Abstract
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.
【초록키워드】 COVID-19, Treatment, SARS-CoV-2, Efficacy, coronavirus, Trial, severe COVID-19, SARS-COV-2 infection, Delta, lung, clinical trials, Intervention, drug, in vitro, severe acute respiratory syndrome Coronavirus, variants, Screening, hACE2, airway, RNA, survival, Viral, SARS-CoV-2 variants, humans, clinical, Lungs, death, pathway, target, respiratory, inhibitor, mouse model, SARS-CoV-2 replication, Fatty acid, K18-hACE2, K18-hACE2 transgenic mice, Lung pathology, cellular, food, airways, Multi-organ damage, leads, orlistat, acute respiratory syndrome, treatment of COVID-19, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, drug candidates, transgenic mice, injection, Injections, Drug administration, drug candidate, contagious, inflammatory disease, metabolic genes, offer, FASN, SARS-CoV-2 viral infection, pharmacological, replication of SARS-CoV-2, Genes, ACACA, SARS-CoV-2 viral, identify, evaluate, inhibit, required, reduced, screened, promote, inhibiting, fatty, 【제목키워드】 block, fatty,