Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 is a virus-induced inflammatory disease of the airways and lungs that leads to severe multi-organ damage and death. Here we show that cellular lipid synthesis is required for SARS-CoV-2 replication and offers an opportunity for pharmacological intervention. Screening a short-hairpin RNA sublibrary that targets metabolic genes, we identified genes that either inhibit or promote SARS-CoV-2 viral infection, including two key candidate genes, ACACA and FASN, which operate in the same lipid synthesis pathway. We further screened and identified several potent inhibitors of fatty acid synthase (encoded by FASN), including the US Food and Drug Administration-approved anti-obesity drug orlistat, and found that it inhibits in vitro replication of SARS-CoV-2 variants, including more contagious new variants, such as Delta. In a mouse model of SARS-CoV-2 infection (K18-hACE2 transgenic mice), injections of orlistat resulted in lower SARS-CoV-2 viral levels in the lung, reduced lung pathology and increased mouse survival. Our findings identify fatty acid synthase inhibitors as drug candidates for the prevention and treatment of COVID-19 by inhibiting SARS-CoV-2 replication. Clinical trials are needed to evaluate the efficacy of repurposing fatty acid synthase inhibitors for severe COVID-19 in humans.

COVID-19 由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起，是一种病毒引起的气道和肺部炎症性疾病，可导致严重的多器官损伤和死亡。在这里，我们表明细胞脂质合成是 SARS-CoV-2 复制所必需的，并为药物干预提供了机会。通过筛选一个针对代谢基因的短发夹 RNA 子文库，我们确定了抑制或促进 SARS-CoV-2 病毒感染的基因，包括两个关键候选基因ACACA和FASN，它们在相同的脂质合成途径中起作用。我们进一步筛选并鉴定了几种有效的脂肪酸合酶抑制剂（由FASN编码）)，包括美国食品和药物管理局批准的抗肥胖药物奥利司他，并发现它可以抑制 SARS-CoV-2 变体的体外复制，包括更具传染性的新变体，例如 Delta。在 SARS-CoV-2 感染的小鼠模型（K18-hACE2 转基因小鼠）中，注射奥利司他可降低肺部的 SARS-CoV-2 病毒水平，减少肺部病理学并提高小鼠存活率。我们的研究结果将脂肪酸合酶抑制剂确定为通过抑制 SARS-CoV-2 复制来预防和治疗 COVID-19 的候选药物。需要进行临床试验来评估重新利用脂肪酸合酶抑制剂对人类严重 COVID-19 的疗效。