A novel assay for drug screening that utilizes the heat shock response of Caenorhabditis elegans nematodes.
A novel assay for drug screening that utilizes the heat shock response of Caenorhabditis elegans nematodes.
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一种用于使用秀丽隐杆线虫线虫的热休克反应的新型药物筛查测定法。
DOI：
10.1371/journal.pone.0240255
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Sesti F
中科院分区：
文献类型：
--
作者：
Chen CH;Patel R;Bortolami A;Sesti F
生物有机体通过招募多个细胞级联反应来应对环境压力，这些细胞级联反应可以减轻损害并最终提高生存率。这意味着与任何这些途径相互作用的化合物可能会改善生物体的生存。在这里，我们报告的初步尝试，开发一种药物筛选试验的基础上的热休克（HS）反应的秀丽隐杆线虫。该方案通过在不存在/存在测试化合物的情况下使蠕虫经受两种HS条件来起作用。热休克后的存活率通过分析z-堆叠图片手动或以半自动方式量化。我们通过Eli Lilly的Open Innovation Drug Discovery项目，对不同开发阶段的72种化合物进行了盲筛选。分析表明，平均而言，与非临床环境中使用的化合物相比，治疗上有用的药物增加了HS的存活率。我们开发了一种形式主义，根据与从35种FDA批准的药物中计算的一组参数的比较，估计化合物提高生存率的概率。该方法根据礼来化合物提高HS存活率的相对能力，正确鉴定了礼来化合物的发育阶段。总之，这些数据提供了原理证明，即测量C.秀丽隐杆线虫可以以成本和时间有效的方式提供生理学和药理学见解。
Biological organisms respond to environmental stressors by recruiting multiple cellular cascades that act to mitigate damage and ultimately enhance survival. This implies that compounds that interact with any of those pathways might improve organism's survival. Here, we report on an initial attempt to develop a drug screening assay based on the heat shock (HS) response of Caenorhabditis elegans nematodes. The protocol works by subjecting the worms to two HS conditions in the absence/presence of the test compounds. Post-heat shock survival is quantified manually or in semi-automatic manner by analyzing z-stack pictures. We blindly screened a cassette of 72 compounds in different developmental stages provided by Eli Lilly through their Open Innovation Drug Discovery program. The analysis indicated that, on average, therapeutically useful drugs increase survival to HS compared to compounds used in non-clinical settings. We developed a formalism that estimates the probability of a compound to enhance survival based on a comparison with a set of parameters calculated from a pool of 35 FDA-approved drugs. The method correctly identified the developmental stages of the Lilly compounds based on their relative abilities to enhance survival to the HS. Taken together these data provide proof of principle that an assay that measures the HS response of C. elegans can offer physiological and pharmacological insight in a cost- and time-efficient manner.
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DOI：
10.1038/nrm.2017.73
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Gomez-Pastor R;Burchfiel ET;Thiele DJ
通讯作者：
Thiele DJ
影响因子：
16.1
作者：
O'Reilly, Linda P.;Luke, Cliff J.;Perlmutter, David H.;Silverman, Gary A.;Pak, Stephen C.
通讯作者：
Pak, Stephen C.
影响因子：
5.6
作者：
Kong, De-Xin;Ren, Wei;Zhang, Hong-Yu
通讯作者：
Zhang, Hong-Yu
影响因子：
64.8
作者：
Petrascheck, Michael;Ye, Xiaolan;Buck, Linda B.
通讯作者：
Buck, Linda B.
影响因子：
2.6
作者：
Cruz-Corchado, Johnny;Ooi, Felicia K.;Prahlad, Veena
通讯作者：
Prahlad, Veena