UV radiation triggers drug antidote
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
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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