Macrocyclic Oxindole Peptide Epoxyketones─A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome

Marion G. Götz, Kacey Godwin, Rachel Price, Robert Dorn, Gabriel Merrill-Steskal, William Klemmer, Hunter Hansen, Gautam Produturi, Megan Rocha, Mathias Palmer, Lea Molacek, Zack Strater, Michael Groll

Research output: Contribution to journalArticlepeer-review

Abstract

Peptide macrocycles have recently gained attention as protease inhibitors due to their metabolic stability and specificity. However, the development of peptide macrocycles with improved binding potency has so far been challenging. Here we present macrocyclic peptides derived from the clinically applied proteasome inhibitor carfilzomib with an oxindole group that mimics the natural product TMC-95A. Fluorescence kinetic activity assays reveal a high potency of the oxindole group (IC50 = 0.19 μM) compared with agents lacking this motif. X-ray structures of the ligands with the β5-subunit of the yeast 20S proteasome illustrate that the installed macrocycle forces strong hydrogen bonding of the oxindole group with β5-Gly23NH. Thus, the binding of our designed oxindole epoxyketones is entropically and enthalpically favored in contrast to more flexible proteasome inhibitors such as carfilzomib.

Original languageEnglish
Pages (from-to)533-539
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume15
Issue number4
DOIs
StatePublished - 11 Apr 2024

Keywords

  • Carfilzomib
  • Epoxyketone
  • Inhibitor
  • Multiple myeloma
  • Peptide macrocycle
  • Proteasome

Fingerprint

Dive into the research topics of 'Macrocyclic Oxindole Peptide Epoxyketones─A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome'. Together they form a unique fingerprint.

Cite this