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A Multivalent Ligand for the Mannose‐6‐Phosphate Receptor for Endolysosomal Targeting of an Activity‐Based Probe
Authors:Dr Sascha Hoogendoorn  Dr Gijs H M van Puijvelde  Prof Dr Johan Kuiper  Prof Dr Gijs A van der Marel  Prof Dr Herman S Overkleeft
Institution:1. Bio‐organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA, Leiden (The Netherlands);2. Dept of Biopharmaceutics, LACDR, Leiden (The Netherlands)
Abstract: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.
Keywords:activity‐based protein profiling  drug delivery  endolysosomal pathway  fluorescent probes  mannose‐6‐phosphate
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