Remdesivir; molecular and functional measures of mitochondrial safety.
Remdesivir; molecular and functional measures of mitochondrial safety.
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Remdesivir;线粒体安全性的分子和功能测量。
DOI：
10.1016/j.taap.2021.115783
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发表时间：
2021-12-15
影响因子：
3.8
通讯作者：
Wallace KB
中科院分区：
文献类型：
--
作者：
Bjork JA;Wallace KB
Remdesivir是少数几种被批准用于治疗住院患者中严重的冠状病毒2（SARS-CoV-2）感染的抗病毒药物之一。前药是一种核苷类似物，通过抑制病毒RNA依赖性RNA聚合酶来干扰病毒复制。该药物也被证明是人类线粒体RNA聚合酶的弱抑制剂，从而可能导致线粒体脱靶和毒性。该研究旨在探索Remdesivir是否会导致线粒体毒性，评估中使用基因组和功能参数。将人源性HepG 2肝细胞在培养物中暴露于增加浓度的瑞德西韦长达48小时。在亚细胞毒性浓度（<1 μM）下，药物未能改变线粒体基因组的拷贝数或表达。线粒体DNA拷贝数不受影响，线粒体呼吸链复合体I和IV的线粒体DNA编码亚基和核编码亚基的相对表达率也不受影响。与此一致的是观察到Remdesivir对线粒体呼吸没有影响，包括基础呼吸、质子泄漏、最大解偶联呼吸、备用呼吸容量或偶联效率。我们的结论是，虽然Remdesivir对线粒体RNA聚合酶具有弱的抑制活性，但线粒体不是药物细胞毒性机制的主要脱靶点。
Remdesivir is one of a few antiviral drugs approved for treating severe cases of coronavirus 2 (SARS-CoV-2) infection in hospitalized patients. The prodrug is a nucleoside analog that interferes with viral replication by inhibiting viral RNA-dependent RNA polymerase. The drug has also been shown to be a weak inhibitor of human mitochondrial RNA polymerase, leaving open the possibility of mitochondrial off-targets and toxicity. The investigation was designed to explore whether remdesivir causes mitochondrial toxicity, using both genomic and functional parameters in the assessment. Human-derived HepG2 liver cells were exposed for up to 48 h in culture to increasing concentrations of remdesivir. At sub-cytotoxic concentrations (<1 μM), the drug failed to alter either the number of copies or the expression of the mitochondrial genome. mtDNA copy number was unaffected as was the relative rates of expression of mtDNA-encoded and nuclear encoded subunits of complexes I and IV of the mitochondrial respiratory chain. Consistent with this is the observation that remdesivir was without effect on mitochondrial respiration, including basal respiration, proton leak, maximum uncoupled respiration, spare respiratory capacity or coupling efficiency. We conclude that although remdesivir has weak inhibitory activity towards mitochondrial RNA polymerase, mitochondria are not primary off-targets for the mechanism of cytotoxicity of the drug.
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影响因子：
158.5
作者：
Grein, J.;Ohmagari, N.;Flanigan, T.
通讯作者：
Flanigan, T.
影响因子：
4.7
作者：
Tchesnokov, Egor P.;Feng, Joy Y.;Gotte, Matthias
通讯作者：
Gotte, Matthias
DOI：
10.1016/j.bbrc.2011.06.067
发表时间：
2011-08-19
影响因子：
3.1
作者：
Malik, Afshan N.;Shahni, Rojeen;Cunningham, Phil
通讯作者：
Cunningham, Phil
影响因子：
--
作者：
Feng JY
通讯作者：
Feng JY
影响因子：
120.7
作者：
Spinner, Christoph D.;Gottlieb, Robert L.;Marty, Francisco M.
通讯作者：
Marty, Francisco M.