Swift Robert V, Amaro Rommie E
Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA.
Expert Opin Drug Discov. 2009 Dec 1;4(12):1281-1294. doi: 10.1517/17460440903373617.
Members of the nucleotidyltransferase superfamily known as DNA and RNA ligases carry out the enzymatic process of polynucleotide ligation. These guardians of genomic integrity share a three-step ligation mechanism, as well as common core structural elements. Both DNA and RNA ligases have experienced a surge of recent interest as chemotherapeutic targets for the treatment of a range of diseases, including bacterial infection, cancer, and the diseases caused by the protozoan parasites known as trypanosomes. OBJECTIVE: In this review, we will focus on efforts targeting pathogenic microorganisms; specifically, bacterial NAD(+)-dependent DNA ligases, which are promising broad-spectrum antibiotic targets, and ATP-dependent RNA editing ligases from Trypanosoma brucei, the species responsible for the devastating neurodegenerative disease, African sleeping sickness. CONCLUSION: High quality crystal structures of both NAD(+)-dependent DNA ligase and the Trypanosoma brucei RNA editing ligase have facilitated the development of a number of promising leads. For both targets, further progress will require surmounting permeability issues and improving selectivity and affinity.
被称为DNA和RNA连接酶的核苷酸转移酶超家族成员执行多核苷酸连接的酶促过程。这些基因组完整性的守护者共享一个三步连接机制以及共同的核心结构元件。作为治疗一系列疾病（包括细菌感染、癌症以及由原生动物寄生虫锥虫引起的疾病）的化疗靶点，DNA和RNA连接酶最近都引起了人们的极大兴趣。目的：在本综述中，我们将重点关注针对病原微生物的研究；具体而言，细菌依赖NAD⁺的DNA连接酶是有前景的广谱抗生素靶点，以及来自布氏锥虫的依赖ATP的RNA编辑连接酶，该物种是导致毁灭性神经退行性疾病非洲昏睡病的病原体。结论：依赖NAD⁺的DNA连接酶和布氏锥虫RNA编辑连接酶的高质量晶体结构促进了一些有前景的先导化合物的开发。对于这两个靶点，进一步的进展将需要克服通透性问题并提高选择性和亲和力。
