High throughput screening of small molecule libraries for modifiers of radiation responses
High throughput screening of small molecule libraries for modifiers of radiation responses
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DOI：
10.3109/09553002.2011.560994
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发表时间：
2011-08-01
影响因子：
2.6
通讯作者：
McBride, William H.
中科院分区：
文献类型：
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作者：
Kim, Kwanghee;Damoiseaux, Robert;McBride, William H.
目的：通过高通量筛选（HTS）化学定义的和生物活性的小分子化合物文库，使用一种公正的药物发现方法来确定辐射损伤的调节剂，重点是辐射保护剂和缓解剂，而不是辐射致敏剂。试验系统终点包括辐射诱导的遗传毒性和酵母DNA损伤以及小鼠淋巴细胞凋亡。对化学多样性文库的大规模数据挖掘确定了对所有端点有效的药物。HTS对小鼠淋巴细胞的生物活性化合物文库分析显示，四环素类、氟喹诺酮类抗生素和环吡唑酸具有活性，结构-活性分析表明它们是共同的药效团。嘌呤核苷、干扰素诱导剂蒂洛酮和亚油酸也被确定为潜在的辐射损伤缓解剂，通常也具有辐射防护作用。这些化合物中有许多能促进DNA修复，具有抗炎活性，并能刺激造血。从这两种类型的文库中选出的这些初步验证命中的化合物确定了小鼠致死性全身照射（WBI）的有效缓解剂。结论：尽管体外HTS有局限性，不能完全概括体内复杂的急性辐射反应的所有方面，但它确定了几类在体内造血系统中具有辐射保护和辐射缓解活性的分子。在未来，增加三维（3-D）或干细胞培养或途径分析，可能会提高HTS的能力，但我们的研究结果表明，可以识别出共同的，进化保守的，典型的途径，可以用来减轻辐射诱导的缺陷。
Purpose: An unbiased approach of drug discovery through high-throughput screening (HTS) of libraries of chemically defined and bioactive small molecule compounds was used to identify modulators of radiation injury with an emphasis on radioprotectors and mitigators rather than radiosensitisers. Assay system endpoints included radiation-induced genotoxicity and DNA damage in yeast and apoptosis in murine lymphocytes. Large-scale data mining of chemically diverse libraries identified agents that were effective with all endpoints. HTS of bioactive compound libraries against murine lymphocytes profiled tetracycline and fluoroquinolone antibiotics and cyclopiazonic acid as having activity, and structure-activity analysis showed a common pharmacophore. Purine nucleosides, the interferon inducer tilorone, and linoleic acid were also identified as potential mitigators of radiation damage that often were also radioprotective. Many of these compounds enhance DNA repair, have anti-inflammatory activity, and stimulate hematopoiesis. Selected compounds within these initial verified hits from both types of libraries identified potent mitigators of lethal whole body irradiation (WBI) in mice.Conclusion: In spite of the fact that in vitro HTS has limitations and is unable to fully recapitulate all aspects of the complex in vivo acute radiation response, it identified several classes of molecules that had activity as radioprotectors and radiomitigators of the hematopoietic system in vivo. In the future, addition of 3-dimensional (3-D) or stem cell cultures or pathway analysis, may improve the power of HTS, but our findings indicate that common, evolutionary conserved, canonical pathways can be identified that could be exploited to mitigate radiation-induced defects.