们介绍了一类新型的肽转运体，其涉及阴离子和阳离子转运功能的整合。值得注意的是， 作为一种分子镊子，与电荷中性肽酪丝亮肽（一种目前处于III期临床试验的抗癌剂）形成稳定的1:1复合物，并通过将其与膜的疏水核心屏蔽来积极促进其跨膜转运，实现了7.5 μM的EC值。首次， 能够显著提高该肽的生物利用度，并在 和 时对MCF-7乳腺癌细胞均表现出明显增强的抗癌作用。
