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Pharmacol Ther. 2012 Nov;136(2):202-15. doi: 10.1016/j.pharmthera.2012.07.011. Epub 2012 Jul 28.

Polyvalent nucleic acid aptamers and modulation of their activity: a focus on the thrombin binding aptamer.

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Dipartimento di Scienze Chimiche, Università di Napoli "Federico II", Via Cintia 21, Complesso Universitario di Monte Sant'Angelo, I-80126 Napoli, Italy.


Nucleic acid-based aptamers can be selected from combinatorial libraries of synthetic oligonucleotides to bind, with affinity and specificity similar to antibodies, a wide range of biomedically relevant targets. Compared to protein therapeutics, aptamers exhibit significant advantages in terms of size, non-immunogenicity and wide synthetic accessibility. Various chemical modifications have been introduced in the natural oligonucleotide backbone of aptamers in order to increase their half-life, as well as their pharmacological properties. Very effective alternative approaches, devised in order to improve both the aptamer activity and stability, were based on the design of polyvalent aptamers, able to establish multivalent interactions with the target: thus, multiple copies of an aptamer can be assembled on the same molecular- or nanomaterial-based scaffold. In the present review, the thrombin binding aptamers (TBAs) are analyzed as a model system to study multiple-aptamer constructs aimed at improving their anticoagulation activity in terms of binding to the target and stability to enzymatic degradation. Indeed - even if the large number of chemically modified TBAs investigated in the last 20 years has led to encouraging results - a significant progress has been obtained only recently with bivalent or engineered dendritic TBA aptamers, or assemblies of TBAs on nanoparticles and DNA nanostructures. Furthermore, the modulation of the aptamers activity by means of tailored drug-active reversal agents, especially in the field of anticoagulant aptamers, as well as the reversibility of the TBA activity through the use of antidotes, such as porphyrins, complementary oligonucleotides or of external stimuli, are discussed.

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