title: Synthesis, biophysical characterization and anti-HIV activity of d(TG3AG) Quadruplexes bearing hydrophobic tails at the 5'-end.
abstract: Novel conjugated G-quadruplex-forming d(TG3AG) oligonucleotides, linked to hydrophobic groups through phosphodiester bonds at 5'-end, have been synthesized as potential anti-HIV aptamers, via a fully automated, online phosphoramidite-based solid-phase strategy. Conjugated quadruplexes showed pronounced anti-HIV activity with some preference for HIV-1, with inhibitory activity invariably in the low micromolar range. The CD and DSC monitored thermal denaturation studies on the resulting quadruplexes, indicated the insertion of lipophilic residue at the 5'-end, conferring always improved stability to the quadruplex complex (20<ΔTm<40°C). The data suggest no direct functional relationship between the thermal stability and anti-HIV activity of the folded conjugated G-quartets. It would appear that the nature of the residue at 5' end of the d(TG3AG) quadruplexes plays an important role in the thermodynamic stabilization but a minor influence on the anti-HIV activity. Moreover, a detailed CD and DSC analyses indicate a monophasic behaviour for sequences I and V, while for ODNs (II-IV) clearly show that these quadruplex structures deviate from simple two-state melting, supporting the hypothesis that intermediate states along the dissociation pathway may exist.
authors.affiliation: Department of Chemical Sciences, University of Napoli 'Federico II', Via Cintia 4, I-80126 Napoli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Romanucci
authors.affiliation: Istituto di Biostrutture e Bioimmagini-Catania, Consiglio Nazionale delle Ricerche, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Milardi
authors.affiliation: Istituto di Biostrutture e Bioimmagini-Catania, Consiglio Nazionale delle Ricerche, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Campagna
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università̀ di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Gaglione
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università̀ di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Messere
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: D'Urso
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Crisafi
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: La Rosa
authors.affiliation: Department of Chemical Sciences, University of Napoli 'Federico II', Via Cintia 4, I-80126 Napoli, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Zarrelli
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Department of Chemical Sciences, University of Napoli 'Federico II', Via Cintia 4, I-80126 Napoli, Italy. Electronic address: difabio@unina.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Fabio
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002478:Cells, Cultured / Q000821:virology; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054856:G-Quadruplexes; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D015498:HIV-2 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D052157:Aptamers, Nucleotide; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D009841:Oligonucleotides; D012709:Serum Albumin; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Anti-HIV activity; Aptamers; Conjugated oligonucleotides; G-quadruplex; Solid phase synthesis