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Bifunctional small molecules that mediate the degradation of extracellular proteins
Open accessPublished version of a preprint
Abstract
Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.
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“MoDE-As, or molecular degraders that degrade extracellular proteins via the asialoglycoprotein receptor (ASGPR), represent a novel extracellular protein degradation technology initially reported by Professor David A. Spiegel of Yale University. MoDE-As comprise three GalNAc ligands recognized by ASGPR, a protein-of-interest (POI) binding element, and a polyethylene glycol (PEG) spacer fragment”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [545]
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Metadata
- Authors
- Caianiello, D. F., Zhang, M., Ray, J. D., Howell, R. A., Swartzel, J. C., Branham, E. M. J., Chirkin, E., Sabbasani, V. R., Gong, A. Z., McDonald, D. M., Muthusamy, V., & Spiegel, D. A.
- Affiliations
- Yale University (US)
- Corresponding author
- Spiegel, David A.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2021-08-19
- Volume
- 17
- Issue
- 9
- Pages
- 947-953
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W3195114088
- Cited by
- 244
- References
- 53
- Citations by year
- 2026: 49 · 2025: 62 · 2024: 51 · 2023: 47 · 2022: 28 · 2021: 7
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Royal College of Surgeons in Ireland (submittedVersion)
- Funders
- U.S. Department of Defense (BC120554)
- Yale University
- National Institute of General Medical Sciences (T32GM067543)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- targeted protein degradation, extracellular proteins, asialoglycoprotein receptor, bifunctional small molecules, lysosomal degradation, endocytosis, antibody depletion, inflammatory cytokines, hepatocytes
- MeSH terms
- Animals, Dinitrophenols, Humans, Male, Mice, Inbred C57BL, Molecular Structure, Asialoglycoprotein Receptor, Mice, Small Molecule Libraries, Hep G2 Cells
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