New peptide-based pharmacophore activates 20S proteasome

Paweł A. Osmulski , Przemysław Karpowicz , Elżbieta Jankowska , Jonathan Bohmann , Andrew M. Pickering , Maria Gaczyńska


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.
Author Paweł A. Osmulski
Paweł A. Osmulski,,
, Przemysław Karpowicz (FCh / DOCh)
Przemysław Karpowicz,,
- Department of Organic Chemistry
, Elżbieta Jankowska (FCh / DBCh / LMCh)
Elżbieta Jankowska,,
- Laboratory of Medical Chemistry
, Jonathan Bohmann
Jonathan Bohmann,,
, Andrew M. Pickering
Andrew M. Pickering,,
, Maria Gaczyńska
Maria Gaczyńska,,
Journal seriesMolecules, ISSN 1420-3049, (N/A 100 pkt)
Issue year2020
Publication size in sheets0.8
Article number1439
Keywords in Englishproteasome, activation, allostery, peptides, beta turn, proteasome dynamics, atomic force microscopy
ASJC Classification1605 Organic Chemistry
Languageen angielski
LicenseRepository; published final; Uznanie Autorstwa (CC-BY); with publication
Osmulski_Pawel_New_peptide_besed_pharmacophore_2020.pdf 2.65 MB
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 24-03-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 1.146; WoS Impact Factor: 2018 = 3.06 (2) - 2018=3.38 (5)
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LicencjaUtwór jest udostępniany na licencji Creative Commons Uznanie autorstwa 4.0 Międzynarodowe (CC BY 4.0)
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