Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2

Abstract

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.

Keywords: ACE2; COVID-19; coronavirus; flavonoid.

Figure 1

The rise in active cases of coronavirus [2].

Figure 2

(A) The structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (https://www.economist.com/briefing/2020/03/12/understanding-sars-cov-2-and-the-drugs-that-might-lessen-its-power) and (B) its genome [51].

Figure 3

The life cycle of SARS-CoV. The spike (S) protein of SARS-CoV binds with the angiotensin-converting enzyme 2 (ACE2) receptor to enter host cells and release the RNA genome into the target cells. Structural and nonstructural proteins of CoV and the RNA genome assemble into virions, which are released from target cells.

Figure 4

(a) Structure of the receptor-binding domain (RBD) of the S protein in SARS-CoV-2 (blue and green ribbons) complexed with human ACE2. The green ribbon denotes the receptor-binding motif (RBM) within amino-acid residues 424–494 or 438–504 [62,64]. (b) The active site of ACE2 (yellow color) that directly interacts with the RBD of the S protein of SARS-CoV-2. The interaction between the S protein of SARS-CoV-2 and hACE2 is stabilized by a hydrogen bond (green lines) between Arg439 (S protein SARS-CoV-2) and Glu329 (hACE2). The figure was created using Discovery Studio Biovia through visualization of the Protein Data Bank (PDB) structure 6VW1 [65].

Figure 5

Flavan core of flavonoids.

Figure 6

Overview of the most important functional groups of flavonoids that might be involved in ACE2 inhibition.