Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting

Nathalie M. Grob, Daniel Haussinger, Xavier Deupi, Roger Schibli, Martin Behe (Corresponding author), Thomas L. Mindt (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-p interaction of the aromatic triazole moiety with the Arg(356) residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.
Original languageEnglish
Pages (from-to)4484-4495
Number of pages12
JournalJournal of Medicinal Chemistry
Volume63
Issue number9
DOIs
Publication statusPublished - 14 May 2020

Austrian Fields of Science 2012

  • 301904 Cancer research
  • 301305 Medical chemistry

Keywords

  • CHOLECYSTOKININ-B/GASTRIN RECEPTORS
  • CATION-PI INTERACTIONS
  • SOLID-PHASE
  • IN-VIVO
  • BINDING-SITE
  • XPLOR-NIH
  • 1,2,3-TRIAZOLES
  • PEPTIDES
  • AMIDE
  • MECHANISMS

Fingerprint

Dive into the research topics of 'Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting'. Together they form a unique fingerprint.

Cite this