Evidences for supramolecular organization of nucleopeptides: synthesis, spectroscopic and biological studies of a novel dithymine l-serine tetrapeptide

Abstract

This work concerns a dithymine tetrapeptide, which can be seen as a new analogue of a dinucleoside monophosphate, made of both unfunctionalized and thymine-containing L-serine units alternated in the sequence. The new nucleopeptide was obtained on the solid phase by two different synthetic strategies. The first one is suitable to easily realize nucleopeptides with homonucleobase sequences, obtained by assembling an oligoserine backbone and then simultaneously coupling the free serine hydroxyl groups with the carboxymethylated nucleobase. The other strategy, which makes use of a Fmoc-protected nucleo-L-serine monomer, allows for the obtainment of nucleopeptides with mixed nucleobase sequences. CD spectroscopic studies and laser light scattering experiments, performed on solutions of the novel nucleopeptide, suggested the formation of supramolecular networks based on the self-assembly of the dithymine tetrapeptide molecules. Furthermore, CD binding studies with natural nucleic acids revealed a very weak interaction between the nucleopeptide and DNA (but not RNA). Molecular networks based on this biodegradable and water-soluble nucleopeptide, which is more resistant in plasma than standard tetrapeptides (and oligopeptides), contain a hydrophobic core which could provide the necessary environment to incorporate poorly water-soluble drugs, as evidenced by fluorescence spectroscopy. Furthermore, our studies evidenced that the structure of the tetrapeptide-based supramolecular assembly can be modified by metal ions as evidenced by UV interaction studies with Cu(2+).