Proteasome Activation to Combat Proteotoxicity

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, 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.

New Peptide-Based Pharmacophore Activates 20S Proteasome

“…In our previous studies, we noted that short peptide fragments of HIV-1 Tat displayed peculiar in vitro properties: they inhibited detergent-treated core particle but mildly activated the latent core [22][23][24]. However, treatment with sodium dodecyl sulfate detergent, although convenient for in vitro assays, yields mildly denatured proteasome and, under these far-from-physiological conditions, likely with destroyed natural allosteric routes [10]. Therefore, we turned our attention to the activating properties of HIV-1 Tat protein-derived "TAT peptides".…”

“…The complex structure protein degradation is a hallmark of both cellular aging [4,5] and neurodegenerative diseases [6][7][8][9], enhancement of the enzyme's activity should be considered an attractive therapeutic option. The complex structure of the catalytic core 20S proteasome (the "core particle"; Figure 1A) presents fascinating options for allostery-based augmentation, comprehensively reviewed in this issue [10,11]. The peptidase responsible for post-hydrophobic (chymotrypsin-like, ChT-L) cleavages is considered a rate-limiting "workhorse" and is the major target for inhibitors and activators alike [3,12].…”

Recent Advances in the Synthesis of Imidazolines (2009–2020)

“…Furthermore, various substituted imidazolines have illustrated potential therapeutic value for the treatment of different diseases as antihelminthics, [5] antifungal, [6] antitumor, [7] hypertension, [8] hyperglycemia, [9] as well as for the potential treatment of Parkinson's, [10] and Alzheimer's disease. [11] In addition, imidazolines have been used as chiral catalysts, [12] transition metal ligands [13] and as different synthetic intermediates. [14] In recent years, many imidazoline compounds have been used as chiral auxiliaries [15] in enantioselective reactions, as a result of the relative ease of insertion of chirality around the imidazoline ring.…”

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

“…[3][4][5] Enhancing the proteolytic activity of only the 20S isoform of the human proteasome represents a new strategy to reduce aberrant signaling of dysregulated IDPs. [6][7][8][9][10][11] IDPs are typically short-lived and are rapidly and unremittingly degraded by the proteasome. However, when production of a specific IDP outpaces proteasome degradation, the accumulated IDP can induce aberrant and toxic signaling events.…”

“…Dysregulated IDPs are involved in the pathogenesis of many diseases including neurodegenerative disorders and cancer. 6,7,12,13 Overexpression of the intrinsically disordered oncoprotein, c-MYC, is found more than 50% of all human cancer, with high prevalence in cancers of hematopoietic origin, such as acute lymphoblastic leukemia and multiple myeloma. 14 In normal cells, c-MYC protein levels are kept in check through multiple posttranslational modifications that alter susceptibility toward proteasomal degradation by default.…”