MyosinA is a druggable target in the widespread protozoan parasite Toxoplasma gondii.
MyosinA is a druggable target in the widespread protozoan parasite Toxoplasma gondii.
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DOI：
10.1371/journal.pbio.3002110
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发表时间：
2023-05
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
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弓形虫是一种分布广泛的尖端复合体寄生虫，可在其人类宿主中引起严重疾病。弓形虫和其他顶丝复合体寄生虫入侵、排出和在它们感染的宿主细胞之间移动的能力对寄生虫的毒力和疾病进展至关重要。一种罕见的高度保守的寄生虫肌球蛋白马达(TgMyoA)在弓形虫的运动中起着核心作用。这项工作的目的是确定是否可以通过药物抑制TgMyoA来扰乱寄生虫的运动和溶解周期，作为改变体内疾病进展的一种方法。为此，我们首先试图通过筛选50,000个结构不同的小分子来识别TgMyoA的抑制剂，以寻找重组马达肌动蛋白激活的ATPase活性的抑制剂。屏幕上出现的最热门的KNX-002抑制了TgMyoA，而对所测试的任何脊椎动物肌球蛋白几乎没有影响。KNX-002对寄生虫也有抑制作用，抑制寄生虫的运动和生长，呈剂量依赖关系。我们使用化学诱变、KNX-002筛选和靶向测序来鉴定TgMyoA(T130A)的突变，该突变使重组马达对化合物不那么敏感。与野生型寄生虫相比，表达T130A突变的寄生虫在运动和生长试验中对KNX-002的敏感性降低，证实TgMyoA是KNX-002的生物学相关靶标。最后，我们提出了证据表明，KNX-002可以减缓感染野生型寄生虫的小鼠的疾病进展，但不能减缓表达耐药TgMyoA T130A突变的寄生虫。综上所述，这些数据证明了KNX-002在体外和体内对TgMyoA的特异性，并验证了TgMyoA作为弓形虫感染的可药物靶点。由于TgMyoA是致病所必需的，在顶端复合体寄生虫中是保守的，并且与在人类中发现的肌球蛋白截然不同，因此药物抑制MyoA为治疗弓形虫和其他顶复合体寄生虫引起的破坏性疾病提供了一条很有前途的新途径。弓形虫是一种分布广泛的尖端复合体寄生虫，可在其人类宿主中引起严重疾病。这项研究表明，弓形虫肌球蛋白A的小分子抑制剂降低了体内寄生虫的运动能力，改变了疾病的进展，为治疗顶复合体寄生虫感染提供了一种新的方法。
Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. The ability of T. gondii and other apicomplexan parasites to invade into, egress from, and move between cells of the hosts they infect is critical to parasite virulence and disease progression. An unusual and highly conserved parasite myosin motor (TgMyoA) plays a central role in T. gondii motility. The goal of this work was to determine whether the parasite’s motility and lytic cycle can be disrupted through pharmacological inhibition of TgMyoA, as an approach to altering disease progression in vivo. To this end, we first sought to identify inhibitors of TgMyoA by screening a collection of 50,000 structurally diverse small molecules for inhibitors of the recombinant motor’s actin-activated ATPase activity. The top hit to emerge from the screen, KNX-002, inhibited TgMyoA with little to no effect on any of the vertebrate myosins tested. KNX-002 was also active against parasites, inhibiting parasite motility and growth in culture in a dose-dependent manner. We used chemical mutagenesis, selection in KNX-002, and targeted sequencing to identify a mutation in TgMyoA (T130A) that renders the recombinant motor less sensitive to compound. Compared to wild-type parasites, parasites expressing the T130A mutation showed reduced sensitivity to KNX-002 in motility and growth assays, confirming TgMyoA as a biologically relevant target of KNX-002. Finally, we present evidence that KNX-002 can slow disease progression in mice infected with wild-type parasites, but not parasites expressing the resistance-conferring TgMyoA T130A mutation. Taken together, these data demonstrate the specificity of KNX-002 for TgMyoA, both in vitro and in vivo, and validate TgMyoA as a druggable target in infections with T. gondii. Since TgMyoA is essential for virulence, conserved in apicomplexan parasites, and distinctly different from the myosins found in humans, pharmacological inhibition of MyoA offers a promising new approach to treating the devastating diseases caused by T. gondii and other apicomplexan parasites. Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. This study shows that a small-molecule inhibitor of Toxoplasma myosin A reduces parasite motility and alters disease progression in vivo, suggesting a new approach to treating infections by apicomplexan parasites.
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影响因子：
6.7
作者：
Frénal K;Marq JB;Jacot D;Polonais V;Soldati-Favre D
通讯作者：
Soldati-Favre D
DOI：
10.1084/jem.20020258
发表时间：
2002-06-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Barragan A;Sibley LD
通讯作者：
Sibley LD
影响因子：
6.7
作者：
Nebl T;Prieto JH;Kapp E;Smith BJ;Williams MJ;Yates JR 3rd;Cowman AF;Tonkin CJ
通讯作者：
Tonkin CJ
影响因子：
48
作者：
Andenmatten, Nicole;Egarter, Saskia;Jackson, Allison J;Jullien, Nicolas;Herman, Jean-Paul;Meissner, Markus
通讯作者：
Meissner, Markus
影响因子：
5.6
作者：
Kortagere S;Welsh WJ;Morrisey JM;Daly T;Ejigiri I;Sinnis P;Vaidya AB;Bergman LW
通讯作者：
Bergman LW