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, 5F-C12, 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 EC50 value of 7.5 μM. For the first time, 5F-C12 could remarkably enhance the peptide's bioavailability and exhibit a pronounced enhanced anticancer effect against MCF-7 breast cancer cells both in vitro and in vivo.
Keywords: H-bonds; artificial peptide transporters; cancer therapy; supramolecular chemistry; transmembrane transport.
© 2025 The Authors. Published by American Chemical Society.