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 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.
Highlights
IntroductionAs the central protease of the ubiquitin–proteasome pathway, the proteasome has long been considered an attractive target for drugs potentially affecting multiple aspects of cell physiology [1]
As the central protease of the ubiquitin–proteasome pathway, the proteasome has long been considered an attractive target for drugs potentially affecting multiple aspects of cell physiology [1].small molecules targeting the proteasome have entered the clinic with great success [2].their scope at present is very limited: all proteasome-modifying compounds currently approved or clinically tested as drugs are competitive inhibitors and all are used to treat advanced blood cancers [1,3]
In that a separate study,stimulation we found that proteasome by TAT peptides and mortality in animal models
Summary
As the central protease of the ubiquitin–proteasome pathway, the proteasome has long been considered an attractive target for drugs potentially affecting multiple aspects of cell physiology [1]. Since dysfunction of proteasome-mediated controlled 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. Tat protein inhibits the core proteasome [21]. The HIV-1 Tat protein inhibits the core proteasome [21]. After observing a strong in vitro proteasome augmentation properties of HIV-1 Tat “TAT protein-derived “TAT peptides”. A separate proteasome augmentation by modified HIV-1 Tat-derived peptides, we tested selectedIn compounds study, we found proteasome by TAT peptidesstimulation partially prevented cognitivepartially deficits in cell culture. Results and Discussion from [22,24]
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