PDF(Pubmed)
Abstract：
Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor\'s selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.
摘要：
对凝血的结构同源蛋白酶的有效和选择性抑制对药物开发提出了挑战。嗜血生物体通常通过形成结合了exosite和活性位点结合基序的肽抑制剂来实现这一点。受到这种生物学策略的启发，我们通过连接EXosite结合适体和小分子ACTive位点抑制剂,从头创建了几种靶向凝血酶和Xa因子的EXACT抑制剂.EXACT抑制剂内的适体组分(1)与小分子活性位点抑制剂协同作用并将其效力增强数百倍(2)可以将活性位点抑制剂的选择性重定向到不同的蛋白酶，和(3)能够通过破坏二价结合的解毒剂有效逆转抑制。一种确切的抑制剂,HD22-7A-DAB,表现出非凡的抗凝活性，表现出巨大的潜力，快速起效的抗凝以支持心血管手术。使用这种可推广的分子工程策略，选择性,强力，和快速可逆的EXACT抑制剂可以通过简单的寡核苷酸缀合产生针对许多酶的许多研究和治疗应用。
