Coordination of transition metals to peptides, either through the incorporation of unnatural chelating groups or amino acid ligating side-chains, expands the utility of peptides for biological studies. The first part of this project describes induction of α-helical secondary structure in pentapeptides upon side-chain coordination of inert transition metal ions. The second part of this project describes the syntheses of biologically active peptide species that contain a macrobicyclic hexaamine ligand that can complex radioactive metal ions for diagnostic imaging purposes. / Short peptide sequences do not form thermodynamically stable α-helices in water. The capacity of two metal clips, cis-[Ru(NH3)4(solvent)2]2+ and cis [Pd(en)(solvent)2]2+ to induce α-helicity in peptides that are five amino acids long, Ac HARAH NH2 and Ac MARAM-NH2 has been explored. In all cases at pH < 5, the metal ions bind to the side-chains of amino acid residues at positions i, i+4 of the pentapeptides resulting in formation of bidentate macrocyclic species. Circular dichroism and 1H nuclear magnetic resonance data indicate that the metal complexes of Ac-MARAM-NH2 are highly α helical in water, and in the most spectacular case, coordination of Ac-MARAM-NH2 to cis-[Ru(NH3)4(solvent)2]2+ results in up to 80% α-helicity. In contrast, metal complexes of Ac-HARAH-NH2 exhibit significantly less α-helicity in water. / 64Cu-radiolabelled peptides have been investigated for their ability to target specific tissue or cell types. These peptides require a chelating group that binds copper ions strongly. Macrobicyclic hexaamine ligands, based on the compound commonly referred to as “sarcophagine”, have demonstrated extremely high stability under biological conditions. Here we describe the synthesis of diaminosarcophagine chelators with carboxylate groups for conjugation to peptides. These new chelators have been attached to the N-terminus or lysine side-chain of biologically-active peptides, including Tyr3 octreotate, Lys3-bombesin and an integrin targeting peptide. Spectroscopic and voltammetric studies of these species suggest that the conjugated sarcophagine group retains the high metal binding affinity and structural properties of the parent species, diaminosarcophagine. These are among the first sarcophagine-peptide compounds that have been properly characterised. The new sarcophagine-peptide conjugates can be easily radiolabelled with 64Cu2+ over a wide pH range at ambient temperature.
| Identifer | oai:union.ndltd.org:ADTP/269919 |
| Date | January 2010 |
| Creators | Ma, Michelle Therese |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Restricted Access: Abstract and Citation Only Available |
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