Synthesis and characterization of a mini-library of new conjugated d(TGGGAG) oligonucleotides with potential anti-HIV activity.

In the search for ODNs endowed with relevant antiviral properties, Hotoda and coworkers investigated a series of G-quadruplex-forming ODNs, finally focusing on modified d(TGGGAG) ODNs conjugated with aromatic residues at the 5-end. These were found to exhibit potent anti-HIV activity associated with low cytotoxicity when carrying at the 5′-end bulky aromatic residues. Recently we described a general approach to obtain a mini library of new d(TGGGAG) ODNs, conjugated with different aromatic groups at the 5’-end through a phosphodiester bond. Several modified sequences showed pronounced anti-HIV-1 activity and they showed high binding affinities for the HIV-1 envelope gp120 and gp41. In these structures the 5-end residues play a major role on the G-quadruplex stability, dramatically enhancing stability of the quadruplex complexes (Tm>20°C). With the final goal to expand the repertoire of accessible end-modified G-rich ODNs, and to get a more complete picture of their structure-activity relationships, we describe herein the synthesis and characterization of a mini-library of new d(5’TGGGAG3’) carrying hydrophobic groups at the 5’-end and 2-hydroxyethylphosphate group at the 3'-end, connected through phosphodiester and phosphoramidate bonds, respectively. In order to study the influence of the conjugation at the ends of the oligonucleotide chains on their ability to form quadruplex structures, a CD analysis was undertaken on the conjugated oligomers in comparison with the corresponding unmodified d(TGGGAG) oligomer.