Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N-terminally modified peptide aldehydes and their antitumor activity

Marta Lubos , Dawid Dębowski , Ewelina Barcińska , Meid Annika , Iwona Inkielewicz-Stepniak , Burster Timo , Krzysztof Rolka


The conversion of primary structures of novel, highly selective and sensitive, internally quenched peptide substrates of the human 20S proteasome into peptide aldehydes is presented. Such covalent and reversible inhibitors differ in their primary structures and chemical moieties attached to their N-terminal amino group. Inhibitory potency is primarily tested against proteolytic subunits of human constitutive 20S proteasome (β1c, β2c, and β5c subunits), but in some cases, also against 20S immunoproteasome β5i. Most of the peptide aldehydes act nonspecifically and bind equipotently to the corresponding proteolytic subunits of both forms of proteasome (β5c and β5i). Two inhibitors are 2.7-times more specific for immunoproteasome over its constitutive counterpart. The antitumor activity of the selected inhibitors and MG132 (used here as the reference) is analyzed using MTT assay against nonmalignant human fetal osteoblastic hFOB 1.19, malignant human osteosarcoma MG-63, human pancreatic cancer MiaPaCa-2, and human acute leukemia Jurkat T cell lines. All inhibitors tested are able to decrease cell viability in a concentration-dependent manner. One of the peptide aldehydes exerted stronger, as compared to the MG132, activity against human glioblastoma cell line U87-MG. Moreover, its combination with dinaciclib, which is a novel, potent inhibitor of cyclindependent kinases, reduces cellular metabolic activity more potently as compared to either proteasome inhibitor or dinaciclib alone.
Publication typeIn press (online first, early view)
Author Marta Lubos (FCh / DMB / LBCh)
Marta Lubos,,
- Laboratory of Bioorganic Chemistry
, Dawid Dębowski (FCh / DMB / LBCh)
Dawid Dębowski,,
- Laboratory of Bioorganic Chemistry
, Ewelina Barcińska
Ewelina Barcińska,,
, Meid Annika
Meid Annika,,
, Iwona Inkielewicz-Stepniak
Iwona Inkielewicz-Stepniak,,
, Burster Timo
Burster Timo,,
, Krzysztof Rolka (FCh / DMB / LBCh)
Krzysztof Rolka,,
- Laboratory of Bioorganic Chemistry
Journal seriesPeptide Science, ISSN 0006-3525, e-ISSN 1097-0282 [2475-8817], (A 25 pkt)
Issue year2018
Noonline first
Publication size in sheets0.5
Keywords in Englishglioblastoma, immunoproteasome, peptide aldehydes, proteasome inhibitors
Languageen angielski
Score (nominal)25
ScoreMinisterial score = 25.0, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, ArticleFromJournal
Publication indicators WoS Impact Factor: 2017 = 1.99 (2) - 2017=2.165 (5)
Citation count*
Share Share

Get link to the record

* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.