Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.
Mol Neurobiol. 2020 Jan;57(1):566-584. doi: 10.1007/s12035-019-01724-4. Epub 2019 Aug 9.
In recent years, neurological disorders have globally become a leading cause of disability and death. Neurological disorders are very common in both high- and low-income countries, and the number of patients is predicted to increase in the coming decades. Disorders caused by the expanded trinucleotide repeats (CAG, CGG, CCG, CTG, CUG, GAA, and GCN) in the genome, also described as trinucleotide repeat expansion disorders (TREDs), comprise of the major class of neurological diseases. Various TREDs have different modes of pathogenesis, but the severity and time of onset of disease depends on the trinucleotide repeat numbers. Numerous therapeutic strategies, including symptomatic treatment, blockage of mutant protein synthesis, targeting the toxic protein aggregates and degradation of RNA transcripts have been developed for the treatment of these diseases. However, various limitations to these therapeutic strategies have been reported, and therefore, researchers are exploring different avenues of therapeutics development. One of the recent developments include targeting the expanded repeats with small molecules. Small molecule binds with the secondary/tertiary structure of RNA (like bulges, loops, and hairpins) irrespective of its sequences. Altogether, small molecule-based therapeutics may have the advantage over others to be able to overcome the hurdles of the blood-brain barrier, poor absorption, and allergic reactions. In this review, we have summarized various TREDs and envisage the potential of small molecule-based therapeutics for targeting these hitherto incurable neurological disorders.
近年来，神经紊乱疾病已在全球范围内成为导致残疾和死亡的主要原因。神经紊乱疾病在高收入和低收入国家都很常见，预计在未来几十年内患者人数将会增加。由基因组中扩展的三核苷酸重复（CAG、CGG、CCG、CTG、CUG、GAA 和 GCN）引起的疾病，也称为三核苷酸重复扩展疾病（TREDs），构成了主要的一类神经疾病。各种 TREDs 具有不同的发病机制，但疾病的严重程度和发病时间取决于三核苷酸重复的数量。已经开发出了许多治疗策略，包括对症治疗、阻断突变蛋白合成、靶向毒性蛋白聚集体以及降解 RNA 转录本，用于治疗这些疾病。然而，据报道，这些治疗策略存在各种局限性，因此研究人员正在探索不同的治疗方法。最近的发展之一是使用小分子靶向扩展重复。小分子与 RNA 的二级/三级结构（如凸起、环和发夹）结合，而不考虑其序列。总的来说，小分子治疗可能具有优于其他治疗方法的优势，能够克服血脑屏障、吸收不良和过敏反应等障碍。在这篇综述中，我们总结了各种 TREDs，并设想了小分子治疗针对这些迄今无法治愈的神经紊乱疾病的潜力。
