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UV radiation triggers drug antidote

Nov 2006
Gwynne D. Koch

Drug-inhibiting antidotes are important for preventing unwanted side effects caused by overdosing, particularly for drugs that inhibit blood clotting, where an overdose could lead to life-threatening bleeding and even death.

The one anticoagulant drug (used to treat embolisms and heart attacks) for which a specific antidote exists is frequently used in situations where there is a high risk of bleeding, even though its use is associated with drawbacks such as immune reactions. Now, researchers Alexander Heckel, Günter Mayer and Bernd Pötzsch at the University of Bonn in Germany have developed a molecule that acts as an anticoagulant and its own antidote. The antidote part of the molecule remains inactive until it is triggered with UV radiation.

The molecule is based on an aptamer that binds to and blocks thrombin, a key protein involved in blood clotting. Aptamers are short, single strands of nucleic acids that fold into well-defined three-dimensional shapes and bind with high specificity to their target molecules, inhibiting the function of these molecules. When the nucleic acids are locked in a hairpin shape, the drug does not bind to thrombin.

Researchers have developed a molecule that functions as a blood-clotting inhibitor and that contains its own antidote. UV radiation activates the antidote, which causes the molecule to fold into its inactive hairpin shape (left), rapidly reversing the drug’s effect. Reprinted with permission of Angewandte Chemie. (NPE=1-(2-nitro-phenyl)ethyl.

The researchers synthesized a photolabile protecting group that served as a phototrigger and bound it to the antidote region of the aptamer. Irradiation with three 360-nm LEDs of 100 mW each for three minutes removed the protecting group and uncaged the antidote region. When released, the antidote caused the drug molecule to fold into the hairpin shape and become inactive. The changes in shape of the molecule were determined from circular dichroism spectra.

According to Heckel, 360-nm radiation was used because shorter wavelengths are damaging to cells and tissues, and longer wavelengths in the visible range would force research to be conducted in dark rooms, which is impractical. Although not used in the current experiment, nonlinear optics and confocal microscopy techniques combined with the researchers’ approach can be used to selectively trigger biological processes in individual cells. The scientists are pursuing using similar techniques to turn genes on or off in individually selectable cells.

They demonstrated that their aptamer combines the advantages of a highly specific anticoagulant with quick and effective control of its function. Such drugs may prove useful in clinical applications in which rapid reversal of the drug’s activity is required, such as in surgeries involving heart-lung machines. Because aptamers are cleared rapidly from the bloodstream, their therapeutic applications currently focus on treating transient conditions such as blood clotting. This characteristic also may be advantageous in applications such as in vivo diagnostic imaging.

Angewandte Chemie International Edition, Oct. 13, 2006, pp. 6748-6750.


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