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High Throughput Screen Identifies Interferon γ-Dependent Inhibitors of Toxoplasma gondii Growth
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2018-07-30 00:00:00 , DOI: 10.1021/acsinfecdis.8b00135
Joshua B Radke 1 , Kimberly L Carey 2 , Subrata Shaw 3 , Shailesh R Metkar 3 , Carol Mulrooney 3 , Jennifer P Gale 3 , Joshua A Bittker 3 , Robert Hilgraf 3 , Eamon Comer 4 , Stuart L Schreiber 4, 5 , Herbert W Virgin 6 , Jose R Perez 3 , L David Sibley 1
Affiliation  

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low μM concentrations and that demonstrated enhanced potency in the presence of a low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of light chain 3 (LC3) to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ dependence was shared among the majority of analogs from 6 priority scaffolds, and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

中文翻译:

高通量筛选确定了弓形虫生长的干扰素γ依赖性抑制剂

弓形虫是专性的细胞内寄生虫,能够因先天性感染以及免疫系统受损的患者引起严重疾病。感染的控制取决于强大的Th1型免疫反应,包括产生干扰素γ(IFN-γ),这对于控制至关重要。IFN-γ激活宿主细胞中的多种抗菌机制,从而能够控制细胞内的寄生虫,例如弓形虫。尽管这些途径在控制急性感染方面是有效的,但免疫系统仍无法根除可以持续一生的慢性感染。同样,尽管抗生素治疗可以控制急性感染,但无法消除慢性感染。为了鉴定可与IFN-γ协同作用的化合物,我们对各种小分子文库进行了高通量筛选,以鉴定弓形虫的抑制剂。我们鉴定了许多可在体外抑制寄生虫生长的化合物在低μM浓度下,在低水平的IFN-γ存在下显示出增强的效力。这些化合物的一个子集通过增强轻链3(LC3)向含寄生虫的液泡的募集起作用,表明它们通过自噬相关过程起作用,而其他化合物则独立于该途径。来自6个优先支架的大多数类似物共享IFN-γ依赖性模式,对一类此类的结构活性关系进行分析后发现,与该功能相关的特定立体化学。这些IFN-γ依赖性前导的鉴定由于其与免疫应答的协同相互作用而可能导致改进的治疗剂的开发。
更新日期:2018-07-30
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