Press Release
Angewandte Chemie International Edition 2006, 45, 6748–6750 doi: 10.1002/anie.200602346 Nr. 38/2006 Built-in BlockerDrug and antidote in the same molecule: New blood-clotting inhibitor that can be switched off by irradiationContact: Alexander Heckel, Universität Bonn (Germany) Registered journalists may download the original article here: An Anticoagulant with Light-Triggered Antidote Activity
In cases of serious side effects or overdoses of medications, it can be
vital to have a fast-acting antidote on hand. This is especially true of
drugs that inhibit blood clotting, which are used to prevent and treat
thromboses and embolisms, to treat heart attacks, and, in higher doses,
in dialysis and in heart surgeries involving a heart-lung machine.
Overdoses can lead to life-threatening hemorrhages.
Unfractionated heparin is so far the only blood-clotting inhibitor for
which a specific antidote exists. This classic thus continues to be the
fallback agent for patients with a high risk of bleeding and in
applications requiring rapid reversal of the anticoagulating effect,
even though a number of newly developed blood-clotting inhibitors would
be more advantageous with regard to their other characteristics.
A research team led by Alexander Heckel, Günter Mayer, and Bernd Pötzsch
in Bonn, Germany, has now developed an anticoagulant that brings along
its own antidote. Irradiation with UV light activates the part of the
molecule that acts as the antidote, which almost immediately halts the
blood-clotting inhibition.
This new substance is based on an aptamer that binds to thrombin, a key
protein in blood clotting, and blocks it. Aptamers are short, single
strands of nucleic acid (DNA) that can bind to another molecule—thrombin
in this case—with strength and specificity similar to those of an
antibody. In doing this, the aptamer folds into a three-dimensional
structure that is perfectly tailored to the structure of the target
molecule. The researchers bound another short DNA strand to the
thrombin-binding aptamers. This fragment can act as antidote as soon as
its “starter” is activated. As long as the antidote hasn’t been
activated, the new drug is a highly effective anticoagulant.
If the aptamer’s blood-clotting inhibition needs to be switched off, the
drug is irradiated with UV light to activate the starter. The short
antidote DNA strand is complementary (the counterpart) to a segment of
the thrombin-binding aptamer strand—except for a special, slightly
altered nucleotide that acts like an error in the sequence. DNA
fragments that are complementary to each other have the tendency to
stick together to form a double strand; however, this is initially
inhibited by the altered nucleotide. UV light causes a part of this
altered nucleotide to split off, thus making it a normal nucleotide. The
sequence error is removed and thus the counterpart can bind tightly to
the aptamer strand, forcing the drug into a hairpin-like form. The
previous three-dimensional structure of the aptamer is disrupted—and so
is its bond to thrombin as well as its anticoagulating effect.
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