Nasim Fouzia, Qureshi Insaf Ahmed
Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Prof. C.R. Rao Road, Hyderabad 500046, India.
ACS Omega. 2023 Apr 10;8(17):14884-14899. doi: 10.1021/acsomega.3c00826. eCollection 2023 May 2.
The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.
氨酰tRNA合成酶系被视为蛋白质翻译机制的关键组成部分。随着基于结构的tRNA合成酶 - 配体复合物研究的不断增加，这些酶的详细情况正变得清晰起来。由于已知它们在解读生命系统遗传密码中的关键作用，它们一直被选为抗菌药物开发的重要靶点之一。后来，氨酰tRNA合成酶（aaRSs）在锥虫生存能力方面的作用也得到了验证。通过多项基因敲除研究表明，靶向这些酶中的任何一种都会极大地影响寄生虫的生长。这些成功的研究激发了研究人员寻找能够特异性靶向锥虫aaRSs的抑制剂，他们的不懈努力也取得了丰硕成果。综合所有这些研究，这些至关重要的大分子值得进一步研究，以开发治疗由锥虫引起的一系列感染的药物。在这篇综述中，我们汇总了十多年来在以锥虫aaRSs作为主要关注靶点来设计药物方面所取得的进展。其中一些抑制剂在极低的浓度范围内就能发挥作用，且对哺乳动物细胞没有任何威胁，这是药物发现过程中非常关键的一个方面。在利用结构生物学作为重要工具来分析锥虫aaRSs的结构以及研制对其靶点具有更高特异性的抑制剂方面已经取得了进展。还附录了一些已在其他寄生虫上成功测试但尚未在这些锥虫上验证其疗效的抑制剂。
