Degradation from the outside in: Targeting extracellular and membrane proteins for degradation through the endolysosomal pathway

Ahn, Green; Banik, Steven M.; Bertozzi, Carolyn R.

doi:10.1016/j.chembiol.2021.02.024

Cited by 46 publications

(59 citation statements)

References 63 publications

(68 reference statements)

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“…The target binding molecule can be composed of antibodies or antibody fragments, but the design is not limited to antibodies (e.g., protein adhesives) (Figure ). Development of LYTAC molecules utilizing specific lysosomal-targeting receptors also enables targeted degradation of a given lysosome expressed in specific cell types …”

Section: Targeted Protein Degradation For Neurodegenerative Disease T...mentioning

confidence: 99%

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

et al. 2022

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Neurodegenerative diseases (NDs) are currently incurable diseases that cause progressive degeneration of nerve cells. Many of the disease-causing proteins of NDs are “undruggable” for traditional small-molecule inhibitors (SMIs). None of the compounds that attenuated the amyloid-β (Aβ) accumulation process have entered clinical practice, and many phase III clinical trials of SMIs for Alzheimer’s disease (AD) have failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), and autophagy-targeting chimeras (AUTACs) with TPD-assistive technologies such as click-formed proteolysis-targeting chimeras (CLIPTACs) and deubiquitinase-targeting chimera (DUBTAC) have developed rapidly. In vitro and in vivo experiments have also confirmed that TPD technology can target the degradation of ND pathogenic proteins, bringing hope for the treatment of NDs. Herein, we review the latest TPD technologies, introduce their targets and technical characteristics, and discuss the emerging TPD technologies with potential in ND research, with the hope of providing a new perspective for the development of TPD technology in the NDs field.

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Section: Targeted Protein Degradation For Neurodegenerative Disease T...mentioning

confidence: 99%

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

et al. 2022

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“…Lysosome-dependent protein degradation is another commonly employed strategy for the degradation of target proteins. One such strategy is the recently developed LYTAC system (reviewed by Bertozzi et al 145 ). LYTACs can bind both to target proteins and endocytic receptors, leading to endocytosis and, subsequently, lysosomal degradation (Fig.…”

Section: Targeted Depletion or Degradation Of Suppressive Componentsmentioning

confidence: 99%

New opportunities for immunomodulation of the tumour microenvironment using chemical tools

2022

Chem. Soc. Rev.

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“…In contrast, extracellular and membrane-associated proteins involved in diseases such as cancer or autoimmune disorders are difficult to address using TPD. 50 However, one could degrade these extracellular proteins by using an “outside-in” strategy, bringing the targeted extracellular proteins inside the cell lysosomal compartment to access the cellular degradation machinery. For example, a cell surface protein receptor, low-density lipoprotein receptor (LDLR), binds to the proprotein convertase subtilisin kexin 9 (PCSK9) and promotes the trafficking of these binding complexes to the lysosome for degradation.…”

Section: Targeted Protein Degradation Using M6p-based Lytac and Galnac-based Lytacmentioning

confidence: 99%

“…For example, a cell surface protein receptor, low-density lipoprotein receptor (LDLR), binds to the proprotein convertase subtilisin kexin 9 (PCSK9) and promotes the trafficking of these binding complexes to the lysosome for degradation. 50 …”

Section: Targeted Protein Degradation Using M6p-based Lytac and Galnac-based Lytacmentioning

confidence: 99%

Lysosome-Targeting Strategy Using Polypeptides and Chimeric Molecules

et al. 2021

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Lysosomes are membranous compartments containing hydrolytic enzymes, where cellular degradation of proteins and enzymes among others occurs in a controlled manner. Lysosomal dysfunction results in various pathological situations, such as several lysosomal storage disorders, neurodegeneration, infectious diseases, cancers, and aging. In this review, we have discussed different strategies for synthesizing peptides/chimeric molecules, their lysosome-targeting ability, and their ability to treat several lysosomal associated diseases, including lysosomal storage diseases and cancers. We have also discussed the delivery of cargo molecules into the lysosome using lysosome-targeting ligand-decorated nanocarriers. The introduction of a protein-binding ligand along with a lysosome-targeting ligand to manufacture a chimeric architecture for cell-specific protein (extracellular and membrane protein) degradation ability has been discussed thoroughly. Finally, the future applications of these lysosome-targeting peptides, nanocarriers, and chimeric molecules have been pointed out.

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Degradation from the outside in: Targeting extracellular and membrane proteins for degradation through the endolysosomal pathway

Cited by 46 publications

References 63 publications

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

New opportunities for immunomodulation of the tumour microenvironment using chemical tools

Lysosome-Targeting Strategy Using Polypeptides and Chimeric Molecules

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