Peptide Targeting of an Intracellular Receptor of the Secretory Pathway

Numerous peptides serve as natural ligands of intra- and extracellular receptors. The presence of charged amino acids, however, often hinders the membrane-crossing ability of some of these peptides and renders them unsuitable as chemical probes for perturbing or imaging intracellular targets. In this report, we show that addition of a few natural and unnatural amino acids enhances the cellular uptake and intracellular localization of a highly charged Lys-Asp-Glu-Leu (KDEL) peptide to target the corresponding receptor of the secretory pathway. Live-cell imaging experiments revealed that, through interaction with the KDEL receptor, the peptide is delivered to the endoplasmic reticulum (ER), where it accumulates preferentially. The enhanced uptake and selectivity of this peptide make it a good probe for monitoring disruptions in retrograde transport and ER stress in living cells without any genetic modifications.