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Molecules
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Proteasome Regulators: Activators and Inhibitors
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Proteasome Regulators: Activators and Inhibitors

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 26588

Special Issue Editor

Dr. Jetze J. Tepe

E-Mail Website
Guest Editor
Michigan State University, Department of Chemistry, East Lansing, MI 48824, USA
Interests: proteasome; heterocycles; drug discovery; chemotherapy; NF-kB; marine sponge metabolites

Special Issue Information

Dear Colleagues,

We are pleased to announce that submissions for the Molecules Special Issue "Proteasome Regulators: Activators and Inhibitors" are now open.

FDA (Food and Drug Administration) approval of the proteasome inhibitors bortezomib and carfilzomib (as well as ixazomib for some patients) as front-line therapy for multiple myeloma and mantle cell lymphoma has validated the proteasome as an important therapeutic target. Following that breakthrough, new research has illuminated other methods of proteasome regulations that have the potential to expand its therapeutic applications.

This Special Issue will focus on new directions in proteasome regulation including proteasome activation and alternative methods of inhibiting its proteolytic activity by small molecules. Original research articles as well as reviews that are able to make substantial advances in this field are welcome.

Dr. Jetze J. Tepe
Guest Editor

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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.

Published Papers (4 papers)

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Research

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17 pages, 2786 KiB  
Article
New Peptide-Based Pharmacophore Activates 20S Proteasome
by Paweł A. Osmulski, Przemysław Karpowicz, Elżbieta Jankowska, Jonathan Bohmann, Andrew M. Pickering and Maria Gaczyńska
Molecules 2020, 25(6), 1439; https://doi.org/10.3390/molecules25061439 - 22 Mar 2020
Cited by 13 | Viewed by 3790
Abstract
The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively [...] Read more.
The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use. Full article
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
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Review

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30 pages, 1974 KiB  
Review
Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease
by David J. Sherman and Jing Li
Molecules 2020, 25(3), 671; https://doi.org/10.3390/molecules25030671 - 05 Feb 2020
Cited by 57 | Viewed by 10822
Abstract
The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome [...] Read more.
The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases. Full article
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
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28 pages, 7794 KiB  
Review
Proteasome Activation to Combat Proteotoxicity
by Corey L. Jones and Jetze J. Tepe
Molecules 2019, 24(15), 2841; https://doi.org/10.3390/molecules24152841 - 05 Aug 2019
Cited by 27 | Viewed by 5892
Abstract
Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, [...] Read more.
Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators. Full article
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
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14 pages, 2168 KiB  
Review
Methods to Discover and Evaluate Proteasome Small Molecule Stimulators
by Rachel A. Coleman and Darci J. Trader
Molecules 2019, 24(12), 2341; https://doi.org/10.3390/molecules24122341 - 25 Jun 2019
Cited by 13 | Viewed by 5569
Abstract
Protein accumulation has been identified as a characteristic of many degenerative conditions, such as neurodegenerative diseases and aging. In most cases, these conditions also present with diminished protein degradation. The ubiquitin-proteasome system (UPS) is responsible for the degradation of the majority of proteins [...] Read more.
Protein accumulation has been identified as a characteristic of many degenerative conditions, such as neurodegenerative diseases and aging. In most cases, these conditions also present with diminished protein degradation. The ubiquitin-proteasome system (UPS) is responsible for the degradation of the majority of proteins in cells; however, the activity of the proteasome is reduced in these disease states, contributing to the accumulation of toxic protein. It has been hypothesized that proteasome activity, both ubiquitin-dependent and -independent, can be chemically stimulated to reduce the load of protein in diseased cells. Several methods exist to identify and characterize stimulators of proteasome activity. In this review, we detail the ways in which protease activity can be enhanced and analyze the biochemical and cellular methods of identifying stimulators of both the ubiquitin-dependent and -independent proteasome activities. Full article
(This article belongs to the Special Issue Proteasome Regulators: Activators and Inhibitors)
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