Cyclization of peptide structures by creating metal foldamers using 99m-Tc/Re(CO)3
Abstract
Constrained peptides have been successful as therapeutics owing to the rigidity in their framework, allowing them to have enhanced pharmacological properties. Apart from covalent bond based cyclization, constraints can be induced by cyclization using metal coordination. The metals Re and 99mTc are one of the few metals which have not been studied in great detail for their ability to cyclize linear peptides. A tri-alanine sequence was employed in the peptide backbone due to its ability to form stable helices. In addition, another tripeptide sequence RGD, which is recognized by the integrin avb3, was also used. These tripeptide sequences flanked by unnatural amino acid and synthetic chelating agent on the terminal ends, were cyclized using [Re(CO)3(OH2)3]+ to form a 2+1 chelation complex. This involved chelation to the metal through a bidentate ligand, pyridyl triazole acetic acid or 2,2’-bipyridine-4-carboxylic acid (synthetic chelating ligand), and a monodentate ligand 3-Pal (unnatural amino acid) from N- and C- terminal respectively. NMR spectroscopy was used to compare the changes in chemical shift between linear and cyclic peptides. Specific changes in the NMR of cyclic peptide confirmed the formation of 2+1 chelation system. Circular dichroism spectroscopy was able to confirm the formation of a turn into the linear peptide on cyclization. Variable temperature NMR spectroscopy suggested the formation of a secondary structure by detecting intramolecular hydrogen bonding in the cyclic peptide. Lastly, the linear peptide pyta-Ala-Ala-Ala-3Pal was successfully radiolabeled using [99mTc(CO)3(OH2)3]+. Linear peptides were successfully cyclized through 99mTc/Re(CO)3, thus creating metal foldamers where the metal acts as the central core around which the turn occurs.