Many recent investigations have demonstrated that ad hoc modified G-rich oligonucleotides can efficiently inhibit HIV replication in several cell lines, with different mechanisms of action being invoked (1). In the course of our studies on modified oligonucleotides, the hexamer d(5’TGGGAG3’), previously found to be active at micromolar conc. if 5’-conjugated with large aromatic tethers (2), was taken as a lead sequence for further synthetic elaborations. A series of mono- and bis-conjugated oligonucleotides carrying this sequence have been synthesized and characterized in our group in order to elucidate their structure-activity relationships, showing that the kinetically and thermodynamically favored formation of G-quadruplex complexes is a crucial prerequisite for the antiviral activity (3-5). In the search for more effective anti-HIV agents, a small library of d(5’TGGGAG3’) oligonucleotides, conjugated with different aromatic groups linked at the 5’-end through phosphodiester bonds, has been designed and synthesized (6). The synthetic strategy here adopted is based on the simple conversion of the chosen aromatic alcohols or phenols into the corresponding phosphoramidite derivatives, incorporated in the last step of the ODN chain assembly exploiting a standard, fully automated phosphoramidite-based solid-phase strategy (7). The target 5’-end conjugated-oligonucleotides were characterized by MALDI-TOF spectrometry and CD analysis. Tested for anti-HIV-1 and anti-HIV-2 activity, potent inhibition of HIV-1 in CEM cells (from 0.068 up to 0.50 M), associated with highly favourable selectivity indexes (S.I. > 3x103) was found for four compounds (6). The biological activity of the novel samples will be presented and discussed in the light of the structural features of the modified oligomers and their propensity to generate stable tetramolecular G-quadruplex complexes.
Exploring the potential of G-quadruplex-based aptamers as anti-HIV agents: design, synthesis and biological evaluation of novel modified G-rich oligonucleotides / Montesarchio, Daniela. - (2010). (Intervento presentato al convegno Guanosines and Quadruplexes COST Action MP0802 Annual Meeting tenutosi a Londra nel 15 - 17 September 2010).
Exploring the potential of G-quadruplex-based aptamers as anti-HIV agents: design, synthesis and biological evaluation of novel modified G-rich oligonucleotides
MONTESARCHIO, DANIELA
2010
Abstract
Many recent investigations have demonstrated that ad hoc modified G-rich oligonucleotides can efficiently inhibit HIV replication in several cell lines, with different mechanisms of action being invoked (1). In the course of our studies on modified oligonucleotides, the hexamer d(5’TGGGAG3’), previously found to be active at micromolar conc. if 5’-conjugated with large aromatic tethers (2), was taken as a lead sequence for further synthetic elaborations. A series of mono- and bis-conjugated oligonucleotides carrying this sequence have been synthesized and characterized in our group in order to elucidate their structure-activity relationships, showing that the kinetically and thermodynamically favored formation of G-quadruplex complexes is a crucial prerequisite for the antiviral activity (3-5). In the search for more effective anti-HIV agents, a small library of d(5’TGGGAG3’) oligonucleotides, conjugated with different aromatic groups linked at the 5’-end through phosphodiester bonds, has been designed and synthesized (6). The synthetic strategy here adopted is based on the simple conversion of the chosen aromatic alcohols or phenols into the corresponding phosphoramidite derivatives, incorporated in the last step of the ODN chain assembly exploiting a standard, fully automated phosphoramidite-based solid-phase strategy (7). The target 5’-end conjugated-oligonucleotides were characterized by MALDI-TOF spectrometry and CD analysis. Tested for anti-HIV-1 and anti-HIV-2 activity, potent inhibition of HIV-1 in CEM cells (from 0.068 up to 0.50 M), associated with highly favourable selectivity indexes (S.I. > 3x103) was found for four compounds (6). The biological activity of the novel samples will be presented and discussed in the light of the structural features of the modified oligomers and their propensity to generate stable tetramolecular G-quadruplex complexes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
