Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus

Montrose, Kristopher; Krissansen, Geoffrey W.

doi:10.1016/j.bbrc.2014.10.006

Cited by 63 publications

(50 citation statements)

References 26 publications

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“…Theo xygen-dependent degradation (ODD) domain of HIF-1a recognized by the VHL E3 ligase was conjugated to the X-protein oligomerization domain with an additional polyarginine cell-penetrating peptide.T he corresponding peptidic PROTACSc aused almost complete degradation of both the full-length and truncated forms of the X-protein. [26] Inspired by early work on phosphopeptidic PROTACs,an all-peptide-based PhosphoPROTAC ( ErbB2 PP PI3K )w as designed to induce conditional knockdown of PI3K upon growth-factor stimulation ( Figure 4). Like earlier PROTACs, this degradation molecule consisted of the VHL peptidic binding fragment and apoly-d-Arg sequence to enhance cell permeability.However,instead of asmall-molecule ligand to recruit at arget protein, ap hosphoPROTAC uses a" conditional" protein ligand, that is,o ne that binds its cognate partner only upon the addition of growth factor to the cells.…”

Section: Peptidic Protacsmentioning

confidence: 99%

Small‐Molecule PROTACS: New Approaches to Protein Degradation

2016

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The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.

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Section: Peptidic Protacsmentioning

confidence: 99%

Small‐Molecule PROTACS: New Approaches to Protein Degradation

2016

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“…Fused with an octa D-Arg stretch for cellular uptake, this peptidic VHL recruiting motif was used successfully to degrade AR- and FKBP12-GFP fusions in whole cell experiments (Schneekloth, JR et al, 2004). Furthermore, the hydroxyproline peptide sequence has been proven active in the degradation of ERα (Zhang et al, 2004; Bargagna-Mohan et al, 2005; Rodriguez-Gonzalez et al, 2008; Cyrus et al, 2010a; Cyrus et al, 2010b), the aryl hydrocarbon receptor (Lee et al, 2007; Puppala et al, 2008), the X-protein of the hepatitis B virus (Montrose and Krissansen, 2014), Akt (Henning et al, 2016), Smad3 (Wang et al, 2016) and Tau (Chu et al, 2016). The first PROTAC successfully studied in live animals was a dipeptidic phosphorylation-dependent PROTAC comprised of a VHL-engaging octa D-Arg/hydroxylproline sequence coupled to a tyrosine phosphorylation sequence of Her3 (Hines et al, 2013).…”

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

327

261

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Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell’s own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

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“…26 The X-protein is essential for viral replication, with 154 aa residues, and is a major risk for patients with hepatocellular carcinoma (HCC) developed from chronical infection with HBV. 26 The X-protein is essential for viral replication, with 154 aa residues, and is a major risk for patients with hepatocellular carcinoma (HCC) developed from chronical infection with HBV.…”

Section: Peptide-based Protac Technologymentioning

confidence: 99%

“…34 They took advantage of CMA and designed PROTACs against death associated protein kinase 1 (DAPK1), scaffolding protein PSD-95, and a-synuclein. 26,33,36 To show the biological function of the peptide-based PROTACs, Crews group examined their PROTACs on targeting ER (named Protac-B for ERα) and AR (named Protac-A for AR). They confirmed that this homo multiple-peptide efficiently knocked down the targeted protein not only in the cultured cells but also in the brains of intact rats because of CMPD, which made the peptide permeable to plasma membrane and the blood brain barrier.…”

Section: Peptide-based Protac Technologymentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

201

135

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Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. Significance of the study This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

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Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus

Cited by 63 publications

References 26 publications

Small‐Molecule PROTACS: New Approaches to Protein Degradation

Small‐Molecule PROTACS: New Approaches to Protein Degradation

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

The PROTAC technology in drug development

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