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Metformin Suppresses SARS-CoV-2 in Cell Culture

Parthasarathy et al., bioRxiv, doi:10.1101/2021.11.18.469078
Nov 2021  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
*, now known with p < 0.00000000001 from 87 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
In Vitro study showing metformin inhibits SARS-CoV-2 in Caco2 cells. Metformin reduced viral titers by nearly 99%, and by about 90% when cells were treated prior to infection.
7 preclinical studies support the efficacy of metformin for COVID-19:
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) Wang. Metformin inhibits SARS-CoV-2 in vitro Parthasarathy, Ventura-López, minimizes LPS-induced cytokine storm in a mouse model Taher, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS Miguel, may protect against SARS-CoV-2-induced neurological disorders Yang, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation Zhang, reduces UUO and FAN-induced kidney fibrosis Miguel, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells Miguel, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity Petakh.
Parthasarathy et al., 19 Nov 2021, preprint, 3 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMetforminAll
Metformin Suppresses SARS-CoV-2 in Cell Culture
Haripriya Parthasarathy, Dixit Tandel, Abdul Hamid Siddiqui, Krishnan H Harshan
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.
AMPK is activated. In this context, it is interesting to note that N protein was detected at modestly higher abundance during pharmacological activation of AMPK unlike the viral RNA and infectious titer, indicating that viral protein translation is not inhibited during the treatments. However, a significant drop in N levels during the postinfection treatment suggested an overall inhibition of viral life-stages concurrent with an overall drop of cellular activities indicated by MTT results. Inhibition of metabolic activities particularly in the infected cells upon post-infection metformin treatment indicated that metformin treatment specifically targeted the infected cells for destruction. This could be viewed as beneficial to the system fighting to clear the virus from it. Although multiple reports show AMPK as the major effector of metformin action, it is now well established that metformin exerts its affects through other pathways such as PKA and FBPase-1 mediated regulation as well (Pernicova & Korbonits, 2014) . Further study into the mechanism SARS-CoV-2 inhibition by metformin could pave the way for it to be a possible therapeutic target for COVID-patients. From a clinical perspective, our study provides some answers to the favorable prognosis of metformin-treated diabetic patients who contracted COVID-19. Institutional biosafety Institutional biosafety clearance was obtained for the experiments pertaining to SARS-CoV-2.
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