Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.
Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.
Biochimie. 2019 Aug;163:21-32. doi: 10.1016/j.biochi.2019.05.001. Epub 2019 May 8.
Huntington's diseases (HD) is a very devastating disease caused by r(CAG) expansion in HTT gene, encoding the huntingtin protein. r(CAG) expansion causes disease via multiple pathways including, 1) loss of normal protein function like sequestration of RNA binding protein such as Muscleblind-like (MBNL) and nucleolin, 2) Gain of function for mutant proteins and 3) repeat-associated non-ATG (RAN) translation; in which expanded r(CAG) translates into toxic poly glu, poly ser, or poly ala without the use of any canonical start codon. Herein, we have rationally designed and synthesized a unique class of pyridocoumarin derivatives that target the r(CAG) involved in HD and spinocerebellar ataxia (SCA) pathogenesis. Notably, compounds 3 and 15 showed higher affinity (nanomolar K) and selectivity for diseased r(CAG) RNA compared to regular duplex AU-paired RNA. Interestingly, both scaffolds are cell permeable, exhibit low toxicity to healthy fibroblast cells and are also capable of reducing the level of poly Q aggregation in cellular models. Indeed, our current study offers promising facet for selectively targeting repeats containing RNAs that cause severe diseases like HD and SCAs.
亨廷顿病（HD）是一种非常严重的疾病，由 HTT 基因中的 r(CAG)扩展引起，该基因编码亨廷顿蛋白。r(CAG)扩展通过多种途径导致疾病，包括 1）正常蛋白功能丧失，如 RNA 结合蛋白如 Muscleblind-like (MBNL) 和核仁素的隔离，2）突变蛋白的获得功能，和 3）重复相关的非 ATG（RAN）翻译；其中扩展的 r(CAG) 翻译成没有使用任何典型起始密码子的毒性聚谷氨酰胺、聚丝氨酸或聚丙氨酸。在此，我们合理设计并合成了一类独特的吡啶并 coumarin 衍生物，它们靶向与 HD 和脊髓小脑共济失调（SCA）发病机制相关的 r(CAG)。值得注意的是，与常规的 AU 配对 RNA 相比，化合物 3 和 15 对患病 r(CAG)RNA 具有更高的亲和力（纳摩尔 K）和选择性。有趣的是，这两种支架都具有细胞通透性，对健康成纤维细胞的毒性低，并且还能够降低细胞模型中聚 Q 聚集的水平。事实上，我们目前的研究为选择性靶向导致 HD 和 SCA 等严重疾病的含有重复序列的 RNA 提供了有希望的方面。
