Cited by 245Protein Degradation and InhibitorsChemical Synthesis and AnalysisRNA Interference and Gene Delivery

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Bifunctional small molecules that mediate the degradation of extracellular proteins

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Caianiello, David F., Zhang, Mengwen, Ray, Jason D., Howell, Rebecca A., Swartzel, Jake C., Branham, Emily M. J., Chirkin, Egor, Sabbasani, Venkata R., Gong, Angela Z., McDonald, David M., Muthusamy, Viswanathan, Spiegel, David A.·2021·Nature Chemical Biology

DOI 10.1038/s41589-021-00851-1

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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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Research works printed but not linked: 2

Spiegel, D. A., Caianiello, D. & Zhang, M. Bifunctional small molecules to target the selective degradation of circulating proteins. PCT patent WO 2019/199634. US patent US62/655,055 US62/788,040 (2019).
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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: Zhang, Mengwen
Ray, Jason D.
Howell, Rebecca A.
Branham, Emily M. J.
Sabbasani, Venkata R.
Gong, Angela Z.
McDonald, David M.
Muthusamy, Viswanathan
Spiegel, David A.
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2021-08-19
Volume: 17
Issue: 9
Pages: 947-953
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/s41589-021-00851-1
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: cc-by-nc-nd
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Bifunctional small molecules that mediate the degradation of extracellular proteins

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