Systematic Cell Line-Based Identification of Drugs Modifying <i>ACE2</i> Expression

Abstract

The COVID-19 pandemic caused by SARS-COV-2 has infected over 500,000 people causing over 25,000 deaths in the last 10 weeks. A key host cellular protein required for the virus entry is angiotensin-converting enzyme 2 (ACE2). Recent studies have reported that patients with hypertension and diabetes treated with ACE inhibitors or angiotensin receptor blockers might be at a higher risk of COVID-19 infection as these drugs have been reported to increase ACE2 expression. This has raised the need to systematically investigate the effect of different drugs including antihypertensives on modulating ACE2 expression. Here, we analyzed a publicly available CMAP dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules. We show that only one subclass of antihypertensives drugs - ACE inhibitors, are significantly enriched for drugs up-regulating ACE2 expression. Studying the effects of the 672 clinically approved drugs in CMAP, we chart the drug categories that affect ACE2 expression. Specifically, we find that panobinostat (an HDAC inhibitor) confers the highest up-regulation of ACE2 expression while isotretinoin (a vitamin A derivative) is its strongest down-regulator. Our results provide initial candidates guiding further in vitro and in vivo studies aimed at assessing drug effects on ACE2 expression.

The Food Systems in the Era of the Coronavirus (COVID-19) Pandemic Crisis

“…This vitamin comprises a group of fat-soluble compounds (including retinol, retinoic acid, and β-carotene) that play an essential role in the immune function and are known to lower the susceptibility to infections [14]. For instance, isotretinoin (a derivative of vitamin A) mediates the down-regulation of angiotensin-converting enzyme 2 (ACE2), which is a crucial host cellular protein required for the entry of SARS-COV-2 in the body [15]. Besides, supplementation with Vitamins D and E may boost our resistance to COVID-19 [16], as the decrease in cattle's levels of Vitamins D and E could lead to infection by a bovine coronavirus [17].…”

Could patients taking isotretinoin therapy be immune against SARS‐CoV ‐2?

“…the skin, ACE2 immunoreactivity was detected in basal cell layer of epidermis and hair follicles, eccrine glands, blood vessels and capillaries, sebaceous glands, and its surrounding smooth muscle cells. 1 ACE2-expressing cells can act as home cells and are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and replication. 1 genes, 3 and is a deubiquitinating enzyme, which modulates the host cell ubiquitination machinery to the advantage of the virus, 4 so it is considered one of the important proteins that should be targeted in COVID-19 treatment.…”

“…1 ACE2-expressing cells can act as home cells and are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and replication. 1 genes, 3 and is a deubiquitinating enzyme, which modulates the host cell ubiquitination machinery to the advantage of the virus, 4 so it is considered one of the important proteins that should be targeted in COVID-19 treatment. 3 In addition, isotretinoin was reported to increase CD4 counts and markedly decrease viremia in HIV-positive patients suffering from acne vulgaris.…”

Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19

“…Currently, the association of panobinostat with ACE2 expression is also being investigated by two other research groups [22,23]. Those two groups adopted very similar approaches; they re-analyzed the same publically available data, comprising gene expression pro les for thousands of perturbagens at a variety of time points, doses, and cell lines [24] in order to identify drugs that could signi cantly modify ACE2 expression.…”