Targeting protein-protein interactions for parasite control.
Targeting protein-protein interactions for parasite control.
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DOI：
10.1371/journal.pone.0018381
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发表时间：
2011-04-27
期刊：
影响因子：
3.7
通讯作者：
Mitreva M
中科院分区：
文献类型：
--
作者：
Taylor CM;Fischer K;Abubucker S;Wang Z;Martin J;Jiang D;Magliano M;Rosso MN;Li BW;Fischer PU;Mitreva M
寻找致病性感染的新药物靶标将对人类有很大的用处，因为由于目前治疗的耐药性和副作用的发展，很需要开发新的药物来对抗感染。目前针对病原体感染的药物靶标仅涉及单一蛋白质。然而，蛋白质很少单独起作用，大多数生物学过程都是通过与其他蛋白质的相互作用发生的，因此蛋白质-蛋白质相互作用（PPI）提供了一个尚未探索的潜在药物靶点领域，并被认为是下一代药物靶点。选择寄生虫进行这项研究是因为它们对人类健康、牲畜和植物有有害影响，每年给社会造成数十亿美元的损失，并且有许多测序的基因组可用。在这项研究中，我们提出了一种计算方法，利用6寄生虫和1自由生活的蠕虫物种和2主机的全基因组。这些物种被放置在orthopolgous组，然后分箱在物种特异性orthopolgous组。跨门物种中的必需和保守蛋白质具有最大价值，因为它们为制定广泛的控制策略提供了基础。使用两个PPI数据库在物种特异性箱中查找PPI。具有独特蠕虫蛋白的PPI和相对于宿主具有独特特征的蠕虫蛋白，如插入缺失，优先作为药物靶标。基于RNAi表型和与PDB（蛋白质数据库）的同源性对PPI进行评分。还考虑了不同生命阶段的EST数据、GO注释和可药用性。本研究中出现了几种PPI作为潜在的药物靶点。一些相互作用得到了M中表达共定位的支持。incognita和B. malayi（H. sapiens寄生虫），它们具有极其不同的寄生模式。随着更多病原体基因组的测序和PPI数据库的扩展，这种方法将变得越来越适用。
Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs) offer a realm of unexplored potential drug targets and are thought to be the next-generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific ortholgous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank). EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite) and B. malayi (H. sapiens parasite), which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly applicable.
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影响因子：
3.7
作者：
Caffrey CR;Rohwer A;Oellien F;Marhöfer RJ;Braschi S;Oliveira G;McKerrow JH;Selzer PM
通讯作者：
Selzer PM
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
2.9
作者：
Fry, David C.
通讯作者：
Fry, David C.
影响因子：
56.9
作者：
Li, SM;Armstrong, CM;Vidal, M
通讯作者：
Vidal, M
影响因子：
3.2
作者：
Fatumo, Segun;Plaimas, Kitiporn;Koenig, Rainer
通讯作者：
Koenig, Rainer