Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

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.

Integration of omics data to generate and analyse COVID-19 specific genome-scale metabolic models

“…FASN (Fatty Acid Synthase) is one of the rate-limiting enzymes in fatty acid synthesis and the key enzyme in the synthesis of palmitate. Knockdown of FASN in cell lines resulted in lower SARS-CoV-2 infection and lower quantity of viral RNA [ 80 ]. The same study also showed that inhibiting fatty acid synthesis by drugs, such as orlistat, lowered viral levels in the lung and increased survival in a mouse model.…”

Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection

“…1D ). Since pharmacological inhibition of fatty acid synthesis in SARS-CoV-2 infected hPSC-AO, HEK293T-hACE2 cells and K18-hACE2 mice inhibits viral replication ( 14, 40 ), induction of fatty acid biosynthesis must be required for viral replication, perhaps for the formation of the viral double membrane assembly structures ( 41 ).…”

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

“…It is possible that high level of ACSL1 expression induced by coronavirus infection can directly enhance inflammatory phenotypes of infected macrophages via a remodeling of lipid metabolism. Although inhibiting fatty acid synthesis was reported to block SARS-CoV-2 replication [69], it is still unclear how coronavirus infection alters the cellular lipid metabolism, especially the involvement of acyl-CoA synthetase long-chain family members. As an acyl-CoA synthetase long-chain family member, ACSL1 was recently identified to promote α-eleostearic acid triggered ferroptosis.…”