Roche Innovation Center Shanghai, Shanghai, 201203, China.
Roche Innovation Center Shanghai, Shanghai, 201203, China.
Antiviral Res. 2021 Mar;187:105015. doi: 10.1016/j.antiviral.2021.105015. Epub 2021 Jan 12.
The newly emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coronavirus initiated a pneumonia outbreak (COVID-19) that rapidly spread worldwide and quickly became a public health emergency of international concern; However to date, except Remdesivir, there are no clinically approved specific or effective medicines to prevent or treat COVID-19. Therefore, the development of novel treatments against coronavirus infections caused by the current SARS-CoV-2 virus, as well as other highly pathogenic human coronaviruses, represents an urgent unmet need. Stimulator of interferon genes (STING) plays a central role in host defense mechanisms against microbial infections. STING activation leads to the induction of both type I interferon and autophagy responses, which elicit strong inhibitory effect against the infections caused by a broad range of microbial pathogens. However, whether STING activation can impact infections from SARS-CoV-2 or other coronaviruses remains largely unknown. In this study, we investigated the anti-coronavirus activity triggered by STING activation. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the common cold human coronavirus 229E (HCoV-229E) and SARS-CoV-2 in cell culture systems. In addition, we demonstrated that the antiviral activity of diABZI was dependent on the interferon pathway in HCoV-229E infected normal human fibroblast lung cells (MRC-5) and reconstituted primary human airway air-liquid interface (ALI) cultures. Furthermore, low-dose of diABZI treatment at 0.1 μM effectively reduced the SARS-CoV-2 viral load at the epithelial apical surface and prevented epithelial damage in the reconstituted primary human bronchial airway epithelial ALI system. Our findings have thus revealed the therapeutic potential of STING agonists, such as diABZI, as treatments for SARS-CoV-2 and other human coronavirus infections.
新出现的严重急性呼吸综合征冠状病毒 2 型（SARS-CoV-2）冠状病毒引发了肺炎疫情（COVID-19），该疫情迅速在全球蔓延，并迅速成为国际关注的公共卫生紧急事件；然而，迄今为止，除瑞德西韦外，尚无临床批准的预防或治疗 COVID-19 的特效药物。因此，针对当前 SARS-CoV-2 病毒以及其他高致病性人类冠状病毒引起的冠状病毒感染，开发新型治疗方法是一个紧迫的未满足需求。干扰素基因刺激物（STING）在宿主防御微生物感染的机制中发挥核心作用。STING 的激活导致 I 型干扰素和自噬反应的诱导，从而对广泛的微生物病原体引起的感染产生强烈的抑制作用。然而，STING 的激活是否能影响 SARS-CoV-2 或其他冠状病毒的感染仍知之甚少。在这项研究中，我们研究了 STING 激活引发的抗冠状病毒活性。我们发现，二聚酰胺苯并咪唑（diABZI），一种合成的小分子 STING 受体激动剂，在细胞培养系统中对普通感冒人类冠状病毒 229E（HCoV-229E）和 SARS-CoV-2 均具有强大的抗冠状病毒活性。此外，我们证明 diABZI 的抗病毒活性依赖于 HCoV-229E 感染的正常人类成纤维细胞肺（MRC-5）和重建的原代人气道气液界面（ALI）培养物中的干扰素途径。此外，低剂量（0.1 μM）的 diABZI 治疗可有效降低上皮顶表面的 SARS-CoV-2 病毒载量，并防止重建的原代人支气管气道上皮 ALI 系统中的上皮损伤。我们的研究结果表明，STING 激动剂（如 diABZI）具有治疗 SARS-CoV-2 和其他人类冠状病毒感染的潜力。
