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首页> 外文期刊>Biochemistry >Eukaryotic Ribosomal Expansion Segments as Antimicrobial Targets
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Eukaryotic Ribosomal Expansion Segments as Antimicrobial Targets

机译：真核核糖体膨胀区段作为抗微生物靶标

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摘要

Diversity in eukaryotic rRNA structure and function offers possibilities of therapeutic targets. Unlike ribosomes of prokaryotes, eukaryotic ribosomes contain species-specific rRNA expansion segments (ESs) with idiosyncratic structures and functions that are essential and specific to some organisms. Here we investigate expansion segment 7 (ES7), one of the largest and most variable expansions of the eukaryotic ribosome. We hypothesize that ES7 of the pathogenic fungi Candida albicans (ES7CA) could be a prototypic drug target. We show that isolated ES7CA folds reversibly to a native-like state. We developed a fluorescence displacement assay using an RNA binding fluorescent probe, F-neo. F-neo binds tightly to ES7CA with a Kd of 2.5 × 10–9 M but binds weakly to ES7 of humans (ES7HS) with a Kd estimated to be greater than 7 μM. The fluorescence displacement assay was used to investigate the affinities of a library of peptidic aminosugar conjugates (PAs) for ES7CA. For conjugates with highest affinities for ES7CA (NeoRH, NeoFH, and NeoYH), the lowest dose needed to induce mortality in C. albicans (minimum inhibitory concentration, MIC) was determined. PAs with the lowest MIC values were tested for cytotoxicity in HEK293T cells. Molecules with high affinity for ES7CA in vitro induce mortality in C. albicans but not in HEK293T cells. The results are consistent with the hypothesis that ESs represent useful targets for chemotherapeutics directed against eukaryotic pathogens.]]>
机译：<！[cdata [ src ='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/bichaw/2017/bichaw.2017.56.issue-40/acs.biochem.7b00703/ 20171004 / Images / Medium / Bi-2017-00703K_0010.gif“>真核rRNA结构和功能的多样性提供了治疗目标的可能性。与原核生物的核糖体不同，真核核糖体含有特异性rRNA膨胀区段（ESS），其具有属于和特异性的特质和特异性的功能。在这里，我们调查扩展段7（ES7），是真核核糖体的最大和最可变的扩展之一。我们假设致病性真菌的ES7 念珠菌蛋白酶（ES7 Ca ）可以是原型药物靶标。我们展示了孤立的ES7 Ca 可逆地折叠到本土状态。我们使用RNA结合荧光探针，F-NeO开发了荧光位移测定。 F-neo紧密结合到ES7 Ca ，其中 k d 为2.5×10 -9 m，但弱束缚对人体的ES7（ES7 Hs ），其中 k d 估计大于7μm。荧光位移测定用于研究ES7 Ca 肽氨糖蛋白缀合物（PAS）文库的亲和力。对于具有最高亲和力的ES7 Ca （NeoRh，Neofh和Neoyh）的缀合物，所需的最低剂量在 c中诱导死亡率。测定albicans （最小抑制浓度，MIC）。在HEK293T细胞中测试具有最低MIC值的PAS。对于ES7 Ca 在体外具有高亲和力的分子在 c中诱导死亡率。 albicans 但不是在HEK293T细胞中。结果与该假设一致，即ESS代表针对真核病原体的化学治疗剂的有用靶标。]]]>

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  • 来源
    《Biochemistry》 |2017年第40期|共12页
  • 作者

    Lizzette M. Gómez Ramos; Natalya N. Degtyareva; Nicholas A. Kovacs; Stefany Y. Holguin; Liuwei Jiang; Anton S. Petrov; Marcin Biesiada; Michael Y. Hu; Katarzyna J. Purzycka; Dev P. Arya; Loren Dean Williams;

  • 作者单位

    School of Chemistry and Biochemistry Georgia Institute of Technology 315 Ferst Drive NW Atlanta Georgia 30332-0363 United States;

    NUBAD LLC 900 B West Farris Road Greenville South Carolina 29605 United States;

    School of Chemistry and Biochemistry Georgia Institute of Technology 315 Ferst Drive NW Atlanta Georgia 30332-0363 United States;

    School of Chemical and Biomolecular Engineering Georgia Institute of Technology 311 Ferst Drive NW Atlanta Georgia 30332-0100 United States;

    Department of Chemistry Clemson University 436 Hunter Laboratories Clemson South Carolina 29634-0973 United States;

    School of Chemistry and Biochemistry Georgia Institute of Technology 315 Ferst Drive NW Atlanta Georgia 30332-0363 United States;

    RNA Structure and Function Laboratory Institute of Bioorganic Chemistry Polish Academy of Sciences Poznan 61-704 Poland;

    School of Chemistry and Biochemistry Georgia Institute of Technology 315 Ferst Drive NW Atlanta Georgia 30332-0363 United States;

    RNA Structure and Function Laboratory Institute of Bioorganic Chemistry Polish Academy of Sciences Poznan 61-704 Poland;

    NUBAD LLC 900 B West Farris Road Greenville South Carolina 29605 United States;

    School of Chemistry and Biochemistry Georgia Institute of Technology 315 Ferst Drive NW Atlanta Georgia 30332-0363 United States;

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  • 正文语种 eng
  • 中图分类 生物化学;
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