Background: Thrombin binding aptamer (TBA) is endowed with antiproliferative properties but its potential development is counteracted by concomitant anticoagulant activity. Methods: Five oligonucleotides (ODNs) based on TBA sequence (GGTTGGTGTGGTTGG) and containing L-residues or both L-residues and inversion of polarity sites have been investigated by NMR and CD techniques for their ability to form G-quadruplex structures. Furthermore, their anticoagulant (PT assay) and antiproliferative properties (MTT assay), and their resistance in fetal bovine serum have been tested. Results: CD and NMR data suggest that investigated ODNs are able to form right- and left-handed G-quadruplex structures. All ODNs do not retain anticoagulant activity characteristic of TBA but are endowed with a significant antiproliferative activity against two cancerous cell lines. Their resistance in biological environment after six days is variable, depending on ODN. Conclusions: A comparison between results and literature data suggests that antiproliferative activity of TBA analogues investigated could depends on two factors: a) biological pathways and targets different from those already identified or proposed for other antiproliferative G-quadruplex aptamers, and b) contribution of the guanine-based degradation products. General significance: Modified TBA analogues containing L-residues and inversion of polarity sites lose the anticoagulant activity but gain antiproliferative properties against two cancer cell lines.

Backbone modified TBA analogues endowed with antiproliferative activity

ESPOSITO, VERONICA
Primo
;
RUSSO, ANNAPINA
Secondo
;
AMATO, TERESA;VARRA, MICHELA;VELLECCO, VALENTINA;BUCCI, MARIAROSARIA;RUSSO, GIULIA;VIRGILIO, ANTONELLA
Penultimo
;
GALEONE, ALDO
Ultimo
2017

Abstract

Background: Thrombin binding aptamer (TBA) is endowed with antiproliferative properties but its potential development is counteracted by concomitant anticoagulant activity. Methods: Five oligonucleotides (ODNs) based on TBA sequence (GGTTGGTGTGGTTGG) and containing L-residues or both L-residues and inversion of polarity sites have been investigated by NMR and CD techniques for their ability to form G-quadruplex structures. Furthermore, their anticoagulant (PT assay) and antiproliferative properties (MTT assay), and their resistance in fetal bovine serum have been tested. Results: CD and NMR data suggest that investigated ODNs are able to form right- and left-handed G-quadruplex structures. All ODNs do not retain anticoagulant activity characteristic of TBA but are endowed with a significant antiproliferative activity against two cancerous cell lines. Their resistance in biological environment after six days is variable, depending on ODN. Conclusions: A comparison between results and literature data suggests that antiproliferative activity of TBA analogues investigated could depends on two factors: a) biological pathways and targets different from those already identified or proposed for other antiproliferative G-quadruplex aptamers, and b) contribution of the guanine-based degradation products. General significance: Modified TBA analogues containing L-residues and inversion of polarity sites lose the anticoagulant activity but gain antiproliferative properties against two cancer cell lines.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/654260
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