Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting
- Author(s)
- Nathalie M. Grob, Daniel Haussinger, Xavier Deupi, Roger Schibli, Martin Behe, Thomas L. Mindt
- 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.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Eidgenössische Technische Hochschule Zürich, Universität Basel, Medizinische Universität Wien, Paul Scherrer Institute
- Journal
- Journal of Medicinal Chemistry
- Volume
- 63
- Pages
- 4484-4495
- No. of pages
- 12
- ISSN
- 0022-2623
- DOI
- https://doi.org/10.1021/acs.jmedchem.9b01936
- Publication date
- 05-2020
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research, 301305 Medical chemistry
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/triazolopeptidomimetics-novel-radiolabeled-minigastrin-analogs-for-improved-tumor-targeting(4065c66e-d5ca-4109-aa11-74c408c36313).html