de Oliveira Pedro Gonçalves, Termini Lara, Durigon Edison Luiz, Lepique Ana Paula, Sposito Andrei C, Boccardo Enrique
Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP 01246-903, Brazil; Sport Traumatology Group, Department of Orthopaedics and Traumatology, Santa Casa de São Paulo School of Medical Sciences , São Paulo, SP 01221-020, Brazil.
Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246-000, Brazil.
Med Hypotheses. 2020 Nov;144:109920. doi: 10.1016/j.mehy.2020.109920. Epub 2020 Jun 1.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 19 (COVID-19), was declared pandemic by the World Health Organization in March 2020. SARS-CoV-2 binds its host cell receptor, angiotensin-converting enzyme 2 (ACE2), through the viral spike (S) protein. The mortality related to severe acute respiratory distress syndrome (ARDS) and multi-organ failure in COVID-19 patients has been suggested to be connected with cytokine storm syndrome (CSS), an excessive immune response that severely damages healthy lung tissue. In addition, cardiac symptoms, including fulminant myocarditis, are frequent in patients in a severe state of illness. Diacerein (DAR) is an anthraquinone derivative drug whose active metabolite is rhein. Different studies have shown that this compound inhibits the IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-α, NF-κB and NALP3 inflammasome pathways. The antiviral activity of rhein has also been documented. This metabolite prevents hepatitis B virus (HBV) replication and influenza A virus (IAV) adsorption and replication through mechanisms involving regulation of oxidative stress and alterations of the TLR4, Akt, MAPK, and NF-κB signalling pathways. Importantly, rhein inhibits the interaction between the SARS-CoV S protein and ACE2 in a dose-dependent manner, suggesting rhein as a potential therapeutic agent for the treatment of SARS-CoV infection. Based on these findings, we hypothesize that DAR is a multi-target drug useful for COVID-19 treatment. This anthraquinone may control hyperinflammatory conditions by multi-faceted cytokine inhibition and by reducing viral infection.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可引发冠状病毒病19（COVID-19），2020年3月世界卫生组织宣布其为大流行病。SARS-CoV-2通过病毒刺突（S）蛋白与宿主细胞受体血管紧张素转换酶2（ACE2）结合。有研究表明，COVID-19患者中与严重急性呼吸窘迫综合征（ARDS）和多器官衰竭相关的死亡率与细胞因子风暴综合征（CSS）有关，CSS是一种过度免疫反应，会严重损害健康的肺组织。此外，处于重病状态的患者经常出现心脏症状，包括暴发性心肌炎。双醋瑞因（DAR）是一种蒽醌衍生物药物，其活性代谢产物是大黄酸。不同研究表明，该化合物可抑制白细胞介素-1、白细胞介素-2、白细胞介素-6、白细胞介素-8、白细胞介素-12、白细胞介素-18、肿瘤坏死因子-α、核因子-κB和NLRP3炎性小体途径。大黄酸的抗病毒活性也有文献记载。这种代谢产物通过涉及调节氧化应激以及改变Toll样受体4、蛋白激酶B、丝裂原活化蛋白激酶和核因子-κB信号通路的机制，阻止乙型肝炎病毒（HBV）复制以及甲型流感病毒（IAV）吸附和复制。重要的是，大黄酸以剂量依赖的方式抑制SARS-CoV S蛋白与ACE2之间的相互作用，这表明大黄酸是治疗SARS-CoV感染的潜在治疗药物。基于这些发现，我们推测双醋瑞因是一种可用于治疗COVID-19的多靶点药物。这种蒽醌可能通过多方面抑制细胞因子和减少病毒感染来控制过度炎症状态。
