Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo.
Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo.
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DOI：
10.1186/s12936-022-04228-0
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发表时间：
2022-06-29
期刊：
影响因子：
3
通讯作者：
Syafruddin, Din
中科院分区：
文献类型：
--
作者：
Asih, Puji B. S.;Siregar, Josephine E.;Dewayanti, Farahana K.;Pravitasari, Normalita E.;Rozi, Ismail E.;Rizki, Andita F. M.;Risandi, Rifqi;Couper, Kevin N.;Oceandy, Delvac;Syafruddin, Din
关键词：
疟原虫对抗疟疾药物主要成分的抗性的快速出现推动了持续的努力以发现靶向感染期间不同生化途径的新型药物。质膜钙+ 2 ATP酶（PMCA 4）是一种调节红细胞（RBC）、内皮细胞和血小板等多种细胞中钙水平的新型质膜蛋白，是一种新的可能干扰疟疾易感性的生化途径。本研究鉴定了几种PMCA 4的药理学抑制剂，即ATA和白藜芦醇，并使用恶性疟原虫3D 7株、伯氏疟原虫ANKA株和约氏疟原虫17 XL株作为模型，测试了它们的体外和体内抗疟疾活性。恶性疟原虫3D 7菌株在宽浓度范围抑制剂存在下的体外繁殖表明，寄生虫生长以剂量依赖性方式受到抑制，IC 50分别为634和0.231 µM。结果证实，这两种化合物都表现出中等至有效的抗疟疾活性，其中白藜芦醇在0.231 µM时表现出最强的寄生虫生长抑制作用。使用伯氏疟原虫ANKA用于实验性脑型疟疾和使用约氏疟原虫17 XL用于寄生虫生长的体内模型显示，最高剂量的ATA（30 mg/kg BW）增加了小鼠的存活。同样，白藜芦醇以100 mg/kg BW的剂量腹腔注射4天后抑制寄生虫的生长。这些发现表明，人类宿主的PMCA 4可能是新型抗疟疾药物的潜在靶点，无论是作为单一药物还是与目前可用的有效抗疟疾药物组合。
Rapid emergence of Plasmodium resistance to anti-malarial drug mainstays has driven a continual effort to discover novel drugs that target different biochemical pathway (s) during infection. Plasma membrane Calcium + 2 ATPase (PMCA4), a novel plasma membrane protein that regulates Calcium levels in various cells, namely red blood cell (RBC), endothelial cell and platelets, represents a new biochemical pathway that may interfere with susceptibility to malaria and/or severe malaria. This study identified several pharmacological inhibitors of PMCA4, namely ATA and Resveratrol, and tested for their anti-malarial activities in vitro and in vivo using the Plasmodium falciparum 3D7 strain, the Plasmodium berghei ANKA strain, and Plasmodium yoelii 17XL strain as model. In vitro propagation of P. falciparum 3D7 strain in the presence of a wide concentration range of the inhibitors revealed that the parasite growth was inhibited in a dose-dependent manner, with IC50s at 634 and 0.231 µM, respectively. The results confirmed that both compounds exhibit moderate to potent anti-malarial activities with the strongest parasite growth inhibition shown by resveratrol at 0.231 µM. In vivo models using P. berghei ANKA for experimental cerebral malaria and P. yoelii 17XL for the effect on parasite growth, showed that the highest dose of ATA, 30 mg/kg BW, increased survival of the mice. Likewise, resveratrol inhibited the parasite growth following 4 days intraperitoneal injection at the dose of 100 mg/kg BW. The findings indicate that the PMCA4 of the human host may be a potential target for novel anti-malarials, either as single drug or in combination with the currently available effective anti-malarials.
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影响因子：
3.7
作者：
Hashem AM;Flaman AS;Farnsworth A;Brown EG;Van Domselaar G;He R;Li X
通讯作者：
Li X
肯尼亚基利比儿童的人类候选基因多态性和严重疟疾的风险：一项病例对照协会的研究。
DOI：
10.1016/s2352-3026(18)30107-8
发表时间：
2018-08
期刊：
The Lancet. Haematology
影响因子：
--
作者：
Ndila CM;Uyoga S;Macharia AW;Nyutu G;Peshu N;Ojal J;Shebe M;Awuondo KO;Mturi N;Tsofa B;Sepúlveda N;Clark TG;Band G;Clarke G;Rowlands K;Hubbart C;Jeffreys A;Kariuki S;Marsh K;Mackinnon M;Maitland K;Kwiatkowski DP;Rockett KA;Williams TN;MalariaGEN Consortium
通讯作者：
MalariaGEN Consortium
影响因子：
16.6
作者：
Band, Gavin;Le, Quang Si;Kwiatkowski, Dominic P.
通讯作者：
Kwiatkowski, Dominic P.
DOI：
10.1016/j.bbamcr.2010.12.007
发表时间：
2011-05-01
影响因子：
5.1
作者：
Oceandy, Delvac;Mohamed, Tamer M. A.;Neyses, Ludwig
通讯作者：
Neyses, Ludwig
影响因子：
56.9
作者：
McMorran, Brendan J.;Marshall, Vikki M.;Foote, Simon J.
通讯作者：
Foote, Simon J.