Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases.
Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases.
复制标题
DOI：
10.1371/journal.ppat.1003149
复制
发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Mitreva M
中科院分区：
文献类型：
--
作者：
Taylor CM;Martin J;Rao RU;Powell K;Abubucker S;Mitreva M
作为最大的蛋白质家族之一，蛋白激酶（PKs）调节细胞内几乎所有的过程，并且被认为是重要的药物靶标。已经对PK的抑制剂进行了大量研究，导致大量靶向PK的化合物具有成为主要驱虫药物的潜力。确定已经开发用于治疗被忽视的热带疾病的化合物是一种有吸引力的方法，可以廉价地获得先导化合物，开发成急需的药物，特别是供发展中国家使用。在这项研究中，从线虫，宿主和DrugBank中鉴定出PK，并将其分为激酶家族和亚家族。将线虫蛋白质置于跨越线虫门的直链组中。确定了线虫门的最小激酶组，并探讨了最小激酶组的性质。基于秀丽隐杆线虫直系同源物的RNAi表型、生命周期中的转录表达和解剖表达模式，将来自最小激酶组的直系同源物组优先用于实验测试。提取与DrugBank中属于最小线虫激酶组中相同激酶家族和亚家族的靶标连接的化合物。35个化合物在非寄生的C. elegans和活性化合物进行了针对具有不同寄生模式的线虫物种、吸血捻转血矛线虫和丝虫马来丝虫的测试。其中18个化合物对C. elegans，并且六种化合物也在至少一种寄生物种中显示出功效。有关的途径的化合物可能的目标和他们的分子机制的活动进行了讨论的假设。寄生线虫感染是一个巨大的全球健康和经济问题，感染了大约20亿人，造成1000亿美元的农作物和牲畜损失。发展中国家的人们通常每天靠一美元生活，因此治疗不会很昂贵，因此使用现有药物作为先导化合物为开始开发负担得起的治疗提供了一种经济的方式。蛋白激酶被选为这项工作的重点，因为大量的预先存在的药物靶向他们和他们的重要作用，在调节几乎所有的活动在细胞。在这里，我们描述了一组保守的蛋白激酶在不同的线虫物种和实验筛选结果的预先存在的药物，针对这些激酶。在体外对C. elegans和寄生线虫H.扭体或B。马来人有进一步优化的潜力。这些化合物有可能为发展中国家的人们提供可获得的治疗，以及改善牲畜的健康和促进全球粮食生产。
As one of the largest protein families, protein kinases (PKs) regulate nearly all processes within the cell and are considered important drug targets. Much research has been conducted on inhibitors for PKs, leading to a wealth of compounds that target PKs that have potential to be lead anthelmintic drugs. Identifying compounds that have already been developed to treat neglected tropical diseases is an attractive way to obtain lead compounds inexpensively that can be developed into much needed drugs, especially for use in developing countries. In this study, PKs from nematodes, hosts, and DrugBank were identified and classified into kinase families and subfamilies. Nematode proteins were placed into orthologous groups that span the phylum Nematoda. A minimal kinome for the phylum Nematoda was identified, and properties of the minimal kinome were explored. Orthologous groups from the minimal kinome were prioritized for experimental testing based on RNAi phenotype of the Caenorhabditis elegans ortholog, transcript expression over the life-cycle and anatomic expression patterns. Compounds linked to targets in DrugBank belonging to the same kinase families and subfamilies in the minimal nematode kinome were extracted. Thirty-five compounds were tested in the non-parasitic C. elegans and active compounds progressed to testing against nematode species with different modes of parasitism, the blood-feeding Haemonchus contortus and the filarial Brugia malayi. Eighteen compounds showed efficacy in C. elegans, and six compounds also showed efficacy in at least one of the parasitic species. Hypotheses regarding the pathway the compounds may target and their molecular mechanism for activity are discussed. Parasitic nematode infection is a large global health and economic problem, infecting around 2 billion people and costing $100 billion in crops and livestock. People in developing countries often live on one dollar per day, so treatments cannot be expensive, therefore using pre-existing drugs as lead compounds provides an economical way to begin to develop affordable treatments. Protein kinases were chosen as the focus of this work due to the large number of pre-existing drugs that target them and their important role in regulating almost all activities in the cell. Herein we describe a set of protein kinases conserved in diverse nematode species and experimental screening results of pre-existing drugs that target these kinases. The compounds that show in vitro efficacy in both C. elegans and parasitic nematodes, H. contortus or B. malayi have potential to be optimized further. These compounds have potential to provide accessible treatment to people in developing countries, as well as improving the health of livestock and boosting food production globally.
登录
查看更多内容
影响因子：
2.1
作者：
Brumlik, Michael J.;Nkhoma, Standwell;Kious, Mark J.;Thompson, George R., III;Patterson, Thomas F.;Siekierka, John J.;Anderson, Tim J. C.;Curiel, Tyler J.
通讯作者：
Curiel, Tyler J.
影响因子：
3.7
作者：
Fong DH;Xiong B;Hwang J;Berghuis AM
通讯作者：
Berghuis AM
影响因子：
7.4
作者：
Dong, Ming;Yan, Bryan P.;Liao, James K.;Lam, Yat-Yin;Yip, Gabriel W. K.;Yu, Cheuk-Man
通讯作者：
Yu, Cheuk-Man
影响因子：
5.8
作者：
Gelmedin, Verena;Caballero-Gamiz, Rocio;Brehm, Klaus
通讯作者：
Brehm, Klaus
影响因子：
3.9
作者：
Christopher, Lisa J.;Cui, Donghui;Iyer, Ramaswamy A.
通讯作者：
Iyer, Ramaswamy A.