Tirla, AlinaRivera-Fuentes, Pablo2019-10-302019-10-302019-10-30201910.1021/acs.biochem.9b00029https://infoscience.epfl.ch/handle/20.500.14299/162475Numerous 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 chem. probes for perturbing or imaging intracellular targets. In this report, we show that addn. 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 expts. 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.amino acidamino acid analysisamino acid KAspAamino acid sequenceAmino acidsArticlecell disruptionCell membranescell transfercellular distributionCharged amino acidscoat protein complex Icontrolled studyDNA modificationendoplasmic reticulumEndoplasmic reticulumendoplasmic reticulum stressfemaleGenetic modificationsGolgi complexhumanhuman cellIntracellular localizationIntracellular receptorslive cell imagingLive-cell imaginglysylaspartylglutamylleucinelysylaspartylglutamylleucine receptormolecular probepeptidepeptide targeting cell receptor secretoryPeptidespriority journalProbesprotein functionprotein interactionprotein structureprotein targetingprotein transportreceptorsecretory pathwaySecretory pathwaystetrapeptidetryptophanylglutamyllysylaspartylglutamylleucineunclassified drugunfolded protein responseUnnatural amino acidstext::journal::journal article::research article