The intense search for oligonucleotides (ODNs) endowed with pharmacological activities has led, in the past decade, to the identification of tens of candidate drugs, now being evaluated in preclinical or clinical trials. Based on G-rich DNA sequences, several aptamers, adopting G-quadruplex structures with different topologies, have been selected as potent in vitro antiviral and/or antitumoral agents. In order to develop novel therapeutically relevant G-quadruplex-based aptamers, we have investigated - as a model compound – the 5’d(TGGGAG)3’ sequence, known to be anti-HIV-1 active if 5’-modified with bulky aromatic residues. A set of 5’-conjugated analogues has been analyzed by integrated CD, DSC and molecular modelling studies, allowing a detailed biophysical characterization of the resulting G-quadruplexes. Following the assumption that the kinetically and thermodynamically favoured formation of the quadruplex complexes is a pre-requisite for their efficient antiviral activity, novel hybrid ODNs, carrying diverse terminal modifications, were prepared via a fully automated, on-line phosphoramidite-based strategy and evaluated for anti-HIV activity.
G-quadruplex forming oligonucletides as finely tunable aptamers: towards better DNA mimics / Montesarchio, Daniela. - In: NUCLEIC ACIDS SYMPOSIUM SERIES. - ISSN 1746-8272. - STAMPA. - 52:(2008), pp. 9-10. (Intervento presentato al convegno 18th International Roundtable on nucleosides, nucleotides and nucleic acids tenutosi a Kyoto (Giappone) nel 8-12 settembre 2008) [10.1093/nass/nrn005].
G-quadruplex forming oligonucletides as finely tunable aptamers: towards better DNA mimics
MONTESARCHIO, DANIELA
2008
Abstract
The intense search for oligonucleotides (ODNs) endowed with pharmacological activities has led, in the past decade, to the identification of tens of candidate drugs, now being evaluated in preclinical or clinical trials. Based on G-rich DNA sequences, several aptamers, adopting G-quadruplex structures with different topologies, have been selected as potent in vitro antiviral and/or antitumoral agents. In order to develop novel therapeutically relevant G-quadruplex-based aptamers, we have investigated - as a model compound – the 5’d(TGGGAG)3’ sequence, known to be anti-HIV-1 active if 5’-modified with bulky aromatic residues. A set of 5’-conjugated analogues has been analyzed by integrated CD, DSC and molecular modelling studies, allowing a detailed biophysical characterization of the resulting G-quadruplexes. Following the assumption that the kinetically and thermodynamically favoured formation of the quadruplex complexes is a pre-requisite for their efficient antiviral activity, novel hybrid ODNs, carrying diverse terminal modifications, were prepared via a fully automated, on-line phosphoramidite-based strategy and evaluated for anti-HIV activity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
