Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge CB2 1GA , U.K.
ACS Chem Biol. 2019 Sep 20;14(9):1904-1912. doi: 10.1021/acschembio.9b00367. Epub 2019 Sep 11.
Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin's lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of their targets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for arabinose nucleotide-mediated inhibition of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of fludarabine could be modified to improve its specificity and affinity toward primase, possibly leading to less toxic and more effective therapeutic agents.
核苷类似物在临床实践中被广泛用作化疗药物。阿拉伯糖核苷衍生物，如氟达拉滨，在治疗急性和慢性白血病及非霍奇金淋巴瘤方面非常有效。尽管核苷类似物通常被认为通过抑制快速增殖细胞中的 DNA 合成而起作用，但它们的靶标和作用机制在分子细节上往往并不清楚。在这里，我们提供了阿拉伯糖核苷酸介导的人引物酶抑制的结构基础，引物酶是负责 DNA 复制中 DNA 合成起始的 DNA 依赖性 RNA 聚合酶。我们的数据表明，可以通过修饰氟达拉滨的化学结构来提高其对引物酶的特异性和亲和力，从而可能产生毒性更低、更有效的治疗剂。
