3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synhesis and Bioimaging Studies.

IF 4 2区 医学 Q2 CHEMISTRY, MEDICINAL
ACS Infectious Diseases Pub Date : 2024-10-11 Epub Date: 2024-09-26 DOI:10.1021/acsinfecdis.4c00304
Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y Botté, Stéphanie A Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet
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引用次数: 0

摘要

凋亡体是恶性疟原虫或弓形虫寄生虫赖以生存的重要细胞器,被认为是开发新型抗疟药物候选靶点的合适药物。Plasmodione 是一种具有氧化还原作用的抗疟先导药物,在低 nM 浓度下对疟原虫的几个血期(如早期环和配子细胞)具有活性。然而,它的精确生物靶标仍然未知。在这里,我们介绍了对无性血型恶性疟原虫和淋病双球菌速殖体有活性的新的疟原虫杂芳香族类似物的合成和评估。利用基于生物成像的分析方法,我们跟踪了淋病双球菌速殖体的形态变化,并发现了药物处理后尖体的特异性缺失。脂质组学和通量组学分析表明,药物处理严重影响了淋病蛛速殖体中顶质寄存的 FASII 的活性,进一步证明了顶质是质子二酮类似物的主要靶标。为了跟踪药物的定位,我们设计了 "可点击 "的plasmodione 类似物,作为通过 Cu(I)- 催化叠氮-炔环加成反应进行荧光成像的工具。将两种探针分别与恶性疟原虫滋养体和淋病双球菌速殖体短时孵育,结果表明点击产物定位于这两种寄生虫的细胞质内或其附近。在恶性疟原虫中,荧光信号也与线粒体有关,这表明质二酮和相关类似物的生物活化和活性可能与疟原虫的这两个细胞器有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies.

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, "clickable" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.

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来源期刊
ACS Infectious Diseases
ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES
CiteScore
9.70
自引率
3.80%
发文量
213
期刊介绍: ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.
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