Metformin and Covid-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit

Ibrahim, Sherehan M.; Lowe, Jamie; Bramante, Carolyn T.; Shah, Surbhi; Klatt, Nichole R.; Sherwood, Nancy E.; Aronne, Louis J.; Puskarich, Michael A.; Tamariz, Leonardo; Palacio, Ana; Bomberg, Eric M.; Usher, Michael; King, Samantha; Benson, Brad; Vojta, Deneen; Tignanelli, Christopher J.; Ingraham, Nicholas E.

doi:10.3389/fendo.2021.587801

Cited by 45 publications

(38 citation statements)

References 107 publications

(142 reference statements)

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“…Metformin is another drug with lipid-lowering effects that have gained interest in recent decades due to its pleiotropic effects and antiviral properties (199). Metformin inhibits cholesterol and fatty acid synthesis by activating the AMPactivated protein kinase (AMPK), involved in multiple energetic pathways in the cell (200).…”

Section: Targeting Cholesterol-rich Lipid Rafts As Potential Therapeutics In Sars-cov-2 Infectionmentioning

confidence: 99%

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

et al. 2021

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Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.

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Section: Targeting Cholesterol-rich Lipid Rafts As Potential Therapeutics In Sars-cov-2 Infectionmentioning

confidence: 99%

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

et al. 2021

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“…Finally, metformin, which in 1940 was used to treat influenza (Bailey, 2017), is another drug with lipid-lowering effects that has gained interest in recent decades due to its pleiotropic effects and its antiviral properties (Ibrahim et al, 2021). As described above, some viruses can modulate AMPK protein activity during infection to their advantage (Bhutta et al, 2021).…”

Section: Lipid-lowering Drugs For Other Viral Infectionsmentioning

confidence: 99%

Anti-flavivirus Properties of Lipid-Lowering Drugs

et al. 2021

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Although Flaviviruses such as dengue (DENV) and zika (ZIKV) virus are important human pathogens, an effective vaccine or antiviral treatment against them is not available. Hence, the search for new strategies to control flavivirus infections is essential. Several studies have shown that the host lipid metabolism could be an antiviral target because cholesterol and other lipids are required during the replicative cycle of different Flaviviridae family members. FDA-approved drugs with hypolipidemic effects could be an alternative for treating flavivirus infections. However, a better understanding of the regulation between host lipid metabolism and signaling pathways triggered during these infections is required. The metabolic pathways related to lipid metabolism modified during DENV and ZIKV infection are analyzed in this review. Additionally, the role of lipid-lowering drugs as safe host-targeted antivirals is discussed.

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“…In the past year, a number of reports have debated the clinical use of metformin in COVID-19 (Bramante et al, 2021;Dardano & del Prato, 2021;Ibrahim et al, 2021;Zangiabadian et al, 2021). Many case studies on metformin treatment report a decrease in hospital mortality rates for patients that were on metformin prior to admission (Dardano & del Prato, 2021;L et al, 2020;Marmor et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Metformin Suppresses SARS-CoV-2 in Cell Culture

Parthasarathy

Tandel

Harshan

2021

Preprint

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People with diabetes are reported to have a higher risk of experiencing severe COVID-19 complications. Metformin, a first-line medication for type 2 diabetes, has antiviral properties. Some studies have indicated its prognostic potential in COVID-19. Here, we report that metformin significantly inhibits SARS-CoV-2 growth in cell culture models. SARS-CoV-2 infection of gut epithelial cell line, Caco2, resulted in higher phosphorylation of AMPK. Metformin reduced viral titers in the infected cells by nearly 99%, and by about 90% when cells were treated prior to infection. Metformin pre-treatment resulted in further phosphorylation of AMPK and caused a ten-fold reduction of viral titers indicating its potential in preventing naïve infections. Confirming the positive impact of AMPK activation, another AMPK activator AICAR substantially inhibited of viral titers and, AMPK inhibitor Compound C, augmented it considerably. Metformin treatment post-SARS-CoV-2 infection resulted in nearly hundred-fold reduction of viral titers, indicating that the antiviral potency of the drug is far higher in infected cells, while still being able to reduce fresh infection. Metformin displayed SARS-CoV-2 TCID50 and TCID90 at 3.5 and 8.9 mM, respectively. In conclusion, our study demonstrates that metformin is very effective in limiting the replication of SARS-CoV-2 in cell culture and thus possibly could offer double benefits to diabetic COVID-19 patients by lowering both blood glucose levels and viral load.

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Metformin and Covid-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit

Cited by 45 publications

References 107 publications

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Anti-flavivirus Properties of Lipid-Lowering Drugs

Metformin Suppresses SARS-CoV-2 in Cell Culture

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