Anti-HIV activity of new higher order G-quadruplex aptamers obtained from tetra-end-linked oligonucleotides

By combining the ability of short G-rich oligodeoxyribonucleotides (ODNs) containing the sequence 5 ′CGGA 3 ′ to form higher order G-quadruplex (G4) complexes with the tetra-end-linked (TEL) concept to produce aptamers targeting the HIV envelope glycoprotein 120 (gp120), three new TEL-ODNs ( 1-3 ) having the sequence 5 ′CGGAGG 3 ′ were synthesized with the aim of studying the effect of G4 dimerization on their anti-HIV activity. Furthermore, in order to investigate the effect of the groups at the 5′ position, the 5′ ends of 1-3 were left uncapped ( 1 ) or capped with either the lipophilic dimethoxytrityl (DMT) ( 2 ) or the hydrophilic glucosyl-4-phosphate ( 3 ) moieties. The here reported results demonstrate that only the DMT-substituted TEL-ODN 2 is effective in protecting human MT-4 cell cultures from HIV infection (76% max protection), notwithstanding all the three new aptamers proved to be capable of forming stable higher order dimeric G4s when annealed in K + -containing buffer, thus suggesting that the recognition of a hydrophobic pocket on the target glycoprotein by the aptamers represents a main structural feature for triggering their anti-HIV activity. The synthesis of a new dimeric G-quadruplex-based DNA aptamer endowed with anti-HIV activity is reported.