The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway
Abstract
Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau. Peptide 1 showed strong in vitro binding with Keap1 and Tau. With proper cell permeability, peptide 1 was found to colocalize with cellular Keap1 and resulted in the coimmunoprecipitation of Tau and Keap1. The results of flow cytometry and western blotting assays showed that peptide 1 can downregulate the intracellular Tau level in both time- and concentration-dependent manner. The application of Keap1 siRNA silencing and the proteasome inhibitor MG132 confirmed that peptide 1 could promote the Keap1-dependent poly-ubiquitination and proteasome-dependent degradation of Tau. The results suggested that using PROTACs to recruit Keap1 to induce the degradation of Tau may show promising character in the treatment of neurodegenerative disease. Besides, our research demonstrated that Keap1 should be a promising E3 ligase adaptor to be used in the design of novel PROTACs.
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In the citing paper
“Importantly, induced turnover of tau by the UPS, and the degradability of tau species, has been demonstrated by a tau–kelch-like ECH-associated protein 1 (KEAP1) chimeric peptide PROTAC molecule188, as well as by a VHL–tau PROTAC189.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [188]
In the citing paper
“Additionally, multiple groups have described a range of pepTACs that harness SKP1/SCF F-box, VHL, KEAP1 and other E3 ligases to degrade tau or α-synuclein in primary neurons and other cell lines188,193,213”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [188]
In the citing paper
“A peptide-based PROTAC which recruits the KEAP1 E3 ligase to degrade Tau protein demonstrates the potential of PROTAC technology to treat neurodegenerative disorders such as Alzheimer’s disease [73].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [73]
In the citing paper
“This PROTAC, termed peptide 1, was able to degrade overexpressed GFP-tagged Tau in different cell lines at 20 µM after 6–12 h of treatment times to various degrees.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
In the citing paper
“Recently, a peptide PROTAC was developed that was able to tether Kelch-like ECH-associated protein-1 (Keap1) and Tau into a ternary complex [105].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
In the citing paper
“Generation of the full-length peptide decreased Keap1 affinity tenfold and exhibited affinity towards Tau in the sub-micromolar range.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
In the citing paper
“Proof of concept for hijacking the BTB E3 ligases has been provided by a peptide PROTAC targeting Tau for degradation by KEAP1 (ref. 79 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [79]
Citations
Cites
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Classification of Intrinsically Disordered Regions and Proteins
van der Lee, R., Buljan, M., Lang, B., Weatheritt, R. J., Daughdrill, G. W., Dunker, A. K., Fuxreiter, M., Gough, J., Gsponer, J., Jones, D. T., et al. (2014) · Chemical Reviews · doi:10.1021/cr400525m · Cited by 2,249
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 815
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Research works printed but not linked: 1
- Lu, 2016, The Keap1–Nrf2–ARE pathway as a potential preventive and therapeutic target: an update, Med. Res. Rev., 36, 924, 10.1002/med.21396 · DOI
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Items 301–321 of 321
BindingDB Entry 50019525: PROTACS: A technology with a gold rush-like atmosphere.
BindingDB (2024) · UC San Diego · doi:10.7270/q2hq4488
BindingDB Entry 50013121: Discovery of a PROTAC targeting ALK with in vivo activity.
BindingDB (2022) · UC San Diego · doi:10.7270/q25h7m0f
BindingDB (2025) · UC San Diego · doi:10.7270/q29028gr
BindingDB Entry 50018681: A comprehensive review of BET-targeting PROTACs for cancer therapy.
BindingDB (2024) · UC San Diego · doi:10.7270/q2930zdd
BindingDB Entry 50023187: Recent advances in developing targeted protein degraders.
BindingDB (2026) · UC San Diego · doi:10.7270/q26t0sjf
BindingDB (2023) · UC San Diego · doi:10.7270/q2pv6qh4
BindingDB Entry 50018333: Recent progress in Keap1-Nrf2 protein-protein interaction inhibitors.
BindingDB (2024) · UC San Diego · doi:10.7270/q2b85dbt
BindingDB Entry 50021317: Progress in the controllability technology of PROTAC.
BindingDB (2025) · UC San Diego · doi:10.7270/q27d30rx
BindingDB (2024) · UC San Diego · doi:10.7270/q2pv6qt5
Metadata
- Authors
- Lu, M., Liu, T., Jiao, Q., Ji, J., Tao, M., Liu, Y., You, Q., & Jiang, Z.
- Affiliations
- China Pharmaceutical University (CN)
- Corresponding author
- You, Qidong
- Jiang, Zhengyu
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 146
- Pages
- 251-259
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W2792069216
- Cited by
- 310
- References
- 45
- Citations by year
- 2026: 30 · 2025: 46 · 2024: 48 · 2023: 47 · 2022: 35 · 2021: 36 · 2020: 37 · 2019: 24 · 2018: 6
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81773581, 81602948, 81773639)
- Natural Science Foundation of Jiangsu Province of China (BK20160746)
- National Major Science and Technology Project of China (2015ZX09101032, 2017ZX09302003, 2017ZX09101-004-003-006)
- Research Innovation Program for College Graduates of Jiangsu Province (KYLX16_1169)
- Priority Academic Program Development of Jiangsu Higher Education Institutions, the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZCX201611)
- College Students Innovation Project for the R&D of Novel Drugs (J1310032)
- China Postdoctoral Science Foundation funded project (1600010006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, Keap1, tau protein, ubiquitination, proteasomal degradation, protein degradation, neurodegenerative diseases, polyubiquitination
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Dose-Response Relationship, Drug, Humans, Peptides, Structure-Activity Relationship, Tumor Cells, Cultured, Molecular Structure, tau Proteins, Proteasome Endopeptidase Complex, Ubiquitination, Drug Discovery
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