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Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to α v β 3 without Promoting Integrin Allosteric Activation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Sep 13; Vol. 61 (17), pp. 7474-7485. Date of Electronic Publication: 2018 Jun 26. - Publication Year :
- 2018
-
Abstract
- The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with α <subscript>v</subscript> β <subscript>3</subscript> , an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce α <subscript>v</subscript> β <subscript>3</subscript> allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved α <subscript>v</subscript> β <subscript>3</subscript> -binding properties and devoid of adverse integrin-activating effects.
- Subjects :
- Allosteric Regulation
Binding, Competitive
Cell Line, Tumor
Cell Membrane drug effects
Cell Membrane metabolism
HEK293 Cells
Humans
Integrin alphaVbeta3 antagonists & inhibitors
Integrin alphaVbeta3 chemistry
Magnetic Resonance Spectroscopy
Melanoma pathology
Molecular Docking Simulation
Peptides, Cyclic pharmacology
Protein Conformation
Snake Venoms pharmacology
Structure-Activity Relationship
Tyrosine metabolism
Integrin alphaVbeta3 metabolism
Peptides, Cyclic chemistry
Peptides, Cyclic metabolism
Succinimides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29883545
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00745