Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

中文翻译：

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阿扎那韦单独或与利托那韦合用可抑制SARS-CoV-2复制和促炎细胞因子的产生。

与2002年和2012年以前的致病性冠状病毒（CoVs）相比，严重的急性呼吸系统综合症冠状病毒2（SARS-CoV-2）造成的死亡人数要多得多。确定了可用于2019年CoV疾病的临床批准药物（COVID-19） ）可以快速实施可能挽救生命的程序。根据先前与HIV蛋白酶抑制剂洛匹那韦（LPV）相关的CoV的结果，SARS-CoV-2的主要蛋白酶（Mpro）被认为是有前途的目标。但是，对于其他临床认可的抗逆转录病毒蛋白酶抑制剂，证据有限。阿扎那韦（ATV）作为抗逆转录病毒的广泛使用和以前的证据表明其在呼吸道内的生物利用度促使我们研究了针对SARS-CoV-2的分子。我们的结果表明，ATV停靠在SARS-CoV-2 Mpro的活动站点中，强度大于LPV，从而阻止了Mpro的活动。我们证实，ATV可以单独或与利托那韦（RTV）在Vero细胞和人肺上皮细胞系中抑制SARS-CoV-2复制。ATV / RTV还损害了病毒诱导的白介素6（IL-6）和肿瘤坏死因子α（TNF-α）水平的增强。总之，我们的数据强烈表明，在对抗COVID-19的临床试验中，应将ATV和ATV / RTV考虑为候选的改用药物。ATV / RTV还损害了病毒诱导的白介素6（IL-6）和肿瘤坏死因子α（TNF-α）水平的增强。总之，我们的数据强烈表明，在对抗COVID-19的临床试验中，应将ATV和ATV / RTV考虑为候选的改用药物。ATV / RTV还损害了病毒诱导的白介素6（IL-6）和肿瘤坏死因子α（TNF-α）水平的增强。总之，我们的数据强烈表明，在对抗COVID-19的临床试验中，应将ATV和ATV / RTV考虑为候选的改用药物。