Inhibition of thrombin activity by a covalent-binding aptamer and reversal by the complementary strand antidote
Inhibition of thrombin activity by a covalent-binding aptamer and reversal by the complementary strand antidote
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DOI：
10.1039/d0cc08109d
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发表时间：
2021-03-11
影响因子：
4.9
通讯作者：
Taki, Masumi
中科院分区：
文献类型：
--
作者：
Tabuchi, Yudai;Yang, Jay;Taki, Masumi
减轻不可逆药物不良反应的潜在风险一直是共价药物开发的一个重要且具有挑战性的问题。在这里，我们通过在凝血酶结合适体的适当位置引入磺酰氟弹头来创建武器化的共价药物，从而创建了DNA适体型共价药物。我们展示了通过新方式使凝血酶失活，然后在任意时间通过互补链解毒剂重新激活凝血酶。我们预计，这种共价药物的按需逆转将减轻潜在不可逆转的 ADE 的主要担忧，并加速共价适体药物的转化应用。
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.