As
effective ways to regulate protein levels, targeted
protein
degradation technologies have attracted great attention in recent
years. Here, we established a novel integrin-facilitated lysosomal
degradation (IFLD) strategy to degrade extracellular and cell membrane
proteins using bifunctional compounds as molecular degraders. By conjugation
of a target protein-binding ligand with an integrin-recognition ligand,
the resulting molecular degrader proved to be highly efficient to
induce the internalization and subsequent degradation of extracellular
or cell membrane proteins in an integrin- and lysosome-dependent manner.
As demonstrated in the development of BMS-L1-RGD, which is an efficient
programmed death-ligand 1 (PD-L1) degrader validated both in vitro and in vivo, the IFLD strategy
expands the toolbox for regulation of secreted and membrane-associated
proteins and thus has great potential to be applied in chemical biology
and drug discovery.
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