University Chemical Laboratory, University of Cambridge , Lensfield Road, CB2 1EW Cambridge, United Kingdom.
ACS Chem Biol. 2013 Oct 18;8(10):2122-6. doi: 10.1021/cb400246k. Epub 2013 Aug 13.
As microRNA silencing processes are mediated by the protein Argonaute 2 and for target RNA binding only a short sequence at the microRNA's 5' end (seed region) is crucial, we report a novel inhibitor class: the microRNA-specific Argonaute 2 protein inhibitors that not only block this short recognition sequence but also bind to the protein's active site. We developed a model for rational drug design, enabling the identification of Argonaute 2 active site binders and their linkage with a peptide nucleic acid sequence (PNA), which addresses the microRNA of interest. The designed inhibitors targeting microRNA-122, a hepatitis C virus drug target, had an IC50 of 100 nM, 10-fold more active than the simple PNA sequence (IC50 of 1 μM), giving evidence that the strategy has potential. Due to their lower molecular weight, these inhibitors may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.
作为 microRNA 沉默过程由 Argonaute 2 蛋白介导，并且只有 microRNA 的 5' 端（种子区）的短序列对于靶 RNA 结合至关重要，我们报告了一类新型抑制剂：microRNA 特异性 Argonaute 2 蛋白抑制剂，其不仅阻断该短识别序列，而且还结合到蛋白的活性位点。我们开发了一种合理药物设计模型，能够识别 Argonaute 2 活性位点结合物及其与肽核酸序列（PNA）的连接，该 PNA 序列针对感兴趣的 microRNA。针对丙型肝炎病毒药物靶点 microRNA-122 的设计抑制剂的 IC50 为 100 nM，比简单的 PNA 序列（IC50 为 1 μM）活性高 10 倍，这证明了该策略具有潜力。由于它们的分子量较低，这些抑制剂可能比报道的寡核苷酸抑制剂具有更好的药代动力学特性，使它们有用于潜在治疗用途的可能性。
