Eco-pharma research aimed at developing COVID-19 therapeutic agent

Abstract

A new pandemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged and its severe and prognostic symptoms have become a social problem. SARS-CoV-2 infection is mainly initiated by binding of its surface Spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane followed by internalization via endocytosis-mediated pathway. We eventually found that ACE2 expression levels were upregulated by the exposure to epidemiologically reported risk factors for COVID-19 severity; cigarette side-stream smoke, anti-cancer drug, diabetes and obesity, through formation of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2 on the rodent myocardial plasma membrane. We thus used 20 already approved drugs that has previously reported to have potency to attenuate the formation of TRPC3-Nox2 protein complex and evaluated the inhibitory effect on Spike protein-induced ACE2-GFP internalization in HEK293 cells. We found that several TRPC3-Nox2 complex inhibitors also have potency to inhibit the Spike protein-induced ACE2 internalization, and finally identified one drug that has the most potency to prevent SARS-CoV-2-induced infection and proliferation in TMPRRS2-expressing VeroE6 cells, and fluorescence-labeled S protein-induced pseudo infection in human iPS cardiomyocytes. These results provide a new concept that the inhibition of TRPC3-Nox2 complex formation will be a novel strategy to improve COVID-19 aggravation and sequelae by suppressing ACE2-mediated infection pathway.