Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern
Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern
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DOI：
10.1021/acsinfecdis.1c00278
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发表时间：
2021-10-18
影响因子：
5.3
通讯作者：
Olagnier, David
中科院分区：
文献类型：
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作者：
Carter-Timofte, Madalina Elena;Arulanandam, Rozanne;Olagnier, David
抗微生物药物马拉龙（阿托伐醌/氯胍）作为固定剂量的复方制剂用于治疗患有单纯性疟疾的儿童和成人，或作为预防旅行者疟疾的化学预防剂。它是一种便宜，有效，安全的药物，在世界各地经常被处方。根据来自加拿大魁北克省和安大略省17名患者的轶事证据，表明马拉隆/阿托伐醌可能在预防COVID-19方面具有一些益处，我们试图检查其在细胞感染模型中限制SARSCoV-2复制的抗病毒潜力。在表达人TMPRSS 2和人肺Calu-3上皮细胞的VeroE 6中，我们发现微摩尔浓度的活性化合物阿托伐醌有效抑制SARS-CoV-2和其他相关变体（包括α、β和δ变体）的复制。重要的是，阿托伐醌在原代人气道上皮细胞培养模型中保留了其全部抗病毒活性。从机制上讲，我们证明了阿托伐醌对SARS-CoV-2的抗病毒活性部分依赖于TMPRSS 2的表达，并且该药物可以破坏刺突蛋白与病毒受体ACE 2的相互作用。此外，在阿托伐醌的存在下，尖峰介导的膜融合也减少。在美国，2020年启动了两项阿托伐醌单独给药或与阿奇霉素联合给药的临床试验。在我们等待这些试验结果的同时，我们在细胞感染模型中的发现表明，阿托伐醌是一种有效的抗病毒药物，经FDA批准，可在体外对抗SARS-CoV-2和其他相关变体。
The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/ atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARSCoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.