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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer

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          Abstract 

          Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.

          Most cited references107

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          Recognition and processing of ubiquitin-protein conjugates by the proteasome.

          Daniel Finley (2009)
          The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.
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            The Logic of the 26S Proteasome.

            Galen Andrew Collins, Alfred Goldberg (2017)
            The ubiquitin proteasome pathway is responsible for most of the protein degradation in mammalian cells. Rates of degradation by this pathway have generally been assumed to be determined by rates of ubiquitylation. However, recent studies indicate that proteasome function is also tightly regulated and determines whether a ubiquitylated protein is destroyed or deubiquitylated and survives longer. This article reviews recent advances in our understanding of the proteasome's multistep ATP-dependent mechanism, its biochemical and structural features that ensure efficient proteolysis and ubiquitin recycling while preventing nonselective proteolysis, and the regulation of proteasome activity by interacting proteins and subunit modifications, especially phosphorylation.
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              Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome.

              Maya Dajee, J. Kirk, M Aujay … (2007)
              Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in >80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): dddt
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 19 October 2020
                Publication date Collection: 2020
                Volume: 14
                Pages: 4327-4342
                Affiliations
                [1 ]School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang Province, 310015, People's Republic of China
                [2 ]Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital , Hangzhou, Zhejiang Province, 310023 People's Republic of China
                [3 ]Department of Pharmacy, The First Affiliated Hospital, Zhejiang University , Hangzhou, Zhejiang Province, 310003, People's Republic of China
                Author notes
                Correspondence: Jianjun Xi Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital , Hangzhou, Zhejiang Province310023, People’s Republic of China Email xjianjun@foxmail.com
                Jiankang Zhang School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang Province310015, People’s Republic of China Email zjk0125@yeah.net
                [*]

                These authors contributed equally to this work

                Article
                Publisher ID: 265793
                DOI: 10.2147/DDDT.S265793
                PMC ID: 7585272
                PubMed ID: 33116419
                SO-VID: acca0a99-29f2-406d-8c84-13183e445c46
                Copyright © © 2020 Cao et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 16 June 2020
                Date accepted : 22 September 2020
                Page count
                Figures: 14, Tables: 12, References: 112, Pages: 16
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                The authors thank the support of National Natural Science Foundation of China (81803432) and the Public Welfare Technology Application Projects supported by the Science Technology Department of Zhejiang Province (LGF18H300001).
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: proteasome inhibitor,infectious diseases,autoimmune diseases,neurodegenerative diseases,drugs
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: proteasome inhibitor, infectious diseases, autoimmune diseases, neurodegenerative diseases, drugs

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