Inhibition of thrombin activity by a covalent-binding aptamer and reversal by the complementary strand antidote.

Abstract

Alleviating the potential risk of irreversible adverse drug effects has been an important and challenging issue for the development of covalent drugs. Here we created a DNA-aptamer-type covalent drug by introducing a sulfonyl fluoride warhead at appropriate positions of the thrombin binding aptamer to create weaponized covalent drugs. We showed the de-activation of thrombin by the novel modality, followed by its re-activation by the complementary strand antidote at an arbitrary time. We envision that such on-demand reversal of covalent drugs will alleviate the major concern of potentially irreversible ADEs and accelerate the translational application of covalent aptamer drugs.