Natural Agents Modulating ACE-2: A Review of Compounds with Potential against SARS-CoV-2 Infections

One of the biggest challenges of public health worldwide is reducing the number of events and deaths related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The angiotensinconverting enzyme 2 (ACE-2), a carboxypeptidase that degrades angiotensin II into angiotensin 1-7, has been identified as a potent receptor for SARS-CoV-2. In the last decades, ACE inhibition has assumed a central role in reducing cardiovascular and renal events. However, with the advent of COVID-19, attention has been turned to ACE-2 as a possible target to reduce virus binding to different human cells. This review aims to discuss recent developments related to the medicinal properties of natural compounds as ACE/ACE-2 inhibitors, which should be highlighted in the future development of studies looking for modulators in SARS-CoV-2 infection. Data show that bioactive compounds isolated from several natural products act by inhibiting ACE/ACE-2, which changes the entire axis of this system. Of the compounds addressed in this review, 7 phenolic compounds, including quercetin, curcumin, naringenin, luteolin, hesperidin, mangiferin, and gallic acid showed binding affinity with molecular ACE-2 target in silico, and 1, esculetin, decreased ACE-2 expression in vivo. Regarding terpenoids and alkaloids, nimbin, withaferin A, andrographolide, zingiberene and, berberine, piperine and thebaine, respectively, showed a binding affinity with molecular ACE-2 target in silico. These findings reinforce the need for future preclinical and clinical studies on these compounds and specific inhibitory effects on ACE-2 of all the other compounds described herein only as nonspecific ACE inhibitors. It is important to mention that some natural compounds such as magnolol, resveratrol, rosmarinic acid, tanshinone IIA, and nicotine have also demonstrated the potential to increase the activity or expression of ACE-2, and could therefore aggravate SARS-CoV-2 infection.