Identification of novel anti‐leishmanials targeting glutathione synthetase of the parasite: a drug repurposing approach

IF 3.5 4区生物学 Q1 Biochemistry, Genetics and Molecular Biology

FEBS Letters Pub Date : 2024-09-13 DOI:10.1002/1873-3468.15016

Manash Sarma, Kushal Bora, Preeti Ranjan, Vikash Kumar Dubey

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引用次数: 0

Abstract

Drug repurposing has emerged as an effective strategy against infectious diseases such as visceral leishmaniasis. Here, we evaluated four FDA‐approved drugs–valrubicin, ciclesonide, deflazacort, and telithromycin—for their anti‐leishmanial activity on Leishmania donovani parasites, especially their ability to target the enzyme glutathione synthetase (LdGS), which enables parasite survival under oxidative stress in host macrophages. Valrubicin and ciclesonide exhibited superior inhibitory effects compared to deflazacort and telithromycin, inhibiting the promastigotes at very low concentrations, with IC50 values of 1.09 ± 0.09 μm and 2.09 ± 0.09 μm, respectively. Subsequent testing on amastigotes revealed the IC50 values of 1.74 ± 0.05 μm and 3.32 ± 0.21 μm for valrubicin and ciclesonide, respectively. Molecular and cellular level analysis further elucidated the mechanisms underlying the anti‐leishmanial activity of valrubicin and ciclesonide.

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鉴定以寄生虫谷胱甘肽合成酶为靶点的新型抗利什曼病药物：一种药物再利用方法

药物再利用已成为抗击内脏利什曼病等传染性疾病的有效策略。在这里，我们评估了四种美国食品及药物管理局（FDA）批准的药物--valrubicin、环索奈德、deflazacort 和 telithromycin--对多诺万利什曼寄生虫的抗利什曼病活性，特别是它们靶向谷胱甘肽合成酶（LdGS）的能力，这种酶能使寄生虫在宿主巨噬细胞的氧化应激下存活。与德氟沙星和泰利霉素相比，缬氨噻啶和环索奈德表现出更优越的抑制效果，它们能以极低的浓度抑制原生体，IC50 值分别为 1.09 ± 0.09 μm 和 2.09 ± 0.09 μm。随后对无丝分裂体进行的测试显示，valrubicin 和环索奈德的 IC50 值分别为 1.74 ± 0.05 μm 和 3.32 ± 0.21 μm。分子和细胞水平分析进一步阐明了valrubicin和环索奈德抗利什曼病活性的机制。

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来源期刊

FEBS Letters 生物-生化与分子生物学

CiteScore

7.00

自引率

2.90%

发文量

303

审稿时长

1.0 months

期刊介绍： FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.