Exploring new near-infrared fluorescent disulfide-based cyclic RGD peptide analogs for potential integrin-targeted optical imaging

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 7; pp. 2116 - 2120
• Main Authors: Ye, Yunpeng, Xu, Baogang, Nikiforovich, Gregory V., Bloch, Sharon, Achilefu, Samuel
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2011; Elsevier
• Subjects: Analytical, structural and metabolic biochemistry; binding capacity; Biological and medical sciences; Chromatography, High Pressure Liquid; Cyclization; Disulfide-based cyclization; Disulfides - chemistry; fluorescence; Fluorescent Dyes - chemistry; Fundamental and applied biological sciences. Psychology; General aspects, investigation methods; image analysis; Integrin α vβ 3 binding; integrins; Integrins - chemistry; microscopy; Near-infrared fluorescent probe; Oligopeptides - chemistry; Optical imaging; Proteins; RGD peptide; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Near-Infrared; Integrin α vβ 3 binding; Optical imaging; RGD peptide; Near-infrared fluorescent probe; Disulfide-based cyclization; Cyclic peptides; Integrin α; Cell adhesion molecule; binding; Adhesion; Cyanine dye; αvβ3 Integrin; Organic disulfide; β; Cyclization; Molecular probe; Fluorescent compound; Pentapeptide
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.133

We synthesized disulfide-based cyclic RGD pentapeptides bearing a near-infrared fluorescent dye (cypate), represented by cypate- c(CRGDC) ( 1) for integrin-targeted optical imaging. These compounds were compared with the traditional lactam-based cyclic RGD counterpart, cypate- c(RGDfK) ( 2). Molecular modeling suggests that the binding affinity of 2 to integrin α vβ 3 is an order of magnitude higher than that of 1. This was confirmed experimentally, which further showed that substitution of Gly with Pro, Val and Tyr in 1 remarkably hampered the α vβ 3 binding. Interestingly, cell microscopy with A549 cells showed that 1 exhibited higher cellular staining than 2. These results indicate that factors other than receptor binding affinity to α vβ 3 dimeric proteins mediate cellular uptake. Consequently, 1 and its analogs may serve as valuable molecular probes for investigating the selectivity and specificity of integrin targeting by optical imaging.