恶性疟原虫疟疾传播阻断药物的体外发现和体内试验一条龙管道

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nicolas M. B. Brancucci, Christin Gumpp, Geert-Jan van Gemert, Xiao Yu, Armin Passecker, Flore Nardella, Basil T. Thommen, Marc Chambon, Gerardo Turcatti, Ludovic Halby, Benjamin Blasco, Maëlle Duffey, Paola B. Arimondo, Teun Bousema, Artur Scherf, Didier Leroy, Taco W. A. Kooij, Matthias Rottmann, Till S. Voss
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引用次数: 0

摘要

消灭疟疾将需要对恶性疟原虫成熟V期配子体有有效活性的新药,这是唯一能感染蚊子媒介的阶段。由于配子体的特定生物学特性、其体外培养的挑战以及缺乏适合评估候选药物在体内传输阻断潜力的动物模型,鉴定和全面验证对这些静止阶段有活性的分子是困难的。在这里,我们提出了一个基于转基因NF54/ igp1_re9hul8寄生虫的传播阻断药物发现和开发平台,该平台可以有条件地产生大量表达红移萤火虫荧光素酶活力报告基因的V期配子体。除了建立可靠鉴定V期配子细胞杀灭化合物的体外筛选实验外,我们还建立了基于用纯NF54/ igp1_re9hul8 V期配子细胞感染雌性人源化nodsciil2r γ缺失小鼠的临床前体内疟疾传播模型。利用全动物生物发光成像技术,我们评估了抗疟参比药物和临床候选药物的体内配子体杀伤和清除动力学,并确定了明显不同的药效学反应谱。最后,我们将该小鼠模型与蚊子摄食试验相结合,从而牢固地建立了一种有价值的工具,用于系统地评估传播阻断药物的体内疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs

An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs

Elimination of malaria will require new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages infective to the mosquito vector. The identification and comprehensive validation of molecules active against these quiescent stages is difficult due to the specific biology of gametocytes, challenges linked to their cultivation in vitro and the lack of animal models suitable for evaluating the transmission-blocking potential of drug candidates in vivo. Here, we present a transmission-blocking drug discovery and development platform that builds on transgenic NF54/iGP1_RE9Hulg8 parasites engineered to conditionally produce large numbers of stage V gametocytes expressing a red-shifted firefly luciferase viability reporter. Besides developing a robust in vitro screening assay for the reliable identification of stage V gametocytocidal compounds, we also establish a preclinical in vivo malaria transmission model based on infecting female humanized NODscidIL2Rγnull mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes. Using whole animal bioluminescence imaging, we assess the in vivo gametocyte killing and clearance kinetics of antimalarial reference drugs and clinical drug candidates and identify markedly different pharmacodynamic response profiles. Finally, we combine this mouse model with mosquito feeding assays and thus firmly establish a valuable tool for the systematic in vivo evaluation of transmission-blocking drug efficacy.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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