The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination

Jin, Jinmei; Wu, Ye; Chen, Jin-Jiao; Shen, Yiwen; Zhang, Lijun; Zhao, Hong; Chen, Lili; Yuan, Hebao; Chen, Hongzhuan; Zhang, Weidong; Luan, Xin

doi:10.7150/thno.46985

Cited by 70 publications

(70 citation statements)

References 112 publications

(155 reference statements)

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“…Targeted protein degradation using PROTAC to degrade specific proteins from within cells is a novel drug discovery strategy 14 , 25 . As PROTACs could potentially be generated for any protein including a large subset of 'undruggable' proteins, it may be used to target tau, a natively unfolded undruggable protein.…”

Section: Discussionmentioning

confidence: 99%

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

et al. 2021

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Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo . Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo , which provides a promising drug candidate for AD and the related tauopathies.

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Section: Discussionmentioning

confidence: 99%

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

et al. 2021

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“…Here, we suggest that interaction between the S and N proteins of MERS-CoV and SARS-CoV-2 can serve as a therapeutic target. However, the inhibitory peptides may have pitfalls such as poor permeability and low stability 60 . Furthermore, cell penetrating peptides lack specificity of targeting cells and are susceptible to degradation during experimental or clinical procedures 61 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cell penetrating peptides lack specificity of targeting cells and are susceptible to degradation during experimental or clinical procedures 61 . Therefore, screenings of more stable inhibitors such as peptidomimetics, peptides with chemical modifications, or small molecule inhibitors are required to overcome these difficulties 60 , 62 . An efficient delivery system for the inhibitors will be also needed for therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

MERS-CoV and SARS-CoV-2 replication can be inhibited by targeting the interaction between the viral spike protein and the nucleocapsid protein

Kim

Baek

et al. 2021

Theranostics

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Background: The molecular interactions between viral proteins form the basis of virus production and can be used to develop strategies against virus infection. The interactions of the envelope proteins and the viral RNA-binding nucleocapsid (N) protein are essential for the assembly of coronaviruses including the Middle East respiratory syndrome coronavirus (MERS-CoV). Methods: Using co-immunoprecipitation, immunostaining, and proteomics analysis, we identified a protein interacting with the spike (S) protein in the cells infected with MERS-CoV or SARS-CoV-2. To confirm the interaction, synthetic peptides corresponding to the C-terminal domain of the S protein (Spike CD) were produced and their effect on the interaction was investigated in vitro . In vivo effect of the Spike CD peptides after cell penetration was further investigated using viral plaque formation assay. Phylogeographic analyses were conducted to deduce homology of Spike CDs and N proteins. Results: We identified a direct interaction between the S protein and the N protein of MERS-CoV that takes place during virus assembly in infected cells. Spike CD peptides of MERS-CoV inhibited the interaction between the S and N proteins in vitro. Furthermore, cell penetration by the synthetic Spike CD peptides inhibited viral plaque formation in MERS-CoV-infected cells. Phylogeographic analyses of Spike CDs and N proteins showed high homology among betacoronavirus lineage C strains. To determine if Spike CD peptides can inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we used the same strategy and found that the SARS-CoV-2 Spike CD peptide inhibited virus replication in SARS-CoV-2-infected cells. Conclusions: We suggest that the interaction between the S protein and the N protein can be targeted to design new therapeutics against emerging coronaviruses, including SARS-CoV-2.

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“…The size of a chimera composed of two different ligands is twice as large as traditional drugs, which affects their pharmacokinetics and can potentially cause absorption issues. Surprisingly, PROTAC permeability is relatively high and can be improved by linker modifications or attaching cell-penetrating peptides (Maple et al, 2019;Jin J. et al, 2020;Liu X. et al, 2020). Ligands that bind to the E3 ligase and to the protein of interest can be either small molecules or peptides.…”

Section: Protacsmentioning

confidence: 99%

“…The first PROTACs had peptidic binding moieties; however, because of the relatively poor permeability and stability for peptides, more recent PROTACs now are constructed from small molecules (Sakamoto et al, 2001;Schneekloth et al, 2004;Ishikawa et al, 2020). Nonetheless, the limitations of peptide ligands may in principle be obviated with peptidomimetics, chemical modifications, or fusions with cell-penetrating peptides (Jiang et al, 2018;Lu et al, 2018;Au et al, 2020;Jin J. et al, 2020;Lee et al, 2020;Ma D. et al, 2020). Due to the low toxicity of peptides, their large binding surfaces (which can help overcome the effect of mutations in target proteins), and the possibility of designing multiple potential ligands based on structures of protein complexes, peptide-based PROTACs are still used (Au et al, 2020;Jin J. et al, 2020).…”

Section: Protacsmentioning

confidence: 99%

Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria

Izert

Klimecka

Górna

2021

Front. Mol. Biosci.

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A repertoire of proteolysis-targeting signals known as degrons is a necessary component of protein homeostasis in every living cell. In bacteria, degrons can be used in place of chemical genetics approaches to interrogate and control protein function. Here, we provide a comprehensive review of synthetic applications of degrons in targeted proteolysis in bacteria. We describe recent advances ranging from large screens employing tunable degradation systems and orthogonal degrons, to sophisticated tools and sensors for imaging. Based on the success of proteolysis-targeting chimeras as an emerging paradigm in cancer drug discovery, we discuss perspectives on using bacterial degraders for studying protein function and as novel antimicrobials.

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The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination

Cited by 70 publications

References 112 publications

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

MERS-CoV and SARS-CoV-2 replication can be inhibited by targeting the interaction between the viral spike protein and the nucleocapsid protein

Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria

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