How cigarette smoke is inspiring covid-19 drug research

The findings have appeared in the journal Scientific Report. While smoking is associated with health risks and increased severity of covid-19, some reports have suggested fewer covid cases among smokers.

“We must stress the presence of strong evidence showing that smoking increases the severity of covid-19. But the mechanism we discovered here is worth further investigation as a potential tool to fight SARS-CoV-2 infections," said Keiji Tanimoto of Hiroshima University’s Research Institute for Radiation Biology and Medicine, one of the authors of the paper.

Cigarette smoke contains polycyclic aromatic hydrocarbons (PAHs) that can bind to and activate aryl hydrocarbon receptors (AHRs). A receptor is a structure on the surface of a cell or inside it that is shaped to receive and bind to a particular substance. AHRs are receptors inside mammalian cells that can induce a wide range of cellular activities through their ability to increase or decrease the expression of certain genes.

The researchers investigated the effect of chemicals that activate AHR on the genes that control the production of the ACE2, the receptor protein on the surface of some cells that the SARS-CoV-2 virus can hook onto. The virus that causes covid-19 binds with the ACE2 protein to enter and infect the human cell.

The scientists found that cells in the oral cavity, lungs and liver had the highest ACE2 expression. These cells were then subjected to various doses of cigarette smoke extract for 24 hours.

The scientists found that the greater the dose of the cigarette-smoke extract on the cells, the more the impact on the CYP1A1 gene expression in liver and lung cells. The greater activity of the gene led to less production of the ACE2 proteins that the virus uses to enter cells. This effect was, however, not as pronounced in oral cavity cells.

To understand why this was happening, researchers used RNA sequencing analysis to investigate gene expression. They found that the smoke extracts increased the expressions of genes related to key processes within the cell that AHR regulates.

Researchers then studied the effects of two drugs that can activate AHR in the liver cells. The first drug is a derivative of the amino acid tryptophan, and the second one is omeprazole, a drug widely used to treat acid reflux and peptic ulcers.

The RNA sequencing data suggested that the CYP1A1 gene strongly induced the AHR activators in liver cells, and strongly inhibited the production of ACE2 protein.

The researchers concluded that the two drugs, which act as activators of AHR, can suppress the production of ACE2 in mammalian cells and, thereby, reduce the ability of the SARS-CoV-2 virus to infect the cell.

The scientists are now investigating the two drugs in pre-clinical and clinical trials for the treatment of covid-19.