Hammad Noureddine, Ransy Céline, Pinson Benoit, Talmasson Jeremy, Bréchot Christian, Rossignol Jean-François, Bouillaud Frédéric
Institut Cochin, INSERM, CNRS, Université de Paris, 75014, Paris, France.
Service Analyses Métaboliques-TBMcore, Université Bordeaux - CNRS UAR 3427 - INSERM US005, Bordeaux, France.
Sci Rep. 2024 Dec 28;14(1):30679. doi: 10.1038/s41598-024-78694-8.
Viruses are dependent on cellular energy metabolism for their replication, and the drug nitazoxanide (Alinia) was shown to interfere with both processes. Nitazoxanide is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that mitochondrial uncoupling underlies the antiviral effects of nitazoxanide. Tizoxanide (the active metabolite of nitazoxanide), its derivative RM4848 and the uncoupler CCCP were applied to a virus-releasing cell line to obtain the same increasing levels of mitochondrial uncoupling, hence identical impact on OXPHOS. A decrease in infectious viral particle release was observed and reflected the intensity of impact on OXPHOS, irrespective of the nature of the drug. The antiviral effect was significant although the impact on OXPHOS was modest (≤ 25%), and disappeared when a high concentration (25 mM) of glucose was used to enhance glycolytic generation of ATP. Accordingly, the most likely explanation is that moderate interference with mitochondrial OXPHOS induced rearrangement of ATP use and acquisition of infective properties of the viral particles be highly sensitive to this rearrangement. The antiviral effect of nitazoxanide has been supported by clinical trials, and nitazoxanide is considered a safe drug. However, serious adverse effects of the uncoupler dinitrophenol occurred when used to increase significantly metabolic rate with the purpose of weight loss. Taken together, while impairment of mitochondrial bioenergetics is an unwanted drug effect, moderate interference should be considered as a basis for therapeutic efficacy.
病毒的复制依赖于细胞能量代谢，而药物硝唑尼特（商品名：Alinia）已被证明会干扰这两个过程。硝唑尼特是线粒体氧化磷酸化（OXPHOS）的解偶联剂。我们的假设是线粒体解偶联是硝唑尼特抗病毒作用的基础。将替唑尼特（硝唑尼特的活性代谢产物）、其衍生物RM4848和解偶联剂CCCP应用于一个释放病毒的细胞系，以获得相同程度逐渐增加的线粒体解偶联，从而对OXPHOS产生相同的影响。观察到感染性病毒颗粒释放减少，且这种减少反映了对OXPHOS的影响强度，与药物的性质无关。尽管对OXPHOS的影响较小（≤25%），但抗病毒作用显著，并且当使用高浓度（25 mM）葡萄糖来增强糖酵解产生ATP时，抗病毒作用消失。因此，最可能的解释是对线粒体OXPHOS的适度干扰诱导了ATP利用的重新排列，并且病毒颗粒感染特性的获得对这种重新排列高度敏感。硝唑尼特的抗病毒作用已得到临床试验的支持，并且硝唑尼特被认为是一种安全的药物。然而，解偶联剂二硝基苯酚用于显著提高代谢率以达到减肥目的时，会出现严重的不良反应。综上所述，虽然线粒体生物能量学的损害是一种不良药物效应，但适度干扰应被视为治疗效果的基础。
