Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation

Abstract

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.

Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins

“…Recent advances based on chemical biological approaches to construct bispecific chimeras demonstrate the possibility of using synthetic ligands to engage lysosome-trafficking receptors (LTRs) for protein depletion. [6] Different LTRs, including the cation-independent mannose-6-phosphate receptor, [7] the liver-specific asialoglycoprotein receptor, [8] and the integrin, [9] have been exploited to discover chimeric degraders such as lysosometargeting chimeras (LYTACs). [10] The cell surface scavenger receptors (SRs) as anion ligand binding receptors have been used for cargo delivery in DNA nanotechnology.…”

Harnessing the Lysosomal Sorting Signals of the Cation-Independent Mannose-6-Phosphate Receptor for Targeted Degradation of Membrane Proteins

“…A third strategy, integrin-facilitated lysosomal degradation (IFLD), uses bifunctional compounds for membrane protein degradation by recruiting another cellsurface lysosome-shuttling receptor, integrins. 16 Overall, these current degradation technologies for membrane proteins rely on a specific cell-surface lysosome-targeting receptor for efficacy. However, the expression of these internalizing receptors varies with tissue and cell type, thus posing a significant limitation for their further applications.…”

“…Another elegant approach for membrane protein degradation, including antibody-based PROTACs (AbTACs) and cytokine receptor-targeting chimeras (KineTACs), involves bispecific antibodies with one arm binding to the target protein and another arm binding to a transmembrane E3 ligase (RNF43) or a cytokine receptor (CXCR7). A third strategy, integrin-facilitated lysosomal degradation (IFLD), uses bifunctional compounds for membrane protein degradation by recruiting another cell-surface lysosome-shuttling receptor, integrins . Overall, these current degradation technologies for membrane proteins rely on a specific cell-surface lysosome-targeting receptor for efficacy.…”

Synthetic Site-Specific Antibody–Ligand Conjugates Promote Asialoglycoprotein Receptor-Mediated Degradation of Extracellular Human PCSK9

“…In this way, the LYTAC can bridge the POI and the LTR to enable endocytosis and delivery of POI to the lysosome for degradation. To date, several LTRs, including CI-M6PR (cation-independent mannose-6-phosphate receptor), ASGPR, integrin, and membrane-bound E3 ligase RNF43 have been successfully utilized for targeted protein degradation. ,,− Despite the recent progress in ASGPR-dependent degradation strategies, much remains to be understood about the substrate scope of this receptor and what constitutes an effective glycan ligand for successful lysosomal delivery of the protein target. In fact, since the optimization of the high-affinity synthetic tri-GalNAc ligand for ASGPR, it has been used almost exclusively for the delivery of therapeutics or probes to the liver .…”

“…LYTAC strategies have been attempted for the degradation of several clinically relevant extracellular proteins, such as PDL-1 and HER-2. ,,,, In the present study, we chose the proprotein convertase subtilisin/kexin type 9 (PCSK9) as a target to demonstrate the potential of LYTACs for the treatment of diseases like hypercholesterolemia. PCSK9 is a liver-secreted protease, the presence of which is known to reduce low-density lipoprotein receptor (LDLR) levels, resulting in higher levels of low-density lipoprotein cholesterol (LDL-C) and thus a higher risk of cardiovascular disease .…”