Enzymatic transhalogenation of dendritic RGD peptide constructs with the fluorinase

Abstract

The substrate scope of fluorinase enzyme mediated transhalogenation reactions is extended. Substrate tolerance allows a peptide cargo to be tethered to a 5′-chloro-5′-deoxynucleoside substrate for transhalogenation by the enzyme to a 5′-fluoro-5′-deoxynucleoside. The reaction is successfully extended from that previously reported for a monomeric cyclic peptide (cRGD) to cargoes of dendritic scaffolds carrying two and four cyclic peptide motifs. The RGD peptide sequence is known to bind upregulated α_Vβ₃ integrin motifs on the surface of cancer cells and it is demonstrated that the fluorinated products have a higher affinity to α_Vβ₃ integrin than their monomeric counterparts. Extending the strategy to radiolabelling of the peptide cargoes by tagging the peptides with [¹⁸F]fluoride was only moderately successful due to the poor water solubility of these higher order peptide scaffolds although the strategy holds promise for peptide constructs with improved solubility.