Heparan Sulfate-Based Neoproteoglycan for Targeted Lysosomal Degradation of Amyloid‑β

Targeted
lysosomal degradation of proteins (LDP) represents a promising
strategy for clearing unwanted toxic extracellular and secreted proteins.
Yet, significant challenges persist, including identifying potential
ligands for these proteins and lysosome-driving probes capable of
facilitating their internalization and degradation through receptor-mediated
endocytosis. Herein, we show that synthetic neoproteoglycan probes
stably anchor to the cell membrane, facilitate the internalization
of amyloid-β (Aβ) peptide into the lysosomal compartment,
and mediate the programmed death of Aβ. We have identified sulfated
oligo l-idose tetrasaccharide (ID49) and heparan
sulfate hexasaccharides (HH26S) as potential ligands
for Aβ1–42 peptide. When these molecules are
expressed on the peptide-based fluorescent neoproteoglycan backbone, PG@HH26S persists on the cell membrane and facilitates Aβ1–42 endocytosis to the lysosomal compartment and subsequent
targeted degradation of Aβ1–42. Overall, neoproteoglycans
open a new avenue to generate LDP for degrading HS-binding proteins,
including growth factors, morphogens, and toxic secreted proteins.