Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Cold Spring Harb Perspect Biol. 2018 Jun 1;10(6):a032995. doi: 10.1101/cshperspect.a032995.
The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic translation. Currently, there is much interest in targeting eukaryotic translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease.
利用选择性小分子阻断生物过程具有不同于大多数其他实验方法的优势。这些优势包括起效迅速、快速可逆、能够以遗传方法无法实现的方式探测活性，以及有潜力进一步开发为治疗剂。小分子抑制剂还可用于改变表达和活性，而不会影响相互作用伙伴的化学计量。这些原则在翻译领域尤为明显。小分子抑制剂在使研究人员能够捕获短暂的复合物并表征蛋白质合成的特定步骤方面发挥了重要作用。此外，几种作为现代抗菌药物治疗主要手段的药物是原核翻译的有效抑制剂。目前，靶向真核翻译的兴趣很大，因为数十年的研究表明，癌细胞中失调的蛋白质合成代表了一个可靶向的脆弱性。除了作为潜在的治疗药物外，还表明操纵翻译的小分子会影响认知过程，如记忆。在这篇综述中，我们重点介绍了靶向真核翻译起始装置的小分子调节剂，并提供了它们在疾病治疗中的潜在应用的最新信息。
