Selective Phenylimidazole-Based Inhibitors of the <i>Mycobacterium tuberculosis</i> Proteasome

Wen-hu, Zhan; Hsu, Hao-Chi; Morgan, Trevor; Ouellette, Tierra; Burns-Huang, Kristin; Hara, Ryujiro; Wright, A. G.; Imaeda, Toshihiro; Okamoto, Rei; Sato, Kenjiro; Michino, Mayako; Ramjee, Manoj K.; Aso, Kazuyoshi; Meinke, Peter T.; Foley, Michael A.; Nathan, Carl; Li, Huilin; Lin, Gang

doi:10.1021/acs.jmedchem.9b01187

Cited by 15 publications

(17 citation statements)

References 39 publications

(65 reference statements)

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“…As with malarial proteasome inhibitors, molecules targeting the M. tuberculosis proteasome must be selective over human proteasomes. Significant efforts were made to identify selective M. tuberculosis proteasome inhibitors [245,246], and with growing interest in using proteasome inhibitors to treat infectious diseases amid the threat of drug resistance, this is an exciting time to investigate fundamental properties of bacterial proteasomes and novel ways to distinguish them from human proteasome complexes [246].…”

Section: Other Indications For Proteasome Inhibitorsmentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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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.

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Section: Other Indications For Proteasome Inhibitorsmentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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“…The results of X-ray structures of Mtb20S in complex with A85 and A86 revealed that the two compounds can bind to Mtb20S non-covalently, in which a short antiparallel β -strand between the compounds and the backbone atoms of Thr-21, Gly-47, and Ala-49 was formed. 78 These results indicated that 2-phenylpyrrolidinyl at P3 position was necessary to maintain the potency and selectivity for Mtb20S over human proteasomes.…”

Section: Targeting Proteasome For Various Diseasesmentioning

confidence: 85%

<p>Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer</p>

Cao¹,

Zhu²,

He³

et al. 2020

DDDT

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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.

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“…This analysis identified carfilzomib, a drug recommended for multiple myeloma, as a promising new drug that could be used to fight M. tuberculosis because it is an inhibitor of many of the overexpressed genes during tuberculosis infection. This includes multiple proteasome components such as PSMB8 and PSMB9 [ 9 ], but the mechanism of action of this drug during M. tuberculosis infections is still unclear [ 65 ].…”

Section: Host-directed Therapies (Hdt) Against M Tubercmentioning

confidence: 99%

Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing

et al. 2020

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Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen Mycobacterium tuberculosis and produces 1.5 million deaths every year. The incidence of tuberculosis has decreased during the last decade, but the emergence of MultiDrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) strains of M. tuberculosis is generating a new health alarm. Therefore, the development of novel therapies based on repurposed drugs against MDR-TB and XDR-TB have recently gathered significant interest. Recent evidence, focused on the role of host molecular factors on M. tuberculosis intracellular survival, allowed the identification of new host-directed therapies. Interestingly, the mechanism of action of many of these therapies is linked to the activation of autophagy (e.g., nitazoxanide or imatinib) and other well-known molecular pathways such as apoptosis (e.g., cisplatin and calycopterin). Here, we review the latest developments on the identification of novel antimicrobials against tuberculosis (including avermectins, eltrombopag, or fluvastatin), new host-targeting therapies (e.g., corticoids, fosfamatinib or carfilzomib) and the host molecular factors required for a mycobacterial infection that could be promising targets for future drug development.

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Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome

Cited by 15 publications

References 39 publications

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

<p>Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer</p>

Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing

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