The outbreak of the COVID-19 pandemic in early 2020 poses dramatic problems to the health systems as no vaccine or truly effective drugs are yet available. The international scientific community is struggling to find new substances capable of contrasting the SARS-CoV-2 virus. A straightforward strategy to disclose compounds readily available to clinicians is drug repurposing, i.e. the use of drugs that were previously approved by the FDA for a different therapeutic indication. A few promising compounds against SARS-CoV-2 were identified through drug repurposing, e.g. remdesivir, chloroquine and hydroxychloroquine, tocilizumab, etc., but their therapeutic efficacy in COVID-19 patients is still debated. On the other hand, extensive screenings are conducted on thousands of novel molecules using combinatorial libraries or in silico docking experiments to discover new effective antiviral agents. Despite the intense research efforts, we were surprised to learn that no metal compound is currently being tested against the SARS-CoV-2 virus.(1) Metal based agents form a variegate and attractive class of drugs with a number of therapeutic applications: we strongly encourage the international scientific community to fill this gap quickly and explore the potential of metallodrugs against COVID-19 disease. A simple approach might be represented by the repurposing of clinically approved metal-based drugs. The ideal candidate should associate a good antiviral activity and a tolerable toxicity. To this end we recommend a rapid evaluation of auranofin (Ridaura) (Figure 1), AF hereafter. Figure 1. Chemical structure of auranofin. AF is a drug approved by the FDA in 1985 for the treatment of rheumatoid arthritis mainly acting through a modulation of the immune response. AF shows an acceptable toxicity profile and is safe for human use. The exact mechanism of action of AF, most likely a multitarget one, is still debated. Yet, there is a growing consent in considering thioredoxin reductase 1 as the primary target, leading to perturbation of the main oxidoreductase pathways, dysregulation of intracellular redox homeostasis and reactive oxygen species (ROS) induction; the proteasome is a secondary but still important target.(2−4) AF prompted a lot of interest during the last years for its versatility and for the chance to be repurposed for different therapeutic indications such as an antibacterial, anticancer, or antiparasitic agent.(2) Significant activity against HIV was reported as well; AF entered accordingly clinical trials as an antiretroviral agent. It is worth reminding that AF, in the case of HIV infection, was found to be more effective than hydroxychloroquine and chloroquine in interfering with several processes involved in viral production, latency, and viral reactivation as well as in the reduction of the viral reservoir.(5) Similarly to tocilizumab, AF was reported to interfere with the interleukin 6 signaling by inhibiting phosphorylation of JAK1 and STAT3, to inhibit few selected proteases and to bind preferentially to free cysteine residues in proteins, e.g. in cysteine proteases.(6)Based on these arguments, we support the off label quick evaluation of AF in COVID-19 patients. Remarkably, during the review process of this manuscript, an article concerning AF and COVID-19 appeared in the public domain.(7) In this paper the authors report that AF, at a low micromolar concentration, strongly inhibits SARS-COV-2 replication in human cells with a spectacular 95% reduction in the viral RNA. In addition, AF was found to dramatically reduce the expression of SARS-COV-2-induced cytokines in human cells, in line with the previous observations. These results offer an excellent support to our proposal and suggest that AF, owing to its favorable and multitarget mechanism, might be a useful drug to limit SARS-CoV-2 infection and treat the associated pneumonia. Beyond the specific suggestion of auranofin and related gold compounds, we believe that extensive in vitro testing of a larger panel of representative metal-based agents containing a variety of metal centers, e.g. ruthenium and bismuth, should be pursued. We may reasonably expect that such unusual and unique metal centers, in a few cases, will produce important and favorable effects on this new pathogen that are difficult to predict a priori. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. The authors thank the CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici), Italy. Beneficentia Stiftung (Vaduz, Liechtenstein) and Fondazione CR Firenze (Firenze, Italy) are also acknowledged. This article references 7 other publications.

中文翻译：

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金属基药物在对抗COVID-19感染中的作用？Auranofin案。

2020年初COVID-19大流行的爆发给卫生系统带来了严峻的问题，因为尚无疫苗或真正有效的药物可用。国际科学界正在努力寻找能够与SARS-CoV-2病毒形成对比的新物质。公开易于临床医生使用的化合物的一种直接策略是重新设定药物用途，即使用先前由FDA批准用于不同治疗适应症的药物。通过药物重用鉴定出了一些抗SARS-CoV-2的有前途的化合物，例如瑞德昔韦，氯喹和羟氯喹，托珠单抗等，但它们在COVID-19患者中的治疗效果尚有争议。另一方面，使用组合文库或在计算机对接实验中发现新的有效抗病毒剂。尽管进行了广泛的研究，但我们惊讶地发现没有金属化合物目前正针对SARS-CoV-2病毒进行测试。（1）金属基药物形成具有多种治疗用途的多样化且有吸引力的药物类别：我们强烈建议国际科学界尽快填补这一空白并探​​索其潜力抗COVID-19疾病的金属药物的研发。重新使用临床批准的金属基药物可能代表了一种简单的方法。理想的候选药物应具有良好的抗病毒活性和可耐受的毒性。为此，我们建议对此后快速评估金诺芬（Ridaura）（图1）和AF。图1.金诺芬的化学结构。AF是1985年由FDA批准的用于治疗类风湿性关节炎的药物，其主要通过调节免疫应答起作用。AF显示出可接受的毒性特征，对人类安全。AF的确切作用机制（很可能是多靶点的作用）仍在争论中。然而，越来越多的人同意将硫氧还蛋白还原酶1作为主要靶标，从而导致主要氧化还原酶途径的紊乱，细胞内氧化还原稳态的失调和活性氧（ROS）的诱导。蛋白酶体是次要的但仍是重要的靶标。（2-4）房颤在近几年引起了人们的极大兴趣，因为它具有多功能性，并有机会重新用于不同的治疗适应症，例如抗菌，抗癌或抗寄生虫药。 （2）也报告了抗艾滋病毒的重要活动；AF因此作为抗逆转录病毒药物进入了临床试验。值得提醒的是，在感染艾滋病毒的情况下，房颤基于这些论点，我们支持对COVID-19患者的AF进行标签外快速评估。值得注意的是，在审稿过程中，有关AF和COVID-19的文章出现在公共领域。（7）本文作者报告说，低微摩尔浓度的AF强烈抑制SARS-COV-2复制人体细胞中的病毒RNA显着降低了95％。此外，与以前的观察结果一致，发现AF可以显着降低人细胞中SARS-COV-2诱导的细胞因子的表达。这些结果为我们的建议提供了极好的支持，并提示AF，由于其有利的多靶点机制，可能是限制SARS-CoV-2感染和治疗相关性肺炎的有用药物。除了金诺芬和相关金化合物的具体建议外，我们认为体外广泛应该对包含各种金属中心（例如钌和铋）的较大的代表性金属基试剂进行更大的测试。我们可以合理地预期，在某些情况下，这种不寻常且独特的金属中心将对该新病原体产生重要而有利的影响，而这些作用很难先验地预测。本社论中表达的观点只是作者的观点，不一定是ACS的观点。作者感谢意大利的CIRCMSB（位于法国金属化学研究所的Ricesca的Consorzio Interuniversitario di Ricerca）。Beneficentia Stiftung（列支敦士登瓦杜兹）和Fondazione CR Firenze（意大利佛罗伦萨）也得到了认可。本文引用了其他7种出版物。