| Autor: |
Grob NM; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland., Häussinger D; Department of Chemistry, University of Basel, 4056 Basel, Switzerland., Deupi X; Condensed Matter Theory Group, Laboratory for Scientific Computing and Modelling, Paul Scherrer Institute, 5232 Villigen, Switzerland.; Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland., Schibli R; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland.; Center for Radiopharmaceutical Sciences, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland., Behe M; Center for Radiopharmaceutical Sciences, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland., Mindt TL; Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, 1090 Vienna, Austria.; Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.; Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria. |
| Abstrakt: |
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-π 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. |
