Cell-penetrating peptides (CPPs) comprise efficient peptide-based delivery vectors. Owing to the inherent poor enzymatic stability of peptides, CPPs displaying partial or full replacement of l-amino acids with the corresponding d-amino acids might possess advantages as delivery vectors. Thus, the present study aims to elucidate the membrane- and metabolism-associated effects of l-Penetratin (l-PEN) and its corresponding all-d analog (d-PEN). These effects were investigated when exerted on hepatocellular (HepG2) or intestinal (Caco-2 and IEC-6) cell culture models. The head-to-head comparison of these enantiomeric CPPs included evaluation of their effects on cell viability and morphology, epithelial membrane integrity, and cellular ultrastructure. In all investigated cell models, a rapid decrease in cell viability, pronounced membrane perturbation and an altered ultrastructure were detected upon exposure to d-PEN. At equimolar concentrations, these observations were less pronounced or even absent for cells exposed to l-PEN. Both CPPs remained stable for at least 2 h during exposure to proliferating cells (cultured for 24 h), although d-PEN exhibited a longer half-life when compared with that of l-PEN when exposed to well-differentiated cell monolayers (cultured for 18–20 days). Thus, the stereochemistry of the CPP penetratin significantly influences its effects on cell viability and epithelial integrity when profiled against a panel of mammalian cells.
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A high-resolution crystal structure of the molybdenum insertase Cnx1E from Arabidopsis thaliana reveals two mutually exclusive molybdate binding sites, that have mechanistic implications for the Mo-insertion process into the pterin moiety of the molybdenum cofactor. In this issue of the Biochemical Journal, Kruse et al. found that molybdate is sequentially bound to the entry and the catalytically-productive site, going hand in hand with a distinct backbone conformation shift. In this image, adenylated molybdopterin and the two molybdate ions are shown in front of the Cnx1E active site. (Image provided by J. Krausze, W. A. Sassen and T. Kruse); for details see pages 1739–1753.
Stereochemistry as a determining factor for the effect of a cell-penetrating peptide on cellular viability and epithelial integrity
Ditlev Birch, Malene V. Christensen, Dan Staerk, Henrik Franzyk, Hanne Mørck Nielsen; Stereochemistry as a determining factor for the effect of a cell-penetrating peptide on cellular viability and epithelial integrity. Biochem J 31 May 2018; 475 (10): 1773–1788. doi: https://doi.org/10.1042/BCJ20180155
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