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Histidine–Iridium(III) Coordination-Based Peptide Luminogenic Cyclization and Cyclo-RGD Peptides for Cancer-Cell Targeting

Author:
Ma, Xiaochuan, Jia, Junli, Cao, Rui, Wang, Xiaobo, Fei, Hao
Source:
Journal of the American Chemical Society 2014 v.136 no.51 pp. 17734-17737
ISSN:
1520-5126
Subject:
binding capacity, cell death, cytotoxicity, drugs, fluorescent labeling, histidine, image analysis, integrins, iridium, luminescence, membrane permeability, models, neoplasm cells, neoplasms, peptides, reaction kinetics
Abstract:
In the field of peptide drug discovery, structural constraining and fluorescent labeling are two sought-after techniques important for both basic research and pharmaceutical development. In this work, we describe an easy-to-use approach for simultaneous peptide cyclization and luminescent labeling based on iridium(III)–histidine coordination (Ir–HH cyclization). Using a series of model peptides with histidine flanking each terminus, the binding activity and reaction kinetics of Ir–HH cyclization of different ring sizes were characterized. In the series, Ir–HAₙH (n = 2, 3) with moderate ring sizes provides appropriate flexibility and proper distance between histidines for cyclic formation, which leads to the best binding affinity and structural stability in physiological conditions, as compared to other Ir–HH-cyclized peptides with smaller (n = 0, 1) or larger (n = 4, 5) ring sizes. Ir–HRGDH, an Ir–HH-cyclized peptide containing integrin targeting motif Arg-Gly-Asp (RGD), showed better targeting affinity than its linear form and enhanced membrane permeability in comparison with fluorescein-labeled cyclic RGDyK peptide. Cell death inducing peptide KLA-linked Ir–HRGDH (Ir–HRGDH–KLA) showed dramatically enhanced cytotoxicity and high selectivity for cancer cells versus noncancer cells. These data demonstrate that the method conveniently combines structural constraining of peptides with luminescent imaging capabilities, which facilitates functional and intracellular characterization of potential peptide-based drug leads, thus introducing a new tool to meet emerging needs in medicinal research.
Agid:
5404429