Antimalarial mechanism of action of the natural product 9-methoxystrobilurin G

IF 3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular omics Pub Date : 2024-08-29 DOI:10.1039/d4mo00088a

Philip J. Shaw, Parichat Prommana, Chawanee Thongpanchang, Sumalee Kamchonwongpaisan, Darin Kongkasuriyachai, Yan Wang, Zhihua Zhou, Yiqing Zhou

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Abstract

The natural product 9-methoxystrobilurin G (9MG) from Favolaschia spp basidiomycetes is a potent and selective antimalarial. The mechanism of action of 9MG is unknown. We induced 9MG resistance in Plasmodium falciparum 3D7 and Dd2 strains and identified mutations associated with resistance by genome sequencing. All 9MG-resistant clones possessed missense mutations in the cytochrome b (CYTB) gene, a key component of mitochondrial complex III. The mutations map to the quinol oxidation site of CYTB, which is also the target of antimalarials such as atovaquone. In a complementary approach to identify protein targets of 9MG, a photoactivatable derivative of 9MG was synthesized and applied in chemoproteomic-based target profiling. Three components of mitochondrial complex III (QCR7, QCR9, and COX15) were specifically enriched consistent with 9MG targeting CYTB and complex III function in P. falciparum. Inhibition of complex III activity by 9MG was confirmed by ubiquinone cytochrome c reductase assay using P. falciparum extract. The findings from this study may be useful for developing novel antimalarials targeting CYTB.

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天然产物 9-甲氧基石蒜碱 G 的抗疟作用机制

从 Favolaschia spp basidiomycetes 中提取的天然产物 9-甲氧基石蒜碱 G（9MG）是一种强效的选择性抗疟药物。9MG 的作用机制尚不清楚。我们在恶性疟原虫 3D7 和 Dd2 株系中诱导出了 9MG 抗药性，并通过基因组测序确定了与抗药性相关的突变。所有抗 9MG 的克隆都具有细胞色素 b（CYTB）基因的错义突变，该基因是线粒体复合体 III 的关键组成部分。这些突变位于 CYTB 的醌氧化位点，而该位点也是阿托伐醌等抗疟药的靶点。作为鉴定 9MG 蛋白靶标的补充方法，我们合成了 9MG 的光活化衍生物，并将其应用于基于化学蛋白组学的靶标分析。线粒体复合体 III 的三个组分（QCR7、QCR9 和 COX15）被特异性地富集，这与 9MG 靶向 CYTB 和恶性疟原虫中复合体 III 的功能是一致的。使用恶性疟原虫提取物进行的泛醌细胞色素 c 还原酶测定证实了 9MG 对复合体 III 活性的抑制作用。这项研究的结果可能有助于开发针对 CYTB 的新型抗疟药物。

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来源期刊

Molecular omics Biochemistry, Genetics and Molecular Biology-Biochemistry

CiteScore

5.40

自引率

3.40%

发文量

期刊介绍： Molecular Omics publishes high-quality research from across the -omics sciences. Topics include, but are not limited to: -omics studies to gain mechanistic insight into biological processes – for example, determining the mode of action of a drug or the basis of a particular phenotype, such as drought tolerance -omics studies for clinical applications with validation, such as finding biomarkers for diagnostics or potential new drug targets -omics studies looking at the sub-cellular make-up of cells – for example, the subcellular localisation of certain proteins or post-translational modifications or new imaging techniques -studies presenting new methods and tools to support omics studies, including new spectroscopic/chromatographic techniques, chip-based/array technologies and new classification/data analysis techniques. New methods should be proven and demonstrate an advance in the field. Molecular Omics only accepts articles of high importance and interest that provide significant new insight into important chemical or biological problems. This could be fundamental research that significantly increases understanding or research that demonstrates clear functional benefits. Papers reporting new results that could be routinely predicted, do not show a significant improvement over known research, or are of interest only to the specialist in the area are not suitable for publication in Molecular Omics.

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