Epigenetic Inhibition of ACE2: A Novel Therapeutic Strategy in Severe CoVID19 Disease

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has resulted in a devastating disease pandemic responsible for in excess of 6 million deaths worldwide in just over 2 years. The clinical severity of SARS-CoV-2 infection is increased in individuals with certain comorbidities and correlates with increased pulmonary expression of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2. Despite the existence of effective vaccines, a critical need exists to identify effective therapies for the management of severe SARS-CoV-2-mediated disease. Recent studies suggest that expression levels of ACE2 may be regulated by a class of drugs referred to as epigenetic regulators (ER). ER are currently in clinically use for a range of medical conditions and could be rapidly repurposed for the effective management of severe SARS-CoV-2-mediated disease. Our studies, conducted in collaboration with Prof Sharon Lewin, Director of The Doherty Institute for Infection and Immunity, Melbourne, will screen and evaluate the potential of 2 classes of ER, the histone deacetylase inhibitors (HDACi) and the demethylating agents (DMA) to regulate ACE2 expression in a pulmonary cell system and correlate these findings with effects on SARS-CoV-2 viral burden. Identification of agents with ACE2 suppressive activity and concurrent attenuation of SARS-CoV-2 viral burden will be flagged for rapid clinical development.