A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.
A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.
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DOI：
10.1371/journal.pone.0004413
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Selzer PM
中科院分区：
文献类型：
--
作者：
Caffrey CR;Rohwer A;Oellien F;Marhöfer RJ;Braschi S;Oliveira G;McKerrow JH;Selzer PM
血吸虫病是热带地区流行的慢性蠕虫病。治疗和控制依赖于仅使用一种药物吡喹酮的化疗，如果临床相关的耐药性出现并扩散，这种依赖性将引起关注。因此，为了确定潜在的靶蛋白的药物发现的新途径，我们已经采取了比较化学基因组学的方法，利用曼氏血吸虫的推定蛋白质组相比，两个模式生物，线虫，秀丽隐杆线虫和果蝇，果蝇的蛋白质组。使用基因组比较软件Genlight，实施两个单独的计算机模拟工作流程以衍生一组寄生虫蛋白，对于所述寄生虫蛋白，在两种模式生物体中直系同源物的基因破坏产生有害表型（例如，致命的，运动性的损害），即，是必需的基因/蛋白质。在每个工作流程生成的67和68个序列中，63个在两组中是相同的，导致最终一组72个寄生虫蛋白。除了一个外，所有这些都在感染人类的寄生虫的相关发育阶段表达。随后对组合的工作流程输出进行深入的手动管理，发现了57种候选蛋白质。在文献中，对这些“可药用”蛋白质同源物的仔细检查鉴定了35个S。mansoni序列，其中18个与具有3D结构的蛋白质同源，包括共结晶配体，这将允许进一步的基于结构的药物设计研究。提出的比较化学基因组学策略产生了一组易处理的S。mansoni蛋白作为对抗这种潜伏的人类病原体的药物靶标进行实验验证。
Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for ‘druggable’ protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen.
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