Abstract |
Neurotensin (NT) is a regulatory peptide with nanomolar affinity toward NT receptors, which are overexpressed by different clinically relevant tumors. Its binding sequence, NT(8-13), represents a promising vector for the development of peptidic radiotracers for tumor imaging and therapy. The main drawback of the peptide is its short biological half-life due to rapid proteolysis in vivo. Herein, we present an innovative strategy for the stabilization of peptides using nonhydrolizable 1,4-disubstituted, 1,2,3-triazoles as amide bond surrogates. A " triazole scan" of the peptide sequence yielded novel NT(8-13) analogues with enhanced stability, retained receptor affinity, and improved tumor targeting properties in vivo. The synthesis of libraries of triazole-based peptidomimetics was achieved efficiently on solid support by a combination of Fmoc- peptide chemistry, diazo transfer reactions, and the Cu(I)-catalyzed alkyne azide cycloaddition (CuAAC) employing methods that are fully compatible with standard solid phase peptide synthesis ( SPPS) chemistry. Thus, the amide-to- triazole substitution strategy may represent a general methodology for the metabolic stabilization of biologically active peptides.
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Authors | Alba Mascarin, Ibai E Valverde, Sandra Vomstein, Thomas L Mindt |
Journal | Bioconjugate chemistry
(Bioconjug Chem)
Vol. 26
Issue 10
Pg. 2143-52
(Oct 21 2015)
ISSN: 1520-4812 [Electronic] United States |
PMID | 26347939
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Peptide Fragments
- Peptidomimetics
- Radioisotopes
- Receptors, Neurotensin
- Triazoles
- neurotensin type 1 receptor
- Neurotensin
- Lutetium
- neurotensin (8-13)
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Topics |
- Animals
- Antineoplastic Agents
(chemistry, pharmacokinetics)
- Chemistry Techniques, Synthetic
- Cycloaddition Reaction
- Female
- HT29 Cells
- Half-Life
- Humans
- Isotope Labeling
(methods)
- Lutetium
(chemistry)
- Mice, Nude
- Molecular Targeted Therapy
(methods)
- Neurotensin
(chemistry)
- Peptide Fragments
(chemistry)
- Peptidomimetics
(chemistry, pharmacokinetics)
- Radioisotopes
(chemistry)
- Receptors, Neurotensin
(metabolism)
- Structure-Activity Relationship
- Tissue Distribution
- Triazoles
(chemistry)
- Xenograft Model Antitumor Assays
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