title: Taurine Boosts Cellular Uptake of Small D-Peptides for Enzyme-Instructed Intracellular Molecular Self-Assembly.
abstract: Due to their biostability, D-peptides are emerging as an important molecular platform for biomedical applications. Being proteolytically resistant, D-peptides lack interactions with endogenous transporters and hardly enter cells. Here we show that taurine, a natural amino acid, drastically boosts the cellular uptake of small D-peptides in mammalian cells by >10-fold, from 118 μM (without conjugating taurine) to >1.6 mM (after conjugating taurine). The uptake of a large amount of the ester conjugate of taurine and D-peptide allows intracellular esterase to trigger intracellular self-assembly of the D-peptide derivative, further enhancing their cellular accumulation. The study on the mechanism of the uptake reveals that the conjugates enter cells via both dynamin-dependent endocytosis and macropinocytosis, but likely not relying on taurine transporters. Differing fundamentally from the positively charged cell-penetrating peptides, the biocompatibility, stability, and simplicity of the enzyme-cleavable taurine motif promise new ways to promote the uptake of bioactive molecules for countering the action of efflux pump and contributing to intracellular molecular self-assembly.
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Yamagata
authors.affiliation: Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives / Q000737:chemistry; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry; D002021:Buffers; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000493:pharmacokinetics*; D004705:Endocytosis / Q000187:drug effects; D004952:Esters / Q000737:chemistry; D005453:Fluorescence; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D046529:Microscopy, Electron, Transmission; D013654:Taurine / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000596:Amino Acids; D002021:Buffers; D057846:Cell-Penetrating Peptides; D004952:Esters; D013654:Taurine; D000584:Amiloride; D009327:4-Chloro-7-nitrobenzofurazan; C039614:ethylisopropylamiloride