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Pharmaceuticals
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Targeted Protein Degradation: From Chemical Biology to Drug Discovery
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Targeted Protein Degradation: From Chemical Biology to Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 49867

Special Issue Editors

Dr. Mikihiko Naito

E-Mail Website
Guest Editor
Chief, Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
Interests: protein degradation; ubiquitin; proteasome; deubiquitylating enzyme; IAP; cancer
Dr. Yosuke Demizu

E-Mail Website
Guest Editor
Chief, Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
Interests: peptide; foldamer; non-proteinogenic amino acid; protein–protein interaction

Special Issue Information

Dear Colleagues,

Protein degradation induced by small molecules has been attracting great attention recently as a novel modality for drug development and as a novel method for basic research in chemical biology. This technology hijacks the cellular ubiquitin-proteasome system to induce protein degradation, as demonstrated by chimeric molecules (PROTACs, SNIPERs), small E3 modulators (thalidomides, sulfonamides), SERD (fulvestrant), etc.. Probably, this technology could be extended to the manipulation of other cellular events involving ubiquitin and, further, to other post translational modification systems in the future.

To explore the future possibilities of this novel technology, authors are invited to submit original and review articles on any aspect of the chemical compounds and methods capable of regulating protein degradation and the cellular ubiquitin system, including, but not limited to, protein degraders, protein degradation systems,  modifiers of the ubiquitin system, etc. The collection of manuscripts will be published as a Special Issue of the journal Pharmaceuticals.

Dr. Mikihiko Naito
Dr. Yosuke Demizu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PROTACs
  • SNIPERs
  • E3 Modulators
  • Protein Degradation
  • Ubiquitin
  • Deubiquitylating enzymes

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Published Papers (6 papers)

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Research

Jump to: Review

8 pages, 1459 KiB  
Article
Constructing Auxin-Inducible Degron Mutants Using an All-in-One Vector
by Aisha Yesbolatova, Yuichiro Saito and Masato T. Kanemaki
Pharmaceuticals 2020, 13(5), 103; https://doi.org/10.3390/ph13050103 - 23 May 2020
Cited by 9 | Viewed by 11429
Abstract
Conditional degron-based methods are powerful for studying protein function because a degron-fused protein can be rapidly and efficiently depleted by adding a defined ligand. Auxin-inducible degron (AID) is a popular technology by which a degron-fused protein can be degraded by adding an auxin. [...] Read more.
Conditional degron-based methods are powerful for studying protein function because a degron-fused protein can be rapidly and efficiently depleted by adding a defined ligand. Auxin-inducible degron (AID) is a popular technology by which a degron-fused protein can be degraded by adding an auxin. However, compared with other technologies such as dTAG and HaloPROTAC, AID is complicated because of its two protein components: OsTIR1 and mAID (degron). To simplify the use of AID in mammalian cells, we constructed bicistronic all-in-one plasmids that express OsTIR1 and a mAID-fused protein using a P2A self-cleavage sequence. To generate a HeLa mutant line for the essential replication factor MCM10, we transfected a CRISPR-knockout plasmid together with a bicistronic plasmid containing mAID-fused MCM10 cDNA. After drug selection and colony isolation, we successfully isolated HeLa mutant lines, in which mAID–MCM10 was depleted by the addition of indole-3-acetic acid, a natural auxin. The bicistronic all-in-one plasmids described in this report are useful for controlling degradation of a transgene-derived protein fused with mAID. These plasmids can be used for the construction of conditional mutants by combining them with a CRISPR-based gene knockout. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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13 pages, 2763 KiB  
Article
Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety
by Takuji Shoda, Nobumichi Ohoka, Genichiro Tsuji, Takuma Fujisato, Hideshi Inoue, Yosuke Demizu, Mikihiko Naito and Masaaki Kurihara
Pharmaceuticals 2020, 13(3), 34; https://doi.org/10.3390/ph13030034 - 25 Feb 2020
Cited by 8 | Viewed by 4577
Abstract
Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the [...] Read more.
Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, 2, 3, and 16 induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, 2, 3, and 16 did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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Review

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14 pages, 1703 KiB  
Review
Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation
by Hikaru Tsuchiya, Akinori Endo and Yasushi Saeki
Pharmaceuticals 2020, 13(6), 128; https://doi.org/10.3390/ph13060128 - 23 Jun 2020
Cited by 10 | Viewed by 5545
Abstract
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes [...] Read more.
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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16 pages, 973 KiB  
Review
Molecular Mechanisms of the Teratogenic Effects of Thalidomide
by Tomoko Asatsuma-Okumura, Takumi Ito and Hiroshi Handa
Pharmaceuticals 2020, 13(5), 95; https://doi.org/10.3390/ph13050095 - 13 May 2020
Cited by 48 | Viewed by 14878
Abstract
Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery [...] Read more.
Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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10 pages, 1927 KiB  
Review
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis
by Ryosuke Fukuda and Tsukasa Okiyoneda
Pharmaceuticals 2020, 13(4), 75; https://doi.org/10.3390/ph13040075 - 22 Apr 2020
Cited by 15 | Viewed by 7317
Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that [...] Read more.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF). Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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19 pages, 12595 KiB  
Review
Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs
by Minoru Ishikawa, Shusuke Tomoshige, Yosuke Demizu and Mikihiko Naito
Pharmaceuticals 2020, 13(4), 74; https://doi.org/10.3390/ph13040074 - 21 Apr 2020
Cited by 19 | Viewed by 5208
Abstract
New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article [...] Read more.
New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation. We cover strategies for increasing the degradation activity induced by small molecules, and their scope for application to undruggable proteins. Full article
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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