Cardiovascular Drug Discovery & Therapy (Track)


Vera A. Spiridonova

Lomonosov Moscow State University, Moscow, Russia


Aptamers are small DNA or RNA fragments selected from a large sequence pool so as to bind, strongly and selectively, to a certain target molecule. To date, aptamers have been produced against thousands of proteins, with their specificity and affinity to these molecules being comparable to those of monoclonal antibodies [1, 2]. DNA aptamers against thrombin, the central enzyme of the blood coagulation system [3-6], inhibit its activity in reactions with fibrinogen and blood platelets. We have studied a single-stranded DNA aptamer RE31 consisting of 31 nucleotides, estimating its inhibitory activity from the activated partial thromboplastin time (APTT) and prothrombin time (PT) in human blood  plasma. RE31 proved to inhibit clot formation. Compared to control preparations, this aptamer prolonged APTT and PT by factors of 2 and 3, respectively [7]. In experiments with rats, its effective life span in circulating blood was about 10-15 min. Aptamers administered in the form of protamine-containing polyelectrolyte complexes remained active in vivo for up to 12 hours, compared to 12 hours in the control, confirming that macromolecular prodrugs are very useful  for achieving controlled drug release and drug targeting. Using the SELEX technique [1, 2], we produced a family of DNA aptamers against interleukin-6 (IL-6). To this end, recombinant IL-6 in active form was produced [8]. This cytokine interacts with the cell-surface receptor complex containing signal-transducing glycoprotein gp130. In particular, IL-6 signaling is responsible for proliferation of precursor blood cells [9], and its increasing concentration in the circulating blood creates the risk of more aggressive cancer development. The affinity of aptamer 120G to IL-6 was estimated by means of surface plasmon resonance, a modern physical method. The apparent dissociation constant of the IL-6–120G complex reached 9 nM, being comparable to those of IL-6 complexes with monoclonal antibodies. The method of flow cytometry was used to evaluate the inhibitory effect of this aptamer on the formation of a complex between IL-6 and gp130.

Prospects for using DNA aptamers for therapeutic purposes are discussed. The work was supported by RFBR grant no. 11-04-01530.


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