Structural Basis for Inhibition of Human Primase by Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine.,ACS Chemical Biology

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Structural Basis for Inhibition of Human Primase by Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-09-11 , DOI: 10.1021/acschembio.9b00367
Sandro Holzer ₁ , Neil J Rzechorzek ₁ , Isobel R Short ₁ , Michael Jenkyn-Bedford ₁ , Luca Pellegrini ₁ , Mairi L Kilkenny ₁

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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 in vivo 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.

中文翻译：

阿拉伯呋喃糖基核苷类似物氟达拉滨和阿糖腺苷抑制人引物酶的结构基础。

核苷类似物作为化疗药物广泛应用于临床。阿拉伯糖核苷衍生物如氟达拉滨可有效治疗急慢性白血病和非霍奇金淋巴瘤患者。尽管人们普遍知道核苷类似物通过抑制快速增殖细胞中的 DNA 合成来发挥作用，但其体内靶标的身份和作用机制的分子细节通常未知。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，人引物酶是一种依赖DNA的RNA聚合酶，负责DNA复制中DNA合成的起始。我们的数据表明可以修改氟达拉滨的化学结构以提高其对引物酶的特异性和亲和力，从而可能产生毒性更小且更有效的治疗剂。

更新日期：2019-09-03

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