As with other extracellular degraders, we propose a mechanism in which endocytosis is initiated upon formation of a ternary complex between the target protein, the bifunctional MoDE, and a cell surface endocytic receptor. Such ternary complexes can be inhibited through competition at either terminus of the bifunctional molecule through addition of monovalent ligands or an excess of the bifunctional molecule. Indeed, excess free biotin inhibited MoDE 3 mediated uptake of Streptavidin (Figure ). Interestingly, addition of excess tri-acetyl MoDE 6 did not inhibit streptavidin uptake, likely due to the high avidity of the tetravalent streptavidin:MoDE complex compared to the monomeric inhibitor. Angiopep-2 is believed to be a ligand for the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1), and its CNS targeting activity has been attributed to its interaction with LRP1. However, addition of polyclonal anti-LRP1