1. Targeting GRP receptor: Design, synthesis and preliminary biological characterization of new non-peptide antagonists of bombesin
- Author
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Cristina Airoldi, Martina Arici, Alexandre Orsato, Alessandro Palmioli, Cecilia Ceresa, Paola Coccetti, Barbara La Ferla, Gabriella Nicolini, Marcella Rocchetti, Elisabetta Donzelli, Farida Tripodi, Palmioli, A, Nicolini, G, Tripodi, F, Orsato, A, Ceresa, C, Donzelli, E, Arici, M, Coccetti, P, Rocchetti, M, La Ferla, B, and Airoldi, C
- Subjects
GRP-R antagonist ,Antineoplastic Agents ,Circular dichroism ,01 natural sciences ,Biochemistry ,Epitope ,Gastrin Releasing Peptide (GRP) ,NMR-based structural and conformational analysi ,chemistry.chemical_compound ,Structure-Activity Relationship ,GRP-R ligand ,GRP receptors (GRP-R) ,CHIM/06 - CHIMICA ORGANICA ,Drug Discovery ,Gastrin-releasing peptide receptor ,Tumor Cells, Cultured ,Humans ,Receptor ,Bombesin (BN) ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,MM and MD conformational studie ,Rational design ,Bombesin ,Biological activity ,Transmembrane protein ,0104 chemical sciences ,Receptors, Bombesin ,010404 medicinal & biomolecular chemistry ,CHIM/08 - CHIMICA FARMACEUTICA ,chemistry ,Drug Design ,Biophysics ,Pharmacophore ,Drug Screening Assays, Antitumor ,hormones, hormone substitutes, and hormone antagonists - Abstract
We report the rational design, synthesis, and in vitro preliminary evaluation of a new small library of non-peptide ligands of Gastrin Releasing Peptide Receptor (GRP-R), able to antagonize its natural ligand bombesin (BN) in the nanomolar range of concentration. GRP-R is a transmembrane G-protein coupled receptor promoting the stimulation of cancer cell proliferation. Being overexpressed on the surface of different human cancer cell lines, GRP-R is ideal for the selective delivery to tumor cells of both anticancer drug and diagnostic devices. What makes very challenging the design of non-peptide BN analogues is that the 3D structure of the GRP-R is not available, which is the case for many membrane-bound receptors. Thus, the design of GRP-R ligands has to be based on the structure of its natural ligands, BN and GRP. We recently mapped the BN binding epitope by NMR and here we exploited the same spectroscopy, combined with MD, to define BN conformation in proximity of biological membranes, where the interaction with GRP-R takes place. The gained structural information was used to identify a rigid C-galactosidic scaffold able to support pharmacophore groups mimicking the BN key residues’ side chains in a suitable manner for binding to GRP-R. Our BN antagonists represent hit compounds for the rational design and synthesis of new ligands and modulators of GRP-R. The further optimization of the pharmacophore groups will allow to increase the biological activity. Due to their favorable chemical properties and stability, they could be employed for the active receptor-mediated targeting of GRP-R positive tumors.
- Published
- 2020