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

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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.
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molecules
Review
Natural Flavonoids as Potential
Angiotensin-Converting Enzyme 2 Inhibitors
for Anti-SARS-CoV-2
Muchtaridi Muchtaridi 1, * , M. Fauzi 1, Nur Kusaira Khairul Ikram 2,3 ,
Amirah Mohd Gazzali 4and Habibah A. Wahab 5,*
1Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy,
Universitas Padjadjaran, Jl Raya 21.5, Bandung-Sumedang 45363, Indonesia;
muhammad18254@mail.unpad.ac.id
2Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
nkusaira@um.edu.my
3Centre for Research in Biotechnology for Agriculture (CEBAR), Universiti Malaya,
Kuala Lumpur 50603, Malaysia
4Department of Pharmaceutical Technology, School of Pharmaceutical Sciences, Universiti Sains Malaysia,
Gelugor 11800, Penang, Malaysia; amirahmg@usm.my
5Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences,
Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
*Correspondence: muchtaridi@unpad.ac.id (M.M.); habibahw@usm.my (H.A.W.);
Tel.: +62-22-8784288888 (ext. 3210) (M.M.); +60-4-6532238 (H.A.W.)
Received: 3 August 2020; Accepted: 26 August 2020; Published: 1 September 2020


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 aected 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, eorts 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 eectively 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 ecacy against COVID-19 through ACE2 receptor inhibition.
Keywords: ACE2; COVID-19; flavonoid; coronavirus
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent
of Coronavirus Disease 2019 or COVID-19, triggered a pandemic aecting over 215 countries and
territories around the world [
1
,
2
]. As of August 2020, there are more than 23 million cases worldwide
with over 800,000 deaths, indicating that the virus is highly infectious with its pathogenicity being a
global health threat [
3
5
]. The number of positive cases and deaths due to COVID-19 continues to
Molecules 2020,25, 3980; doi:10.3390/molecules25173980 www.mdpi.com/journal/molecules
Molecules 2020,25, 3980 2 of 20
increase rapidly and, due to the unavailability of eective drugs, recovery is lagging (Figure 1) [
2
,
6
,
7
].
Thus, the search for new drugs to overcome this disease needs to be urgently intensified [2,8].
Molecules 2020, 25, x 2 of 21
increase rapidly and, due to the unavailability of effective drugs, recovery is lagging (Figure 1)[2,6,7].
Thus, the search for new drugs to overcome this disease needs to be urgently intensified [2,8].
Figure 1. The rise in active cases of coronavirus [2].
SARS-CoV-2, which causes severe respiratory syndrome in humans, is a positive-strand RNA
virus. The virus replication cycle begins with the entry of the virus into the human body by attaching
to the host cellular receptor angiotensin-converting enzyme 2 (ACE2), assisted by a protein spike (S),
followed by the release of the virus genome material into the host cell [9]. The viral genome contains
two overlapping polyproteins (polyprotein 1a and polyprotein 1ab), which are cleaved by Mpro (the
main protease) into 16 non-structural proteins, which are then translated into structural (STR
proteins) and non-structural proteins (non-STRs). This is followed by virus assembly, which releases
virions from the infected cells through exocytosis [10,11].
The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral
membrane protein of 805 amino acids containing one HEXXH-E zinc-binding consensus sequence
[12]. ACE2 is involved in regulating cardiac function and is also a functional receptor for the
coronavirus that causes acute respiratory syndrome (SARS). ACE2 receptors are the largest target of
SARS-CoV-2 because they play an important role in the transmission of viruses to alveolar cells [13].
Inhibition or regulation of ACE2 receptors may potentially be effective in the treatment of COVID-
19. COVID-19 is currently being treated with anti-infective drugs such as antimalarial drugs
(chloroquine, hydroxychloroquine [14-17], antiviral drugs (remdesivir [18], saquinavir [19],
favipiravir [20], lopinavir [21], ribavirin [22], and oseltamivir), and certain immunosuppressive drugs
such as tocilizumab [23]. Tocilizumab was approved by the Food and Drug Administration (FDA) to
manage cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor T-cell
therapy. This drug was shown to reduce toxicity and improve immune-related toxicity [24,25].
Tocilizumab can block the activity of proinflammatory interleukin-6 (IL-6), which is involved in the
pathogenesis of pneumonia that causes death in COVID-19 patients [26]. However, to date, we are
still waiting for the results of the ongoing phase 3 clinical trial that might support and prove the
effectiveness of these drugs in treating patients with SARS-CoV-2 infection. For example, Wang et al.
(2020) conducted a randomized study on the use of placebo-controlled and intravenous remdesivir
0
5,000,000
10,000,000
15,000,000
20,000,000
25,000,000
30,000,000
25-Mar-20 25-Apr-20 25-May-20 25-Jun-20 25-Jul-20 25-Aug-20
Total Corona Virus Cases
25-Mar-
20 30-Apr 15-May-
20
15-Jun-
20 15-Jul-20 17-Aug-
20
22-Aug-
20
28-Aug-
20
Confirmed 426998 3104693 4359294 7800518 13157587 21568480 22536278 24628901
recovered 108578 1054822 1777120 4231240 8057606 14784709 15521145 17094868
Deaths 21985 224447 298287 430424 570450 767028 789197 835689
COVID-19 OVERVIEW
Figure 1. The rise in active cases of coronavirus [2].
SARS-CoV-2, which causes severe respiratory syndrome in humans, is a positive-strand RNA
virus. The virus replication cycle begins with the entry of the virus into the human body by attaching
to the host cellular receptor angiotensin-converting enzyme 2 (ACE2), assisted by a protein spike
(S), followed by the release of the virus genome material into the host cell [
9
]. The viral genome
contains two overlapping polyproteins (polyprotein 1a and polyprotein 1ab), which are cleaved by
Mpro (the main protease) into 16 non-structural proteins, which are then translated into structural
(STR proteins) and non-structural proteins (non-STRs). This is followed by virus assembly, which
releases virions from the infected cells through exocytosis [10,11].
The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral
membrane protein of 805 amino acids containing one HEXXH-E zinc-binding consensus sequence [
12
].
ACE2 is involved in regulating cardiac function and is also a functional receptor for the coronavirus that
causes acute respiratory syndrome (SARS). ACE2 receptors are the largest target of SARS-CoV-2 because
they play an important role in the transmission of viruses to alveolar cells [
13
]. Inhibition or regulation of
ACE2 receptors may potentially be effective in the treatment of COVID-19. COVID-19 is currently being
treated with anti-infective drugs such as antimalarial drugs (chloroquine, hydroxychloroquine
[1417]
,
antiviral drugs (remdesivir [
18
], saquinavir [
19
], favipiravir [
20
], lopinavir [
21
], ribavirin [
22
],
and oseltamivir), and certain immunosuppressive drugs such as tocilizumab [
23
]. Tocilizumab was
approved by the Food and Drug Administration (FDA) to manage cytokine release syndrome (CRS) in
patients receiving chimeric antigen receptor T-cell therapy. This drug was shown to reduce toxicity
and improve immune-related toxicity [
24
,
25
]. Tocilizumab can block the activity of proinflammatory
interleukin-6 (IL-6), which is involved in the pathogenesis of pneumonia that causes death in
COVID-19 patients [
26
]. However, to date, we are still waiting for the results of the ongoing phase 3
clinical trial that might support and prove the eectiveness of these drugs in treating patients with
SARS-CoV-2 infection. For example, Wang et al. (2020) conducted a randomized study on the use
of placebo-controlled and intravenous remdesivir in 10 hospitals in Hubei, China [
27
]. The study
found that intravenous remdesivir did not significantly increase the time for clinical improvement,
Molecules 2020,25, 3980 3 of 20
the mortality, or the time for virus clearance in patients with serious SARS-CoV-2 compared to placebo.
However, hydroxychloroquine or chloroquine with or without azithromycin did not enhance clinical
status at 15 days [
28
]. In an eort to find new therapies for COVID-19, natural product sources are also
being explored and re-evaluated for their activity against this deadly virus [24].
Natural compounds with high bioavailability and low cytotoxicity are the most ecient
candidates [
29
]. Flavonoids are structurally heterogeneous, polyphenolic compounds present in
high concentrations. Flavonoids are natural products found in many plants, and they play an important
role in plant physiology; they were intensively investigated for having bioactivity beneficial to health,
such as anti-inflammatory [
30
], anticancer [
31
], antioxidant [
32
], anti-lipogenic [
33
], metal-chelating [
34
],
antimicrobial [
35
], and antiviral [
36
] properties. More than 2000 plant-derived flavonoids have been
identified. Bioactive compounds from flavonoid derivatives are valuable for the development of drugs
and as additional therapies for these infections. Other flavonoids including flavones and flavonoids were
investigated for having antiviral potential, and many of them showed significant antiviral responses
in both
in vitro
and
in vivo
studies. Naringenin and hesperetin (flavanon), hesperidin (flavanonone
glycoside), baicalin and neohesperidin (flavone glycoside), nobiletin (O-methylation), scutellarin
(flavone), nicotinamin (nonproteinogenic amino acids), and glycyrinodin (methylated-eminin-1,3,8-
trihydroxyanthraquinone)are amongst natural ACE2 inhibitors [
37
39
]. This review focuses on the
prospect of utilizing flavonoids as potential treatment for SARS-CoV-2 infection.
2. Methods
This review was based on the literature obtained from PubMed and Google Scholar using
15 keywords. The results of the initial search strategy were firstly filtered by title and abstract. The full
text of the relevant articles was examined for inclusion and exclusion criteria. When an article reported
duplicate information from the same source, the information of the two reports was combined to
obtain the complete data but was only counted as one case. A list of selected references from papers
taken was used to further identify relevant citations. For the purpose of this review, the research
focused on seven key words, namely, “coronavirus”, “angiotensin-converting enzyme”, “angiotensin
converting enzyme II of coronavirus”, “angiotensin-converting enzyme II inhibitor CoV”, “natural
compounds ACE and ACEII inhibitors enzyme II of coronavirus”, “flavonoid as antiviral, antioxidant,
antiinflammation”, and “flavonoid as ACE2 inhibitor
3. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
SARS-CoV-2 initially appeared as part of a major outbreak of respiratory disease centered in
Hubei Province, China. It was identified as a novel type of coronavirus. Coronaviruses belong to the
large and enveloped Coronaviridae family under the Nidovirales order of viruses with positive-stranded
crown-like RNA [
40
,
41
]. The viral genome is 27 to 32 kb in size and is the largest virus among all RNA
viruses [
6
,
42
]. There are six types of coronaviruses, namely, alphacoronavirus 229E, alphacoronavirus
NL63, betacoronavirus OC43, HKU1 betacoronavirus, severe acute respiratory illness coronavirus
(SARS-CoV-1), and Middle East respiratory syndrome coronavirus (MERS-CoV). CoV belongs to
the betacoronavirus class [
37
,
43
]. Phylogenetic analysis shows that SARS-CoV-2 belongs to the
same subgenus as CoVs that caused the outbreak of severe acute respiratory syndrome (SARS)
in 2002–2004 [
44
] addition, the SARS-CoV-2 sequence is similar to CoVs isolated from bats [
45
].
The SARS-CoV-2 genome has an 89% similarity in homology compared to the ZXC21 bat coronavirus
and an 82% similarity to SARS-CoV-1 [
6
,
46
]. Thus, a hypothesis was deduced that SARS-CoV-2
originated from bats, which mutated and became infectious to humans [39,47].
The genome of SARS-CoV-2 contains 14 open reading frames (ORFs) encoding 27 proteins (Figure 2).
The 5
0
terminus encodes for 15 nonstructural proteins collectively involved in virus replication and
possibly in immune evasion, while the 3
0
terminus encodes for structural and accessory proteins [
42
,
48
].
The presence of a spike protein (S protein), which resembles a nail or an arrow on the surface of this virus,
Molecules 2020,25, 3980 4 of 20
makes the structure even more unique than others. This S protein attaches to the angiotensin-converting
enzyme (ACE) 2 receptors on the surface of host respiratory cells [49,50].
Molecules 2020, 25, x 4 of 21
arrow on the surface of this virus, makes the structure even more unique than others. This S protein
attaches to the angiotensin-converting enzyme (ACE) 2 receptors on the surface of host respiratory
cells [49,50].
A.
B.
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].
4. Angiotensin-Converting Enzyme 2 (ACE2)
SARS-CoV-2 uses the angiotensin-converting enzyme (ACE) 2 receptor for entry into target cells.
ACE2 is largely expressed by epithelial cells of the lung, kidney, heart, blood vessels, and intestine.
ACE and ACE2 belong to the ACE family of dipeptidyl carboxydipeptidases, and they have distinct
functions. ACE converts angiotensin I into angiotensin II, which in turn binds and activates
angiotensin II receptor type 1 (AT1R). This activation leads to vasoconstrictive, pro-inflammatory,
and pro-oxidative effects [52]. ACE2 exists in two forms: a soluble form that represents the circulating
ACE2, and a structural transmembrane protein with extracellular domain that serves as a receptor
for the spike protein of SARS-CoV-2. The latter is a polypeptide composed of 805 amino acids [53].
This molecule is an inseparable part of a type 1 membrane protein that breaks down the main residue
(a single hydrophobic molecule) on the carboxy C-terminal of any bound substrate [54]. ACE2
hydrolyzes the C-terminal domain of leucine from Ang I to produce non-peptides angiotensins 1–9
that can be converted into heptapeptides by ACE and other peptidases. Furthermore, ACE2 can
directly reduce angiotensin II to angiotensins 1–7 [55]. Angiotensins 1–7 work on the Mas receptors
to relax blood vessels and exhibit anti-proliferation and anti-oxidative activities. ACE2/angiotensins
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].
4. Angiotensin-Converting Enzyme 2 (ACE2)
SARS-CoV-2 uses the angiotensin-converting enzyme (ACE) 2 receptor for entry into target cells.
ACE2 is largely expressed by epithelial cells of the lung, kidney, heart, blood vessels, and intestine.
ACE and ACE2 belong to the ACE family of dipeptidyl carboxydipeptidases, and they have distinct
functions. ACE converts angiotensin I into angiotensin II, which in turn binds and activates angiotensin
II receptor type 1 (AT1R). This activation leads to vasoconstrictive, pro-inflammatory, and pro-oxidative
eects [
52
]. ACE2 exists in two forms: a soluble form that represents the circulating ACE2, and a
structural transmembrane protein with extracellular domain that serves as a receptor for the spike
protein of SARS-CoV-2. The latter is a polypeptide composed of 805 amino acids [
53
]. This molecule
is an inseparable part of a type 1 membrane protein that breaks down the main residue (a single
hydrophobic molecule) on the carboxy C-terminal of any bound substrate [
54
]. ACE2 hydrolyzes
the C-terminal domain of leucine from Ang I to produce non-peptides angiotensins 1–9 that can
be converted into heptapeptides by ACE and other peptidases. Furthermore, ACE2 can directly
reduce angiotensin II to angiotensins 1–7 [
55
]. Angiotensins 1–7 work on the Mas receptors to relax
Molecules 2020,25, 3980 5 of 20
blood vessels and exhibit anti-proliferation and anti-oxidative activities. ACE2/angiotensins 1–7/Mas
formed by the participation of angiotensins 1–7 can attack certain parts of ACE–angiotensin II–AT1R,
with functions in maintaining the balance of the body [55,56].
The binding of SARS-CoV to the ACE2 receptor regulates the cellular expression of the receptor,
and the binding process induces internalization, which depends on clathrin [
57
]. ACE2 not only
facilitates the invasion and rapid replication of SARS-CoV, but it is also used by the cell membrane,
thus damaging angiontensin II, which results in acute damage of lung tissues [
58
]. Because the lungs
are the main target organs for COVID-19 infection, early onset of respiratory symptoms is common
among patients [
59
]. The results of the study conducted by Imai et al. [
60
] showed that blocking the
renin–angiotensin signaling pathway could relieve severe acute lung injury caused by SARS-CoV-2.
SARS-CoV-2 attaches to human ACE2 through the binding of spike (S) proteins, as shown in
Figure 3[
61
]. The S protein of SARS-CoV-2 contains S1 and S2 subunits. The S1 subunit (Figure 4)
consists of a receptor-binding domain (RBD) that is responsible for binding with the host ACE2, and the
S2 subunit facilitates membrane fusion in the host cells [
62
,
63
]. The RBD contains a loop-binding pocket
(residue 424–494 or 438–506), which is called the receptor-binding motif (RBM) [
62
,
64
]. The RBM
cleaves the ACE2 receptor so that SARS-CoV can enter the host cells. After SARS-CoV binds to
ACE2, the S2 subunit facilitates membrane fusion in the endosomal plasma through conformational
change, thereby releasing the RNA genome into the target cells. After transcription and translation,
the structural and nonstructural proteins of CoV and the RNA genome are further assembled into
virions, which are transported through vesicles and released from target cells.
Molecules 2020, 25, x 5 of 21
1–7/Mas formed by the participation of angiotensins 1–7 can attack certain parts of ACE–angiotensin
II–AT1R, with functions in maintaining the balance of the body [55,56].
The binding of SARS-CoV to the ACE2 receptor regulates the cellular expression of the receptor,
and the binding process induces internalization, which depends on clathrin [57]. ACE2 not only
facilitates the invasion and rapid replication of SARS-CoV, but it is also used by the cell membrane,
thus damaging angiontensin II, which results in acute damage of lung tissues [58]. Because the lungs
are the main target organs for COVID-19 infection, early onset of respiratory symptoms is common
among patients [59]. The results of the study conducted by Imai et al. [60] showed that blocking the
renin–angiotensin signaling pathway could relieve severe acute lung injury caused by SARS-CoV-2.
SARS-CoV-2 attaches to human ACE2 through the binding of spike (S) proteins, as shown in
Figure 3 [61]. The S protein of SARS-CoV-2 contains S1 and S2 subunits. The S1 subunit (Figure 4)
consists of a receptor-binding domain (RBD) that is responsible for binding with the host ACE2, and
the S2 subunit facilitates membrane fusion in the host cells [62,63]. The RBD contains a loop-binding
pocket (residue 424–494 or 438–506), which is called the receptor-binding motif (RBM) [62,64]. The
RBM cleaves the ACE2 receptor so that SARS-CoV can enter the host cells. After SARS-CoV binds to
ACE2, the S2 subunit facilitates membrane fusion in the endosomal plasma through conformational
change, thereby releasing the RNA genome into the target cells. After transcription and translation,
the structural and nonstructural proteins of CoV and the RNA genome are further assembled into
virions, which are transported through vesicles and released from target cells.
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 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.
Molecules 2020,25, 3980 6 of 20
Molecules 2020, 25, x 6 of 21
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].
The Active Site of hACE2 as the Therapeutic Target of COVID-19
The amino-acid sequence of SARS-CoV-2 has a 76.5% similarity to that of SARS-CoV, and their
S proteins are quite homologous [66,67]. As shown in Figure 4, the RBD of the S protein of SARS-
CoV-2 is located within amino-acid residues 318–510 (left side), containing the RBM (green ribbon),
which is on the surface, right in front of ACE2. Arg439 of the RBM in SARS-CoV-2 and Glu329 of
ACE2 interact and form a bridge to stabilize the complex. Based on the interaction of ACE2 with the
S protein in SARS-CoV-2, antibodies or small molecules can be used to target and inhibit SARS-CoV-
2 replication through inhibition of the ACE2 receptor. The S protein, thus, loses its partners to enter
the host cell, as illustrated on the right side of Figure 4. ACE2 can be a target for inhibiting the entry
of SARS-CoV-2 into the host cell because the binding affinity of the S protein of SARS-CoV-2 to the
ACE2 receptor is 10–20-fold stronger than that of the S protein of SARS-CoV [68–70].
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].
The Active Site of hACE2 as the Therapeutic Target of COVID-19
The amino-acid sequence of SARS-CoV-2 has a 76.5% similarity to that of SARS-CoV, and their S
proteins are quite homologous [
66
,
67
]. As shown in Figure 4, the RBD of the S protein of SARS-CoV-2
is located within amino-acid residues 318–510 (left side), containing the RBM (green ribbon), which is
on the surface, right in front of ACE2. Arg439 of the RBM in SARS-CoV-2 and Glu329 of ACE2 interact
and form a bridge to stabilize the complex. Based on the interaction of ACE2 with the S protein in
SARS-CoV-2, antibodies or small molecules can be used to target and inhibit SARS-CoV-2 replication
through inhibition of the ACE2 receptor. The S protein, thus, loses its partners to enter the host cell,
Molecules 2020,25, 3980 7 of 20
as illustrated on the right side of Figure 4. ACE2 can be a target for inhibiting the entry of SARS-CoV-2
into the host cell because the binding anity of the S protein of SARS-CoV-2 to the ACE2 receptor is
10–20-fold stronger than that of the S protein of SARS-CoV [6870].
Han et al. identified the residues of ACE2 that directly interact with the RBD of the SARS-CoV-2 S
protein. The residues involved are Gln24, Thr27, Lys31, His34, Glu37, Asp38, Tyr41, Gln42, Leu45,
Leu79, Met82, Tyr83, Asp90, Gln325, Glu329, Asn330, Lys353, and Gly54. They also determined that
Glu22, Glu23, Lys26, Asp30, Glu35, Glu56, and Glu57 are important in the interaction. Notably, Lys26
and Asp30 play a critical role in the interaction of the RBD S protein of SARS-CoV; thus, Han et al.
concluded that these residues have the potential to be developed as a target for entry inhibitors [
71
].
Moreover, Gln325/Glu329 and Asp38/Gln42 of ACE2 are key binding sites that form hydrogen bonds
with Arg426 and Tyr436 of the S protein SARS-CoV-2 [
72
]. These critical residues are also present
in the S protein of SARS-CoV-2 with a similar sequence [
73
]. Therefore, the residues can be used as
primary target active sites of ACE2 inhibitors. We hypothesize that, if the inhibitors selectively bind to
this active site (shown in yellow color in Figure 2), then they might be able to inhibit the S protein of
SARS-CoV-2 from interacting with hACE2. Guy et al. [
74
] hypothesized that the residues of the ACE2
binding pocket dier slightly from those of the active site of ACE2 (isolated from pig kidney tissue).
However, the types of amino acids involved are nearly the same.
5. Inhibitors of ACE2
5.1. Synthetic Compounds of ACE2 Inhibitors
Research on ACE2 inhibitors or blockers is still lacking, and only very few drugs are currently
available in the clinics. However, ACE1 inhibitors, such as losartan, are widely marketed. Several
countries use ACE1/ARB, such as losartan and telmisartan, to reduce the aggressiveness and mortality
of COVID-19. Kuster et al. proposed that ACE1 therapy should be continued or initiated on patients
with a history of heart failure, hypertension, or myocardial infarction [
75
] Zhang et al. [
76
] found that,
among patients with hypertension who were hospitalized with COVID-19, inpatient treatment with
ACEI/ARB was associated with a lower risk of death from all causes compared to non ACEI/ARB users.
ARB is widely used to treat hypertension, and the use of this drug clinically provides exceptional
tolerance for several groups treated with this class of drugs. In addition, the profile of side eects is
described as “like a placebo”. ARBs are most suitable for antagonizing the proinflammatory eects of
angiotensin II in patients with a recent positive COVID-19 test; thus, this compound may have the
best pharmacological properties for this indication. From the comparative analysis of available ARBs,
telmisartan has traits that make it the best compound [77].
Angiotensin receptor blockers (ARBs) have eects similar to angiotensin-converting enzyme
(ACE) inhibitors, but ACE inhibitors act by preventing the formation of angiotensin II rather than
blocking the binding of angiotensin II to muscles in blood vessels. ARB is used to control high blood
pressure, treat heart failure, and prevent kidney failure in diabetics. Therefore, angiotensin receptor
blockers (ARBs; such as losartan, valsartan, telmisartan, etc.) can be a new therapeutic approach to
block the binding and, hence, the attachment of SARS-CoV-2 RBD to cells that express ACE2, thereby
inhibiting their infection of the host cell [78].
In the past 20 years, MLN-4760 (imidazole) [
79
81
], captopril derivative [
82
,
83
], DX600 and
TAPI-2 peptide [
84
,
85
], losartan and its derivatives (benzimidazole [
56
,
82
,
86
,
87
], chloroquine and
its derivatives (quinolone) [
88
], diminazene aceturate [
89
], cepharanthine (alkaloid) [
75
], thiorphan
(palmitoyl) [
87
], and N-(2-aminoethyl)-1 aziridineethanamine (amino ethyl) [
90
] were discovered
to have potential as ACE2 inhibitors. However, caution should be taken because, although ACE1
inhibitors (such as captopril, enalapril, and lisinopril) and angiotensin II receptor blockers (ARB) (such
as olmesartan, losartan, candesartan, and valsartan) do have inhibitory eects on ACE2 [
91
], several
studies showed that these drugs can increase the ACE2 blood level [
86
], which will likely increase
the risk of contracting SARS [
92
]. This drawback means that the search for new and eective drugs is
Molecules 2020,25, 3980 8 of 20
even more pressing in order to combat the infection of this deadly virus, and we believe that natural
products should be further explored in the quest to find suitable and eective drug candidates [92].
5.2. Natural Compounds Inhibiting ACE1 and ACE2 Receptors
The discovery of novel drugs from natural products helps to improve our understanding of
diseases [
93
,
94
]. The active lead compounds from natural products can be further modified to enhance
their biological activity in order to be developed as drug candidates [
95
,
96
]. Recent progress on natural
products resulted in compounds being developed to treat viral infections [
97
]. Utomo et al. [
98
].
reported the biological activity of natural products in inhibiting SARS-CoV-2 using in silico methods.
Islam et al. comprehensively reviewed studies on natural products with inhibitory activity against CoV.
Natural products such as flavonoids, xanthones, proanthocyanidins, secoiridoids, and peptides
were reported to contain anti-ACE activity; however, further research is needed to confirm the
findings [
24
]. Table 1summarizes the natural compounds that were reported to have inhibitory eects
on ACE1 and ACE2 receptors. From this table, we can conclude that flavonoids are the most researched
with regard to ACE inhibition activity.
Table 1. Bioactive compounds reported to inhibit ACE1 and ACE2 in the literature.
No Inhibitors Derivates Plants Methods Years Source
1. Luteolin
Flavonoid Ailanthus
excelsa
In vitro using ACE2 via Elbl
and Wagner methods 2007 [99]
2. Kaempferol
3. Apigenin
4. Quercetin
5. Luteolin
6. Emodin Anthraquinone
Rheum ocinale
Polygonum multiflorum In vitro using ACE2 2007 [100]
7. Chrysin Flavonoid
8. Rhein Flavonoid
9. Delphinidin Flavonoid Hibiscus sabdariaIn vitro ACE Inhibition assay 2010 [101]
10. Cyanidin Flavonoid
11. Apigenin Flavonoid Apium graveolens In vitro using ACE2 isolated
from kidney 2010 [102]
12. Rhoifolin Flavonoid Rhus succedanea ACE activity was measured
by a fluorometric assay 2012 [103]
13. Rutin and
Quercetine Fagopyrum tataricum
14. Nicotianamine Peptide Glycine max
In vitro using internally
quenched fluorogenic (IQF)
substrate for ACE2
2015 [104]
15. Quercetin
Flavonoid
Actinidia macrosperma
In vitro using a
fluorescence-based
biochemical assay against
ACE enzyme
2018 [103,105]
16. Catechin
17. Quercetin
18. Epigallocatechin
19. Epigallocatechin
gallate
20. Ferulic acid
Phenolic acid
21. Chlorogenic acid
22. Isoferulic acid
23. Caeic acid
Molecules 2020,25, 3980 9 of 20
Table 1. Cont.
No Inhibitors Derivates Plants Methods Years Source
24. δ-Viniferin Flavonoid
Vitis vinifera
Virtual screening against
ACE2 using Autodock Vina 2020 [106]
25. Myritilin Flavonoid
26. Myricitrin Flavonoid
27.
TaiwanhomoflavoneA
Flavonoid Cephalotaxus wilsoniana
28. Lactucopicrin
15-oxalate
Sesquiterpene
lactone Lactuca virosa
29. Nympholide A Flavonoid Nymphaea lotus
30. Afzelin Flavonoid Cornus macrophylla
31. Biorobin Flavonoid Acalypha indica
32. Phyllaemblicin B sesquiterpenoid Phyllanthus emblica
33. Baicalin Flavonoid Scutellaria baicalensis
Using spectroscopy method
to determine renin and ACE
activities
[107]
34. Hesperetin Flavonoid Citrus aurantium
Virtual Screening against
ACE2 using molecular
docking 2020 [108]
35. Baicalin Flavonoid Scutellaria baicalensis
36. Scutellarin Flavonoid
37. Glycyrrhizin Sesquiterpene Glycyrrhiza radix
38. Curcumin Curcuminoids Curcuma xanthoriza
Virtual Screening against
ACE2 using MOE molecular
docking 2020 [98]
39. Tangeretin
Flavonoid Citrus aurantifolia
40. Nobiletin
41. Naringenin
42. Brazilein Flavonoid Caesalpinia sappan
43. Brazilin
44. Galangin Flavonoid
Alpinia galanga
45. Acetoxychavicol
acetate (ACA)
ACA derivatives
6. Flavonoids as ACE2 Inhibitors
Flavonoids are an important class of natural products with several subgroups, including chalcones,
flavones, flavonols, and isoflavones [
109
]. Flavonoids contain a flavan core with a 15-carbon skeleton.
There are two benzene rings (A and C rings), connected by a heterocyclic pyran ring (B ring). The three
cycles or heterocycles in the flavonoid backbone are generally called rings A, B, and C, as shown in
Figure 5. The B ring comprises a C2–C3 double bond and carbonyl groups that play an important
role in the biological activities. The hydroxyl groups (3
0
and 5
0
positions) of the C ring, as well as
the hydroxyl groups of the A ring (7 and 5 positions), are known to be responsible for the radical
scavenging activity of flavonoids [
103
]. The most important functional groups of flavonoids that might
be involved in ACE2 inhibition are illustrated in Figure 6.
Molecules 2020, 25, x 9 of 21
No Inhibitors Derivates Plants Methods Years Source
27. Taiwanhomoflavone
A Flavonoid Cephalotaxus
wilsoniana
28. Lactucopicrin 15-
oxalate
Sesquiterpene
lactone Lactuca virosa
29. Nympholide A Flavonoid Nymphaea lotus
30. Afzelin Flavonoid
Cornus
macrophylla
31. Biorobin Flavonoid Acalypha indica
32. Phyllaemblicin B
sesquiterpenoi
d
Phyllanthus
emblica
33. Baicalin Flavonoid
Scutellaria
baicalensis
Using spectroscopy
method to
determine renin
and ACE activities
[107]
34. Hesperetin Flavonoid Citrus
aurantium Virtual Screening
against ACE2 using
molecular docking
2020 [108]
35. Baicalin Flavonoid
Scutellaria
baicalensis
36. Scutellarin Flavonoid
37. Glycyrrhizin Sesquiterpene Glycyrrhiza radix
38. Curcumin Curcuminoids Curcuma
xanthoriza
Virtual Screening
against ACE2 using
MOE molecular
docking
2020 [98]
39. Tangeretin
Flavonoid Citrus
aurantifolia
40. Nobiletin
41. Naringenin
42. Brazilein Flavonoid Caesalpinia
sappan
43. Brazilin
44. Galangin Flavonoid
Alpinia galanga
45. Acetoxychavicol
acetate (ACA)
ACA
derivatives
6. Flavonoids as ACE2 Inhibitors
Flavonoids are an important class of natural products with several subgroups, including
chalcones, flavones, flavonols, and isoflavones [109]. Flavonoids contain a flavan core with a 15-
carbon skeleton. There are two benzene rings (A and C rings), connected by a heterocyclic pyran ring
(B ring). The three cycles or heterocycles in the flavonoid backbone are generally called rings A, B,
and C, as shown in Figure 5. The B ring comprises a C2–C3 double bond and carbonyl groups that
play an important role in the biological activities. The hydroxyl groups (3 and 5 positions) of the C
ring, as well as the hydroxyl groups of the A ring (7 and 5 positions), are known to be responsible for
the radical scavenging activity of flavonoids [103]. The most important functional groups of
flavonoids that might be involved in ACE2 inhibition are illustrated in Figure 6.
Figure 5. Flavan core of flavonoids.
Figure 5. Flavan core of flavonoids.
Molecules 2020,25, 3980 10 of 20
Molecules 2020, 25, x 10 of 21
Figure 6. Overview of the most important functional groups of flavonoids that might be involved in
ACE2 inhibition.
As can be seen in Figure 6, the resorcinol molecule has two hydroxyl groups in its aromatic ring
structure, and they are located at meta-positions with respect to each hydroxyl group. The high
reactivity of the resorcinol structure is primarily associated with the location of these two hydroxyl
groups in the benzene ring [110]. The resorcinol moiety o f ri ng A might pla y a role in A CE2 inhibiti on,
as this group might disrupt hydrogen bonds between Glu329/Gln325 of ACE2 and Arg426 of the S
protein of SARS CoV-2, which form a salt bridge to stabilize their interaction [72,73].This
hydrophobic interaction occurs in ring C with some non-polar amino acid residues such as Gly354,
Asp355, and Phe356 [111].
As summarized in Table 1, flavonoids have potential as ACE1 and ACE2 inhibitors. Studies on
flavonoids for anti-SARS-CoV activity were widely published. For example, myricetin inhibits viral
replication by affecting the ATPase activity of SARS-CoV [112]. Other flavonoids reported to have
anti-SARS-CoV activity include kaempferol [113], luteolin [114], quercetin, daidzein, EGCG, GCG,
and herbacetin [115,116]. Quercetin functions as an inhibitor or noncompetitive inhibitor of 3-
chymotripsin-like protease (3CLpro) and papain-like protease (PLpro) [117]. Luteolin inhibits furin
proteins which are known to be some of the enzymes that break down the S protein of SARS-CoV, as
reported in the Middle East respiratory syndrome (MERS) [114]. Kaempferol functions as a
noncompetitive inhibitor of 3CLpro and PLpro [117]. Hesperidin inhibits the interaction between the
RBD of the S protein of SARS-CoV-2 and the ACE2 receptor in humans; thus, it was also predicted to
potentially inhibit the entry of SARS-CoV-2 [118].
7. Mode of Action of Flavonoids
Polyphenolic compounds, including flavonoids, terpenoids, hydrolysable tannins, xanthones,
procyanidin, and caffeoylquinic acid derivatives, were discovered to be effective natural ACE
inhibitors [119,120]. Table 2 summarizes the studies on plant extracts rich in flavonoids used as ACE2
inhibitors.
Figure 6.
Overview of the most important functional groups of flavonoids that might be involved in
ACE2 inhibition.
As can be seen in Figure 6, the resorcinol molecule has two hydroxyl groups in its aromatic ring
structure, and they are located at meta-positions with respect to each hydroxyl group. The high reactivity
of the resorcinol structure is primarily associated with the location of these two hydroxyl groups in
the benzene ring [
110
]. The resorcinol moiety of ring A might play a role in ACE2 inhibition, as this
group might disrupt hydrogen bonds between Glu329/Gln325 of ACE2 and Arg426 of the S protein of
SARS CoV-2, which form a salt bridge to stabilize their interaction [
72
,
73
].This hydrophobic interaction
occurs in ring C with some non-polar amino acid residues such as Gly354, Asp355, and Phe356 [111].
As summarized in Table 1, flavonoids have potential as ACE1 and ACE2 inhibitors. Studies
on flavonoids for anti-SARS-CoV activity were widely published. For example, myricetin inhibits
viral replication by aecting the ATPase activity of SARS-CoV [
112
]. Other flavonoids reported to
have anti-SARS-CoV activity include kaempferol [
113
], luteolin [
114
], quercetin, daidzein, EGCG,
GCG, and herbacetin [
115
,
116
]. Quercetin functions as an inhibitor or noncompetitive inhibitor of
3-chymotripsin-like protease (3CLpro) and papain-like protease (PLpro) [
117
]. Luteolin inhibits furin
proteins which are known to be some of the enzymes that break down the S protein of SARS-CoV,
as reported in the Middle East respiratory syndrome (MERS) [
114
]. Kaempferol functions as a
noncompetitive inhibitor of 3CLpro and PLpro [
117
]. Hesperidin inhibits the interaction between the
RBD of the S protein of SARS-CoV-2 and the ACE2 receptor in humans; thus, it was also predicted to
potentially inhibit the entry of SARS-CoV-2 [118].
7. Mode of Action of Flavonoids
Polyphenolic compounds, including flavonoids, terpenoids, hydrolysable tannins, xanthones,
procyanidin, and caeoylquinic acid derivatives, were discovered to be eective natural ACE
inhibitors [
119
,
120
]. Table 2summarizes the studies on plant extracts rich in flavonoids used as
ACE2 inhibitors.
Molecules 2020,25, 3980 11 of 20
Table 2. Plants with potential ACE2 receptor inhibition activity.
Name Inhibition
Approach
Eective
Compound
Inhibition Potential
(IC50/EC50 ) * ADME Reference
Rheum
ocinale (rhubarb)
Viral spike
protein and
human
ACE2
receptor
inhibitor
Emodin 1–10 µM/mL
HIA: 85.74
Caco2: 20.30
PPB: 88.75
BBB: 0.37
[119]
Reynoutria
multiflora
tuber
Viral spike
protein and
human
ACE2
receptor
inhibitor
Emodin 1–10 µM/mL
HIA: 85.74
Caco2: 20.30
PPB: 88.75
BBB: 0.37
[119]
Citrus accumulate
Viral spike
protein and
human
ACE2
receptor
inhibitor
Naringenin Not yet reported
HIA: 87.31
Caco2: 10.52
PPB: 100
BBB: 0.59
[100]
Citrus aurantium and
Citri Reticulatae
Pericarpium
Viral spike
protein and
human
ACE2
receptor
inhibitor
Hesperetin Not yet reported
HIA: 87.19
Caco2: 7.003
PPB: 96.79
BBB: 0.22
[121]
Scutellaria baicalensis
Georgi
Viral spike
protein and
human
ACE2
receptor
inhibitor
Baicalin 2.24 mM
HIA: 32.42
Caco2: 11.55
PPB: 75.69
BBB: 0.02
[108]
Citrus
Viral spike
protein and
human
ACE2
receptor
inhibitor
Neohesperidin
Not yet reported
HIA: 8.80
Caco2: 7.07
PPB: 44.05
BBB: 0.02
[100]
Citrus
Viral spike
protein and
human
ACE2
receptor
inhibitor
Nobiletin Not yet reported
HIA: 98.89
Caco2: 54.05
PPB: 85.16
BBB: 0.044
[100]
Erigeron breviscapus
(Vant.)
Viral spike
protein and
human
ACE2
receptor
inhibitor
Scutellarin Not yet reported
HIA: 13.45
Caco2: 10.13
PPB: 72.90
BBB: 0.029
[121]
Soya bean
(Glycine max)
Viral spike
protein and
human
ACE2
receptor
inhibitor
Nicotinamine 84 nM
HIA: 92.94
Caco2: 20.36
PPB: 2.02
BBB: 0.33
[122]
Licorice root
(Glycyrrhiza radix)
Viral spike
protein and
human
ACE2
receptor
inhibitor
Glycyrrhizin
(saponin) Not yet reported
HIA: 38.22
Caco2: 20.37
PPB: 88.72
BBB: 0.055
[121]
* Inhibitory concentration (IC
50
) is an indication of the concentration (
µ
M or ug/mL) where the activity of the
viral protein is reduced by up to 50%. Eective concentration (EC
50
) is the indication of the concentration (
µ
M or
µ
g/mL) where the activity of the viral growth is reduced by up to 50%. Absorption, distribution, metabolism,
and excretion (ADME): human intestinal absorption (HIA) values of 20–70% indicate suciently absorbed
compounds, and 70–100% HIA values indicate well-absorbed compounds. Caco-2 values <4 indicate low drug
permeability, values from 4–70 indicate moderate permeability, and values >70 indicate high permeability. Plasma
protein binding (PPB) values >90% indicate strong chemical bonds, while values <90% indicate weak chemical
bonds. Blood–brain barrier (BBB) values between 2.0 and 0.1 indicate a moderate absorption rate in the central
nervous system (CNS), while BBB values <0.1 indicate a low absorption rate in the CNS [123].
Molecules 2020,25, 3980 12 of 20
A number of epidemiological studies suggested a negative relationship between the consumption
of flavonoid drugs and the development of various diseases. Flavonoids with typical structures can
interact with enzyme systems involved in important pathways, showing eective poly-pharmacological
behavior. Thus, it is not surprising that the relationship between chemical structures and their activities
was widely studied [
124
]. The presence of C2=C3 double bonds in conjugation with C4 carbonyl groups
of certain groups on flavonoids, as well as hydroxylation patterns, especially the catechol portions
of ring B, methoxyl groups, and fewer saccharide bonds, provides higher antioxidant properties.
The mechanism might involve planarity, which contributes to the shifting of electrons across the next
molecule and aects the dissociation constant of the hydroxyl phenolic group, such that the whole
molecule can bind to the target molecule, similar to an enzyme that matches the pattern [125].
Guerrero et al. [
103
] comprehensively analyzed dierent flavonoids to determine the functional
groups responsible for inhibiting ACE. Quantitative structure–activity relationship (QSAR) modeling
was conducted, and the lack of the B ring in the flavonoid skeleton was shown to reduce the inhibitory
activity of ACE by up to 91%. The absence of carbonyl groups in the B ring also reduced the inhibitory
activity of ACE by 74%. The 3-OH, 3
0
-OH, and 5
0
-OH groups are important since the loss of these
groups reduced inhibitory activity by 44%, 57%, and 78% [
103
], respectively, as shown in Figure 6. These
groups also play an important role in inhibiting neuraminidase receptors of the influenza A viruses
(H1N1 and H3N2) [
126
]. Other studies also reported that losing the 3-OH group significantly reduced
flavonoid antioxidant [
127
] and anti-CoV activities [
115
]. We also observed that 3-OH and catechol of
the C ring moiety of catechin formed strong hydrogen bonds with H1N1 neuraminidase [
126
]. Hošek
and Šmejkal [
128
] reported that these functional groups play an important role in anti-inflammatory
activity against the receptor target of inflammation. Moreover, hesperidin was also reported as an
ACE2 inhibitor since it can interact with the RBD of the S protein SARS-CoV2 and hACE2 interface.
The dihydroflavone moiety of hesperidin was predicted to be parallel to the β-6 RBD S protein sheet,
while the sugar moiety fits into a shallow hole in the direction away from ACE2 [118].
The most critical mechanism of flavonoids as antioxidant, anti-inflammation, anticarcinogenic,
and antiviral compounds is the protection of the body against reactive oxygen species (ROS) [
129
,
130
].
ROS interferes with cellular function through the role of lipid peroxidation, resulting in damaged cell
membranes. An increase in ROS production during tissue injury is due to the depletion of endogenous
scavenger compounds [
131
,
132
]. Flavonoids have a role as endogenous scavenging compounds [
133
];
thus, flavonoids can prevent inflammation or repair cell damage by scavenging ROS. The interaction
between flavonoids and hydrophilic amino-acid residues of protein targets with strong anity is
suggested to be a mechanism of flavonoids in repairing cell damage [130,134].
Based on these findings, we believe that there is a strong relationship among the ACE2 inhibition,
anti-inflammation, and antioxidant activities of flavonoids. However, the correlation among these
three activities needs to be clarified through comprehensive in vitro and in vivo evaluation.
8. Perspectives and Overall Conclusion
The renin–angiotensin system (RAS) controls the homeostatic function of the vascular system.
The two important enzymes involved in the RAS system, ACE1 and ACE2, function in accommodating
rapid but coordinated feedback to any specific situation in the body that may disturb the system
balance [
135
]. Their function is indispensable; hence, the choice to modulate these receptors for
other health conditions, such as against the current COVID-19 infection, would have to be done in a
careful manner.
Based on the information put forth in this review, it can be concluded that ACE2 could be a
key receptor to combat COVID-19 infection. The inhibition of hACE2 may prevent the S protein of
SARS-CoV-2 from fusing and entering host cells. However, as both RAS enzymes influence each other,
inhibition of ACE2 alone in this case would lead to an increase in Ang II blood levels and a parallel
reduction in the blood concentration of vasodilators angiotensins 1–7. In such a case, any disturbance
in circulation homeostasis would not be corrected rapidly due to the absence of angiotensins 1–7.
Molecules 2020,25, 3980 13 of 20
This would be a health risk, especially to susceptible patients such as the elderly and patients with
underlying CVS-related medical conditions. Ironically, these are the group of people that would have
a higher risk of contracting severe COVID-19 infection.
The discovery of ACE2 as a part of the RAS is relatively new; however, some evidence shows
that ACE2 could be more important than ACE1 in the modulation of the whole system. Although the
morphology of ACE1 and ACE2 receptors shares huge similarities, ACE inhibitors (ACEis) cannot
inhibit ACE2 receptors. Hence, the currently available ACEis are not as useful as ACE2 inhibitors [
135
].
This means that the structure of ACEis cannot be used as a building block in the design of ACE2
inhibitors. A new and fresh approach should be taken, and a comprehensive study of the receptor
itself is needed.
Thus, this paper proposes to shift the focus in the design of ACE2 inhibitors toward flavonoids,
which are an abundant group of compounds that can be found in many plants. The functional groups
of flavonoids, such as the pyran moiety in the B ring and hydroxyl groups of the A ring (7- and
8-positions) and C ring (3-, 3
0
-, 4
0
-, and 5
0
-positions), may play an important role in their ACE2
inhibition. Preliminary research showed that Glu22, Glu23, Lys26, Asp30, Glu35, Glu56, and Glu57 of
the hACE2 could be used as primary target sites in the design of an hACE2 inhibitor.
Flavonoids are synthesized by plants in response to microbial attacks; hence, their antibacterial
and antiviral activities are expected. The wide variety of activities reported in the literature depends
on the structures and side chains available in each flavonoid [
127
]. Despite the available data on the
activity of certain flavonoids against ACE1 and ACE2 enzymes, as presented in Table 1, the studies
were stopped at in silico or
in vitro
stages, and no further detailed studies are available. This could be
due to some limitations surrounding the research on natural products, such as diculties in obtaining
a sucient amount of substance through plant extractions or diculties in the chemical synthesis
of the flavonoids. However, the application of flavonoid-based scaolds in the design of new ACE2
inhibitors could be a good approach. Based on the history of drug development, a combination between
natural-based products and chemical synthesis is able to produce potent and eective medications,
such as the anticancer drugs vincristine and vinblastine. This could be an approach to bring forward
natural-based products for human use.
Author Contributions:
M.M. and M.F. discussed and drafted the manuscript. M.M., M.F., N.K.K.I., A.M.G. and
H.A.W. revised and edited the manuscript. M.M. acquired the funding. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by Universitas Padjadjaran through Grant no. 1733/UN6.3.1/LT/2020.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
SARS-CoV: severe acute respiratory syndrome coronavirus, ACE1: angiotensin-converting enzyme 1, ACE2:
angiotensin-converting enzyme 2, ARBs: angiotensin receptor blockers, 3CLpro: 3-chymotripsin-like protease,
PLpro: papain-like protease, Mpro: main protease, MERS: Middle East respiratory syndrome, AT1R: activates
angiotensin II receptor, ORFs: open reading frames, FDA: Food and Drug Administration, CRS: cytokine release
syndrome, RBD: receptor-binding domain, RNA: ribonucleic acid, IQF: internally quenched fluorogenic, MOE:
molecular operating environment, EGCG: epigallocatechin gallate, GCG: gallocatechin gallate, IC
50
: the half
maximal inhibitory concentration, EC
50
: the half maximal eective concentration, ADME: absorption, distribution,
metabolism, and excretion, HIA: human intestinal absorption, PPB: plasma protein binding, BBB: blood–brain
barrier, CNS: central nervous system, QSAR: quantitative structure–activity relationship, ROS: reactive oxygen
species, RAS: renin–angiotensin system.
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... Gao et al., 2021;Gour, Manhas, Bag, Gorain, & Nandi, 2021;H. Chen & Du, 2020;Cherrak, Merzouk, & Mokhtari-Soulimane, 2020;Khan et al., 2021;Mendonca & Soliman, 2020;Muchtaridi, Fauzi, Ikram, Gazzali, & Wahab, 2020;Omotuyi et al., 2021;Russo, Moccia, Spagnuolo, Tedesco, & Russo, 2020;Tutunchi, Naeini, Ostadrahimi, & Hosseinzadeh-Attar, 2020;J. W. Yu, Wang, & Bao, 2020). ...
... In addition, disruption of the interaction between ACE2 and the SARS-CoV-2 spike protein is the main effect of flavonoids. Thus, SARS-CoV-2 cannot fuse with ACE2 (Abderrazak et al., 2015;Muchtaridi et al., 2020;J. W. Yu et al., 2020;Zhai et al., 2020). ...
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The high incidence of post‐covid symptoms in humans confirms the need for effective treatment. Due to long‐term complications across several disciplines, special treatment programs emerge for affected patients, emphasizing multidisciplinary care. For these reasons, we decided to look at current knowledge about possible long‐term complications of COVID‐19 disease and then present the effect of flavonoids, which could help alleviate or eliminate complications in humans after overcoming the COVID‐19 infection. Based on articles published from 2003 to 2021, we summarize the flavonoids‐based molecular mechanisms associated with the post‐COVID‐19 syndrome and simultaneously provide a complex view regarding their prophylactic and therapeutic potential. Review clearly sorts out the outcome of post‐COVID‐19 syndrome according particular body systems. The conclusion is that flavonoids play an important role in prevention of many diseases. We suggest that flavonoids as critical nutritional supplements, are suitable for the alleviation and shortening of the period associated with the post‐COVID‐19 syndrome. The most promising flavonoid with noteworthy therapeutic and prophylactic effect appears to be quercetin.
... Some natural flavonoids have been known to have potent ACE2-inhibitory effect. (Muchtaridi M et al., 2020). April 12-13, 2021, Gaziantep University, Nizip Faculty of Education, Gaziantep, Turkey Symposium Full Text Book 78 www.biltek.org ...
... The 2002-2004 SARS epidemic led to the discovery that some flavonoids have a potential inhibitory effect on ACE2 receptors and the 3CL protease of the coronavirus, both of which are essential for viral invasion and replication. The similarity in the genome of SARS-CoV-1 and SARS-CoV-2 (the causative agent of COVID-19), and some new in vitro studies, suggest that flavonoids represent a new potential therapy for COVID-19 infection (Jo, S. et al, 2020, Liu, Y. et al., 2020, Muchtaridi M et al., 2020. Zhang, Y. Liao, and D. Gong, (2016). ...
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Abstract Energy is the important thing in human life in the world. Electrical energy is the one types form that energy, The Refrigeration, and Air-conditioning systems are consuming a large amount of this energy and we can't neglect the air-conditioning systems because of the importance to give the comfort zone to people. In this project, theoretical and experimental work has been done to calculate heat gain and cooling load for the conference hall in the civil engineering department in the college of engineering at the University of Kirkuk. The temperatures of the walls and Roofs obtained from inside, outside, and ambient temperatures that used to estimate heat gain. The comparison has been done between heat gain experimentally and heat gain calculated theoretically. The MATLAB Program has been done for calculating Cooling Load and CLTD values by using CFFT (Complex Finite Fourier Transform) technique. Keywords: Building walls, heat gain, cooling load, cooling load temperature difference, CLTD.
... Flavonoids, xanthones, proanthocyanidins, secoiridoids. have potential natural therapeutic activity against SARS CoV-2 by blocking ACE 2 (Muchtaridi et al. 2020). Vitamin C (citric acid) has a prominent role in scavenging oxidative damage due to ACE 2-S-protein interaction. ...
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The incidence of the COVID-19 pandemic completely reoriented global socio-economic parameters and human civilization have experienced the worst situation in the recent past. The rapid mutation rates in viruses have continuously been creating emerging variants of concerns (VOCs) which devastated diferent parts of the world with subsequent waves of infection. Although, series of antiviral drugs and vaccines were formulated but cent percent efectiveness of these drugs is still awaited. Many of these drugs have diferent side efects which necessitate proper trial before release. Plants are the storehouse of anti�microbial metabolites which have also long been utilized as traditional medicines against diferent viral infections. Although, proper mechanism of action of these traditional medicines are unknown, they may be a potential source of efective anti�COVID drug for future implications. Advanced bioinformatic applications have opened up a new arena in predicting these repurposed drugs as a potential COVID mitigator. The present review summarizes brief accounts of the corona virus with their possible entry mechanism. This study also tries to classify diferent possible anti COVID-19 plant-derived metabolites based on their probable mode of action. This review will surely provide useful information on repurposed drugs to combat COVID-19 in this critical situation
... A recent study reported that flavonoids could prevent SARS-CoV-2 infection by activating the transcription factor Nrf2 (Mendonca and Soliman, 2020). Flavonoids may also work as an angiotensin-converting enzyme 2 inhibitors for anti-SARS-CoV-2 (Muchtaridi et al., 2020). Forsythoside I, the second most abundant chemical component in QFYD, was also shown to inhibit influenza virus replication in mice (Deng et al., 2016;Law et al., 2017). ...
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Influenza virus-caused lung infection and its pandemic outbreaks are a persistent public health challenge. The H1N1 subtype is the most common type of influenza infection observed in humans. Maxingshigantang decoction, a classic formula of Chinese herbal medicine, has been used for the prevention and treatment of respiratory infection for many centuries. Qingfeiyin decoction, based on Maxingshigantang, has been used in the clinic for decades. To explore the underlying mechanisms, according to the traditional Chinese medicine theory “the lung and the large intestine are interior–exterior,” which can be translated to the “gut–lung axis” in a contemporary term, the composition of gut microbiota was determined using 16S rRNA and the transcriptome of the colon was determined by RNA sequencing. The results showed that Qingfeiyin decoction decreased the viral load, alleviated the lung injury, increased the survival rate, partly restored the shortening of the colon caused by the H1N1 virus, and downregulated inflammatory pathways including MAPK, TNFα, and JAK-STAT signaling pathways. Qingfeiyin decoction increased the relative abundance of the genera of Coprococcus , Ruminococcus, Lactobacillus , and Prevotella and prevented the H1N1 virus-induced decrease in the abundance of the genera of Escherichia , Parabacteroides , Butyricimonas, and Anacrotruncus. These results will help better understand the mechanisms for Qingfeiyin decoction’s protective effect against influenza virus infection.
... Flavonoid is a heterogeneous polyphenolic molecule found in a wide range of plant species. As a natural product that plays an essential role in plant physiology, flavonoid has been studied for their beneficial bioactivity to health in the form of anticancer and antibacterial capabilities as well as their antioxidant and anti-inflammatory effects (Muchtaridi et al., 2020;Vijayakumar et al., 2020). In addition, various studies advise that several types of flavonoids, such as Apigenin, Quercetin, Kaempferol, Naringenin, and Luteolin are the most suggested compounds that may act as potential inhibitors of 3CL pro (Gogoi et al., 2021;Ryu et al., 2010;Sayed et al., 2020). ...
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An outbreak of SARS-CoV-2 (COVID-19) has caused a global health emergency, resulting in hundreds of millions of infections and millions of deaths globally since December 2019. Due to the lack of a particular medicine or treatment approach and the fast spread of the virus around the world, it is imperative to find effective pharmacological molecules to combat the virus. Herein, we carried out docking-based virtual screening of selected 49 bioactive phytochemicals from 20 medicinal plants used in Jamu, an Indonesian traditional herbal medicine along with the 3CLpro inhibitor N3 towards the 3CLpro enzyme of SARS-CoV-2. From a total of 49 bioactive phytochemicals, eleven compounds exhibited good binding affinity against 3CLpro of SARS-CoV-2 (-7.2 to -8.5 kcal/mol). Accordingly, only seven phytochemicals fully obeyed drug-likeness properties. Ultimately, it was observed that both Luteolin and Naringenin have significant interactions with both of the catalytic residues of 3CLpro through hydrogen bonds and hydrophobic interactions, respectively. The drug-like characteristics of Luteolin and Naringenin were also confirmed by pharmacokinetic investigations. Further, an investigation into molecular dynamics (MD) simulations were undertaken to ensure the ligands would remain stable within the binding pocket. Finally, density-functional theory (DFT) calculations revealed the following order for biochemical reactivity: Naringenin > Luteolin > N3. The oxygen and hydrogen atom regions of these investigated ligands are suitable for electrophilic and nucleophilic attacks, respectively. These two bioactive phytochemicals from Tamarindus indica (Luteolin and Naringenin) as well as Citrus aurantifolia (Naringenin) might be potential antagonists of 3CLpro of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
... Natural compounds such as isothymol, thymol, p-cymene, limonene, and gamma-terpinene (from Ammoides verticillata), and 17-organosulfur compounds (from garlic) were also found to be potential inhibitors of ACE2 receptor [1,82]. Further, xanthones, proanthocyanidins, secoiridoids, naringenin, hesperetin, baicalin and neohesperidin, scutellarin, nicotinamin, and glycyrinodin could exhibit ACE2 inhibition activity [58]. Hesperidin can modulate the binding energy of ACE2-spike protein complex and affects the stability of viral-host interaction [12]. ...
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Introduction Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally. However, no specific antivirals are available, although several are in development. Currently approved vaccines and other drug candidates could be associated with several drawbacks urges to develop alternative therapeutic approaches. Aim To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds. Methods Information was gathered from diverse bibliographic platforms such as PubMed, Google scholar, web of science, and ClinicalTrials.gov registry. Results The present review highlights the potential roles of crude extracts of plants as well as plant-derived small molecules in inhibiting SARS-CoV-2 infection by targeting viral or host factors essential for viral entry, polyprotein processing, replication, assembly and release. Their anti-inflammatory and antioxidant properties as well as plant-based therapies that are under development in the clinical trial phases-1 to 3 are also covered. Conclusion This knowledge could further help understanding SARS-CoV2 infection and anti-viral mechanisms of plant-based therapeutics.
... Zheng and Liu (2020) did docking study to find the interaction of flavonoids with ACE2 (Zheng and Liu et al., 2020). The results showed high binding activity between naringin and ACE2 with docking energy of -6.85 kcal/mol and potential binding site at TYR-515, GLU-402, GLU-398, and ASN394, similarly, naringenin shows bind with ACE2 with docking energy of -6.05 kcal/mol and with possible binding site at LEU-143, PRO-146, and LYS-131 (Muchtaridi et al., 2020). Hesperidin and hesperetin also showed potential binding affinity to ACE2 with docking energy of -4.21 kcal/mol and -6.09 kcal/mol with binding sites at ASN-277, ARG-273, HIS-505 with hesperetin, and TRP-69, LEU-351, ASP-350 with hesperidin (Biagioli et al., 2021). ...
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The outbreak of COVID-19 in 2019 followed by its new variants till now in 2021, made it more necessary to find more identify effective antiviral agents to be included in daily life to combat SARS-CoV-2 and support vaccines and their effect. Fruits are always considered good for health and many studies are trying to find the solution and different compounds with antiviral properties in fruits. Recently, many in vivo and docking studies found many phytochemical compounds effective against COVID-19. In this review, we tried to collect data from different studies. We found that fruits are most valuable gift with great healing property.
... It is expected that such therapy may prevent organ and tissue damage due to the suppression of cytokine release and oxidative stress (Assimakopoulos & Marangos, 2020;Poe & Corn, 2020). Recent reviews have also explored other extracts high in polyphenols for reducing the COVID-19 cytokine storm (Liskova et al., 2021;Muchtaridi et al., 2020). Superoxide dismutase and heme oxygenase-1 (HO-1) are major defences against the ROS produced in cells and can improve vascular function (Araujo et al., 2012). ...
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... Zheng and Liu (2020) did docking study to find the interaction of flavonoids with ACE2 (Zheng and Liu et al., 2020). The results showed high binding activity between naringin and ACE2 with docking energy of -6.85 kcal/mol and potential binding site at TYR-515, GLU-402, GLU-398, and ASN394, similarly, naringenin shows bind with ACE2 with docking energy of -6.05 kcal/mol and with possible binding site at LEU-143, PRO-146, and LYS-131 (Muchtaridi et al., 2020). Hesperidin and hesperetin also showed potential binding affinity to ACE2 with docking energy of -4.21 kcal/mol and -6.09 kcal/mol with binding sites at ASN-277, ARG-273, HIS-505 with hesperetin, and TRP-69, LEU-351, ASP-350 with hesperidin (Biagioli et al., 2021). ...
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The outbreak of COVID-19 in 2019 followed by its new variants till now in 2021, made it more necessary to find more identify effective antiviral agents to be included in daily life to combat SARS-CoV-2 and support vaccines and their effect. Fruits are always considered good for health and many studies are trying to find the solution and different compounds with antiviral properties in fruits. Recently, many in vivo and docking studies found many phytochemical compounds effective against COVID-19. In this review, we tried to collect data from different studies. We found that fruits are most valuable gift with great healing property.
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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has spread rapidly across the world and become an international public health emergency. Both SARS-CoV-2 and SARS-CoV belong to subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and they are classified as the SARS-like species while belong to different cluster. Besides, viral structure, epidemiology characteristics and pathological characteristics are also different. We present a comprehensive survey of the latest coronavirus-SARS-CoV-2-from investigating its origin and evolution alongside SARS-CoV. Meanwhile, pathogenesis, cardiovascular disease in COVID-19 patients, myocardial injury and venous thromboembolism induced by SARS-CoV-2 as well as the treatment methods are summarized in this review.
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The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.
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In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002–2003 epidemic. This new disease was named COVID‐19 and the causative virus SARS‐CoV‐2. The SARS‐CoV‐2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein‐ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro‐inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1–7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self‐powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID‐19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open‐label randomized phase II clinical trial for the evaluation of telmisartan in COVID‐19 patients (NCT04355936).
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We study partisan differences in Americans’ response to the COVID-19 pandemic. Political leaders and media outlets on the right and left have sent divergent messages about the severity of the crisis, which could impact the extent to which Republicans and Democrats engage in social distancing and other efforts to reduce disease transmission. We develop a simple model of a pandemic response with heterogeneous agents that clarifies the causes and consequences of heterogeneous responses. We use location data from a large sample of smartphones to show that areas with more Republicans engaged in less social distancing, controlling for other factors including public policies, population density, and local COVID cases and deaths. We then present new survey evidence of significant gaps at the individual level between Republicans and Democrats in self-reported social distancing, beliefs about personal COVID risk, and beliefs about the future severity of the pandemic.
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Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).
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Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1,9) days in HCQ group, which is comparable to that in the control group [2 (1,4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0,2) day after hospitalization, which was also comparable to that in the control group [1 (0,3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.
Article
The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.
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SARS-CoV-2 is the cause of the worldwide outbreak of COVID-19 that has been characterized as a pandemic by the WHO. Since the first report of COVID-19 on December 31, 2019, 179,111 cases were confirmed in 160 countries/regions with 7,426 deaths as of March 17, 2020. However, there have been no vaccines approved in the world to date. In this study, we analyzed the biological characteristics of the SARS-CoV-2 Spike protein, Pro330-Leu650 (SARS-CoV-2-SPL), using biostatistical methods. SARS-CoV-2-SPL possesses a receptor-binding region (RBD) and important B (Ser438-Gln506, Thr553-Glu583, Gly404-Aps427, Thr345-Ala352, and Lys529-Lys535) and T (9 CD4 and 11 CD8 T cell antigenic determinants) cell epitopes. High homology in this region between SARS-CoV-2 and SARS-CoV amounted to 87.7%, after taking the biological similarity of the amino acids into account and eliminating the receptor-binding motif (RBM). The overall topology indicated that the complete structure of SARS-CoV-2-SPL was with RBM as the head, and RBD as the trunk and the tail region. SARS-CoV-2-SPL was found to have the potential to elicit effective B and T cell responses. Our findings may provide meaningful guidance for SARS-CoV-2 vaccine design.