Metformin is a widely used and is a safe anti-diabetic drug. It has also been shown to have anti-inflammatory and anti-viral activities in humans and animal models. Specifically we explored its activity in SARS-CoV-2 initiated COVID19 disease. Here we show that metformin 1. blocks the binding of SARS-CoV-2 spike protein receptor binding domain RBD to human ACE2 receptor 2. We also show that it has anti-inflammatory effects and reduces cytokine secretion as well as blocks the recruitment of monocytes to endothelial cells 3. Finally we show its activity in a hamster in vivo model of SARS-CoV-2 infection as a nasal formulation. Based on the safety and the therapeutic properties relevant to COVID-19 it is feasible to propose a nasal spray of metformin that can be used in treatment of this disease. A nasal spray would deliver the drug to the target organ lung and spare other organs which get exposed upon oral dosing.
SummaryGut-liver axis is the interaction between the gut, its microbiome and the liver. The crosstalk and interaction between these organs plays an important role in their individual health and disease. Alcoholic liver disease (ALD) is a case in point where dysfunction of intestine actively promotes liver damage by alcohol. A flashpoint in ALD is the breach of intestinal integrity caused by gut bacteria Enterococcus faecalis (E.Faecalis). More specifically, Cytolysin, a toxin secreted by this bacteria may have a central role in the genesis of ALD. 3-D bioprinted human simulations of the gut-liver axis may help better understand the genesis of ALD.Here we developed a 3 dimensional bioprinted in vitro model composed of human origin intestinal and liver cells to explore the role of Cytolysin and ethanol in intestinal and liver damage. We find that neither Cytolysin or ethanol are sufficient for cell damage but a combination of the two act in concert to cause maximum breach in intestinal integrity. Secondly we find that enhanced transport of macromolecules thru the intestinal layer is not caused by overt cell toxicity but occurs through potentially paracellular/transcellular pathways. Our model will be used to test repurposed and new drugs/ biologics for treatment of ALD as well as other intestinal inflammatory diseases.
Omicron strain is the latest variant of concern of SarsCov2 virus. The mutations in this strain in the S protein Receptor Binding domain (RBD) enable it to be more transmissible as well as escape neutralizing activity by antibodies in response to vaccine. Thus, Omicron specific strategies are need to counter infection by this strain.We investigated a collection of approved drugs shown to antagonize the binding of native strain RBD to human ACE2, for their ability to antagonize binding to Omicron strain RBD.While most of the drugs the drugs that antagonize binding to native RBD are also active for Omicron RBD but some were inactive, namely drugs that contain iodine are completely inactive against Omicron RBD. Our data strongly indicate that presence of a single iodine molecule in the drug renders it inactive against Omicron strain. Thus, there is molecular specificity of drugs for antagonizing Omicron strain RBD versus native strain RBD of this virus. Such information will pave way for specific drugs for Omicron. A pragmatic message from our data is that the often-used iodine containing mouth wash and rises may be ineffective in antagonizing receptor binding of Omicron strain.
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