Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.
Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.
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DOI：
10.1038/s41467-020-20629-8
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发表时间：
2021-01-11
影响因子：
16.6
通讯作者：
Birkholtz LM
中科院分区：
文献类型：
--
作者：
Reader J;van der Watt ME;Taylor D;Le Manach C;Mittal N;Ottilie S;Theron A;Moyo P;Erlank E;Nardini L;Venter N;Lauterbach S;Bezuidenhout B;Horatscheck A;van Heerden A;Spillman NJ;Cowell AN;Connacher J;Opperman D;Orchard LM;Llinás M;Istvan ES;Goldberg DE;Boyle GA;Calvo D;Mancama D;Coetzer TL;Winzeler EA;Duffy J;Koekemoer LL;Basarab G;Chibale K;Birkholtz LM
需要化学物质来瞄准与疟原虫不同生命周期阶段相关的不同生物学。在这里，我们报告了针对疟疾风险药物(MMV)的平行新筛选，MMV是针对疟原虫无性和肝期寄生虫、IV/V期配子、配子、卵囊和作为杀虫药物的大流行反应盒。独特的化学类型被鉴定为具有多阶段活性或阶段特异性活性，包括结构多样化的配子体靶向化合物，具有强大的传递阻断活性，如JmjC抑制剂ML324和抗结核临床候选药物SQ109。机制研究证明，ML324阻止组蛋白去甲基化，导致配子细胞基因表达异常和死亡。此外，对SQ109耐药的寄生虫的选择意味着可药物的V型H+-ATPase导致敏感性降低。因此，我们的数据提供了一个庞大的化合物数据集，这些化合物可以被重新定向用于抗疟疾的开发，也指向了可以在多个寄生虫生命周期阶段作为靶点的蛋白质。在这里，Reader等人。同时筛选疟疾风险大流行应对药盒，以对抗疟原虫、无性寄生虫和肝期寄生虫、IV/V期配子、配子、卵囊和作为杀虫药物。他们发现了两种有效的传播阻断药物：组蛋白去甲基酶抑制剂ML324和抗结核药物SQ109。
Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages. Here, Reader et al. screen the Medicines for Malaria Venture Pandemic Response Box in parallel against Plasmodiumasexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. They identify two potent transmission-blocking drugs: a histone demethylase inhibitor ML324 and the antitubercular SQ109.
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影响因子：
15.8
作者：
Delves M;Plouffe D;Scheurer C;Meister S;Wittlin S;Winzeler EA;Sinden RE;Leroy D
通讯作者：
Leroy D
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.2
作者：
Delves, Michael J.
通讯作者：
Delves, Michael J.
影响因子：
8.8
作者：
Ebert, Gregor;Lopaticki, Sash;Boddey, Justin A.
通讯作者：
Boddey, Justin A.