Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of NRF2-agonist Sulfodyne®, a stabilized natural Sulforaphane, in cellular and animal models of SARS-CoV-2 infection. In pulmonary or colonic epithelial cell lines, Sulfodyne® elicited a more efficient inhibition of SARS-CoV-2 replication than NRF2-agonists DMF and CDDO. This antiviral activity was not dependent on NRF2 but was associated with the regulation of several metabolic pathways, including the inhibition of ER stress and mTOR signaling, which are activated during SARS-CoV-2 infection. Sulfodyne® also decreased SARS-CoV-2 mediated inflammatory responses by inhibiting the delayed induction of IFNB1 and type I IFN-stimulated genes in infected epithelial cell lines and by reducing the activation of human by-stander monocytes recruited after SARS-CoV-2 infection. In K18-hACE2 mice infected with SARS-CoV-2, Sulfodyne® treatment reduced both early lung viral load and disease severity by fine-tuning IFN-beta levels. Altogether, these results provide evidence for multiple mechanisms that underlie the antiviral and anti-inflammatory activities of Sulfodyne® and pinpoint Sulfodyne® as a potent therapeutic agent against pathogenic effects of SARS-CoV-2 infection.

中文翻译：

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天然抗氧化剂 Sulfodyne® 对抗 SARS-CoV-2 感染致病作用的多种作用机制


治疗 COVID-19 的治疗方案很少。 KEAP1/NRF2 通路是主要的氧化还原反应通路，已成为 COVID-19 的潜在治疗靶点，因为它调节 SARS-CoV-2 感染期间改变的氧化还原稳态和炎症。在这里，我们表征了 NRF2 激动剂 Sulfodyne®（一种稳定的天然萝卜硫素）在 SARS-CoV-2 感染的细胞和动物模型中的作用。在肺或结肠上皮细胞系中，Sulfodyne® 比 NRF2 激动剂 DMF 和 CDDO 更有效地抑制 SARS-CoV-2 复制。这种抗病毒活性不依赖于 NRF2，而是与多种代谢途径的调节有关，包括抑制 ER 应激和 mTOR 信号传导，这些信号在 SARS-CoV-2 感染期间被激活。 Sulfodyne® 还通过抑制受感染上皮细胞系中 IFNB1 和 I 型 IFN 刺激基因的延迟诱导以及减少 SARS-CoV-2 感染后招募的人类旁观者单核细胞的激活来减少 SARS-CoV-2 介导的炎症反应。在感染 SARS-CoV-2 的 K18-hACE2 小鼠中，Sulfodyne® 治疗通过微调 IFN-β 水平，降低了早期肺部病毒载量和疾病严重程度。总而言之，这些结果为 Sulfodyne® 抗病毒和抗炎活性的多种机制提供了证据，并确定 Sulfodyne® 作为对抗 SARS-CoV-2 感染致病作用的有效治疗剂。