Premium
A Multivalent Ligand for the Mannose‐6‐Phosphate Receptor for Endolysosomal Targeting of an Activity‐Based Probe
Author(s) -
Hoogendoorn Sascha,
van Puijvelde Gijs H. M.,
Kuiper Johan,
van der Marel Gijs A.,
Overkleeft Herman S.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201406842
Subject(s) - mannose 6 phosphate , mannose , mannose receptor , endosome , ligand (biochemistry) , chemistry , receptor , biochemistry , cathepsin , glycan , microbiology and biotechnology , biology , glycoprotein , in vitro , enzyme , growth factor , macrophage
The ubiquitously expressed mannose‐6‐phosphate receptors (MPRs) are a promising class of receptors for targeted compound delivery into the endolysosomal compartments of a variety of cell types. The development of a synthetic, multivalent, mannose‐6‐phosphate (M6P) glycopeptide‐based MPR ligand is described. The conjugation of this ligand to fluorescent DCG‐04, an activity‐based probe for cysteine cathepsins, enabled fluorescent readout of its receptor‐targeting properties. The resulting M6P‐cluster–BODIPY–DCG‐04 probe was shown to efficiently label cathepsins in cell lysates as well as in live cells. Furthermore, the introduction of the 6‐ O ‐phosphates leads to a completely altered uptake profile in COS and dendritic cells compared to a mannose‐containing ligand. Competition with mannose‐6‐phosphate abolished all uptake of the probe in COS cells, and we conclude that the mannose‐6‐phosphate cluster targets the MPR and ensures the targeted delivery of cargo bound to the cluster into the endolysosomal pathway.