Molecular basis for fungal selectivity of novel antimitotic compounds
Molecular basis for fungal selectivity of novel antimitotic compounds
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DOI：
10.1128/aac.47.7.2273-2282.2003
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发表时间：
2003-07-01
影响因子：
4.9
通讯作者：
Buysse, J
中科院分区：
文献类型：
--
作者：
Lila, T;Renau, TE;Buysse, J
选择性地干扰真菌有丝分裂的化合物已被证明在控制农业害虫方面是有效的，但还没有专门的有丝分裂抑制剂可用于治疗哺乳动物宿主中的系统性真菌病。为了确定新的有丝分裂抑制物，我们使用了一种基于细胞的筛选策略，该策略利用了酵母α-微管蛋白突变株对抗分裂药物抑制生长的超敏反应。所鉴定的化合物抑制酵母核分裂，并包括一种结构类别的化合物，表明是真菌特有的。MC-305、904及其结构类似物抑制真菌细胞有丝分裂，抑制真菌微管蛋白的体外聚合，但不阻断哺乳动物细胞微管功能和微管蛋白聚合。对改变对MC-305,904结构类似物敏感性的酵母突变的广泛分析表明，该系列化合物与真菌β-微管蛋白上靠近氨基酸198的一个位点结合。所建议的结合位点的特征解释了观察到的真菌微管蛋白系列的特异性，并与相关化合物文库之间的结构-活性关系一致。
Compounds that selectively disrupt fungal mitosis have proven to be effective in controlling agricultural pests, but no specific mitotic inhibitor is available for the treatment of systemic mycoses in mammalian hosts. In an effort to identify novel mitotic inhibitors, we used a cell-based screening strategy that exploited the hypersensitivity of a yeast alpha-tubulin mutant strain to growth inhibition by antimitotic agents. The compounds identified inhibited yeast nuclear division and included one structural class of compounds shown to be fungus specific. MC-305,904 and structural analogs inhibited fungal cell mitosis and inhibited the in vitro polymerization of fungal tubulin but did not block mammalian cell microtubule function or mammalian tubulin polymerization. Extensive analysis of yeast mutations that specifically alter sensitivity to MC-305,904 structural analogs suggested that compounds in the series bind to a site on fungal beta-tubulin near amino acid 198. Features of the proposed binding site explain the observed fungal tubulin specificity of the series and are consistent with structure-activity relationships among a library of related compounds.