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 language | English |
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Pages (from-to) | 4484-4495 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 63 |
Issue number | 9 |
DOIs | |
Publication status | Published - 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