2. Academic Validation
  3. Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

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

  • Nat Metab. 2021 Nov;3(11):1466-1475. doi: 10.1038/s42255-021-00479-4.
Junjun Chu  # 1,  Changsheng Xing  # 1,  Yang Du  # 1,  Tianhao Duan 1,  Siyao Liu 2,  Pengfei Zhang 2,  Chumeng Cheng 3,  Jill Henley 4,  Xin Liu 1,  Chen Qian 1,  Bingnan Yin 1,  Helen Yicheng Wang 1 5,  Rong-Fu Wang 6 7 8
Affiliations

Affiliations

  • 1 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 2 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 3 Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
  • 4 The Hastings and Wright Laboratories, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 5 Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 6 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 7 Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 8 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [email protected].
  • # Contributed equally.
PMID: 34580494 DOI: 10.1038/s42255-021-00479-4
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.

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