Inhibition of fatty acid synthesis blocks SARS-CoV-2 replication

aliml

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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.

 

Steed

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Very interesting, thank you for posting. I wonder if it has something to do with water structure and acidity.
 

Grapelander

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Mildronate blocks Carnitine which then creates FAS inhibition. Niacinamide also works. Idealabs: Lapodin.

Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review
A large number of FAS inhibitors have been reported, most of which can bind to the catalytic sites of the FAS enzyme. The tumour cells treated with FAS inhibitors are found to apoptosis both in vitro and in vivo.
Phenolics
The FAS inhibitory phenolic constituents, distributed widely in plants, particularly, with the conjugated system of phenyl and carbonyl, have been reported.
Catechins
Tea is known for its antioxidant properties, and is considered as a healthy drink by the World Health Organization (WHO). The tea polyphenols, such as catechins, flavones, theaflavins, are reported to inhibit the expression of FAS.
Extra-virgin olive oil (EVOO)-derived phenolics
EVOO-derived phenolics (lignans, secoiridoids, and flavonoids), by blockading the HER2 tyrosine kinase effects (Menendez et al. 2007), drastically suppress the expression of FAS protein.
Flavonoids
Flavonoids are widely distributed in plants. The extracts of parasitic loranthus, polygonum multiforum, galangal, night kodo, maple leaf, containing flavonoids, are reported to inhibit FAS (Tian et al. 2011). In addition, the extracts of Citrus reticulate Blanco (Rutaceae) and Canarium album Raeuseh (Burseraceae) leaves, containing the flavonoids, have better inhibitory effect on FAS compared to C75 (Chen et al. 2009).
Luteolin, from many edible plants, has a similar structure as PI3K inhibitors and inhibits FAS with an IC50 value of 2.5 μg/mL. PI3K is the upstream of FAS that reduces the amount and the enzymatic activity of FAS.
Quercetin is widely distributed in plants, such as apples, lovage and tea, and shows strong and reversible inhibition on FAS, targeting mainly on MAT domain.
Ginkgolic acid derivatives, isolated from Ginkgo biloba L. (Ginkgoaceae), inhibit the expression of FAS.
Terpenoids
Ursolic acid and oleanolic acid, two triterpenoids, are widely distributed in fruits. Ursolic acid strongly inhibits FAS with an IC50 value of 6 μg/mL.
 

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