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Abstract

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE-II, is a type I integral membrane protein of 805 amino acids that contains one HEXXH-E zinc binding consensus sequence. ACE-II has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). In this study, the potential of some flavonoids present in propolis to bind to ACE II receptors was calculated in silico. Binding constants of ten flavonoids, caffeic acid, caffeic acid phenethyl ester, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin and quercetin were measured using the AutoDock 4.2 molecular docking program. And also, these binding constants were compared to reference ligand of MLN-4760. The results are shown that rutin has the best inhibition potentials among the studied molecules with high binding energy -8,97 kcal/mol and Ki 0,261 mM, and it is followed by myricetin, caffeic acid phenethyl ester, hesperetin and pinocembrin. However, the reference molecule has binding energy of -7,28 kcal/mol and 4,65 mM. In conclusion, the high potential of flavonoids in ethanolic propolis extracts to bind to ACE II receptors indicates that this natural bee product has high potential for Covid- 19 treatment, but this needs to be supported by experimental studies.
Article title: An investigation of ethanolic propolis extracts: Their potential inhibitor properties against ACE-II
receptors for COVID-19 treatment by Molecular Docking Study
Authors: Halil Ibrahim Güler[1], Gizem Tatar[2], Oktay Yildiz[3], Ali Osman Belduz[4], Sevgi Kolayli[5]
Affiliations: aradeniz Technical University, Faculty of Science, Department of Molecular Biology and Genetics[1],
Karadeniz Technical University, Faculty of Medicine, Department of Biostatistics and Medical Informatics[2], Karadeniz
Technical University, Faculty of Pharmacy, Basic Pharmaceutical Sciences, Department of Biochemistry[3], Karadeniz
Technical University, Faculty of Science, Department Biology[4], Karadeniz Technical University, Faculty of Science,
Department of Chemisty[5]
Orcid ids: 0000-0002-7261-6790[1]
Contact e-mail: hiboguler@gmail.com
License information: This work has been published open access under Creative Commons Attribution License
http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at
https://www.scienceopen.com/.
Preprint statement: This article is a preprint and has not been peer-reviewed, under consideration and submitted to
ScienceOpen Preprints for open peer review.
DOI: 10.14293/S2199-1006.1.SOR-.PP5BWN4.v1
Preprint first posted online: 22 April 2020
Keywords: Coronavirus, Covid-19, propolis, Flavonoids, ACE-II, Molecular docking
An investigation of ethanolic propolis extracts: Their potential inhibitor
properties against ACE-II receptors for COVID-19 treatment by Molecular
Docking Study
Halil Ibrahim GULER1*, Gizem TATAR2, Oktay YILDIZ3, Ali Osman BELDUZ4, Sevgi
KOLAYLI5
1Karadeniz Technical University, Faculty of Science, Department of Molecular Biology and Genetics,
61080 Trabzon, TURKEY
2Karadeniz Technical University, Faculty of Medicine, Department of Biostatistics and Medical
Informatics, 61080 Trabzon, TURKEY
3Karadeniz Technical University, Faculty of Pharmacy, Basic Pharmaceutical Sciences, Department
of Biochemistry, 61080 Trabzon, TURKEY
4Karadeniz Technical University, Faculty of Science, Department Biology, 61080 Trabzon, TURKEY
5Karadeniz Technical University, Faculty of Science, Department of Chemisty, 61080 Trabzon,
TURKEY
*Corresponding author
E-mail: hiboguler@gmail.com
Phone: +90462 377 3553
Present adress: Karadeniz Technical University, Faculty of Science, Department of Molecular
Biology and Genetics, 61080 Trabzon, Turkey
ORCID: https://orcid.org/0000-0002-7261-6790
Conflict of interest
No conflict of interest is declared.
Abstract
The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE-II, is a type
I integral membrane protein of 805 amino acids that contains one HEXXH-E zinc binding
consensus sequence. ACE-II has been implicated in the regulation of heart function and also
as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome
(SARS). In this study, the potential of some flavonoids present in propolis to bind to ACE II
receptors was calculated in silico.
Binding constants of ten flavonoids, caffeic acid, caffeic acid phenethyl ester, chrysin,
galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin and quercetin were measured
using the AutoDock 4.2 molecular docking program. And also, these binding constants were
compared to reference ligand of MLN-4760.
The results are shown that rutin has the best inhibition potentials among the studied
molecules with high binding energy -8,97 kcal/mol and Ki 0,261 M, and it is followed by
myricetin, caffeic acid phenethyl ester, hesperetin and pinocembrin. However, the reference
molecule has binding energy of -7,28 kcal/mol and 4,65 M. In conclusion, the high potential
of flavonoids in ethanolic propolis extracts to bind to ACE II receptors indicates that this
natural bee product has high potential for Covid- 19 treatment, but this needs to be supported
by experimental studies.
Keywords: Coronavirus, Covid-19, propolis, flavonoids, ACE-II, molecular docking
Introduction
Propolis is a natural mixture that honey bees collect from nature in order to protect their
hives. Honey bees use propolis for insulating hives, mummification of dead insects and bees
and as an antibacterial, antiviral, antioxidant and anti-inflammatory agent for many biological
activities. Crude propolis is a highly viscous, slightly soluble mixture in water and best
dissolved in 60-80% ethanol. Propolis has been an indispensable component of apitherapy for
centuries and has recently been used as a food additive, or supplementary, under the name of
traditional and complementary medicine [1, 2].
Its composition varies according to the flora of the region where it is collected, but the
majority of active ingredients of propolis comprise the family of polyphenols. Phenolic acids,
flavonoids (flavanones, flavones, flavonols etc.), stilbenes, tannins are the active polyphenols
of propolis [1, 3]. Propolis are not consumed as raw, but their ethanolic and aqueous extracts
are widely consumed in different formulations.
It has been reported that polyphenolic agents such as gallic acid, caffeic acid,
protocatechuic acid, chrysin, quercetin, rutin, galangin, kaempferol, hesperetin, pinocembrin,
pinobanksin, apigenin, luteolin, daidzein, caffeic acid phenyl ester (CAPE) are the most active
polyphenols of propolis and these secondary metabolites vary depending on the propolis
source [1, 4, 5].
Studies show that propolis extracts have high immunomodulatory effect and inhibition
potential for some clinically important enzymes, such as urease, xanthine oxidase (XO),
acetylcholinesterase (AChE), -amylase, -glucosidase [6, 7]. In addition, in vivo and in vitro
studies show that flavonoids, one of the active ingredients of propolis, have high potential for
Angiotensin-Converting Enzyme (ACE) Inhibition [8, 9, 10].
The newly discovered SARS-CoV-2 was characterized as a beta-coronavirus and
recognized as the seventh discrete coronavirus species capable of causing human disease. The
disease caused by the virus is officially named Coronavirus Disease 2019 (Covid-19) by
Word Health Organization (WHO). The emerged global epidemic spread rapidly with
2.246.291 confirmed cases and 152.707 deaths across 213 countries, areas and territories
(COVID-19 situation Report WHO, 20 April 2020). Subsequent studies have shown that
SARS-CoV-2 has been suggested to recognize human ACE II more strongly than SARS-
CoV, thereby increasing the ability to be transmitted from person to person [11]. Therefore,
ACE II enzyme inhibition is important for treatments against these virus infections caused by
SARS-CoV-2.
The aim of this study was to calculate the inhibition constants of some flavonoids, one
of the active ingredients of Anatolian propolis, to the ACE II enzyme by molecular modeling
as a positive control (S, S) -2- {1-Carboxy-2- [3- (3,5-Dichloro-Benzyl) -3h-Imidazole-4-Yl] -
Ethylamino}-4-Methyl-Pentanoic Acid (MLN-4760). We analyzed therapeutic potential
compounds of Turkish propolis extracts tested against ACE-II in experimental studies with in
silico methods.
Up to now, there are very limited studies about Covid-19 and most researchers focused
primarily on clinical cases. However, to the authors' knowledge, no study has been made on
inhibition of ACE-II known to be associated with Covid-19. Therefore, the paper will
encourage further researches about Covid-19 and candidate drug compounds.
Materials and Methods
Materials
Raw propolis samples obtained experienced beekeepers in 2018 from Black Sea Region,
Turkey.
Chemicals
All phenolic standard for HPLC analyses of gallic acid, protocathequic acid, p-OH
benzoic acid, catechin, caffeic acid, syringic acid, epicatechin, p-coumaric acid, ferulic acid,
rutin, myricetin, resveratrol, daidzein, luteolin, t-cinnamic acid, hesperetin, chrysin,
pinocembrin, caffeic acid phenethyl ester (CAPE) were purchased from Sigma Chemical
Co.(St Louis, MO, USA). All solvent for using mobile phases were analytical grade.
Preparation of propolis extracts
The raw propolis samples were frozen at -20 °C and then grinded to powder. The
following method was used to prepare the ethanolic propolis extract: 10 g powdered crude
propolis was placed with 100 mL 70% ethanol in a glass flask and stirred with shaker
(Heidolph Promax 2020, Schwabach, Germany) at room temperature for 24 h and then
filtered with Whatman paper.
Determination of phenolic profiles
In this study, nineteen phenolic standards were used to high-performance liquid
chromatography (HPLC) (Elite LaChrom Hitachi, Japan) with a UV detector. Separation was
performed on a column with a reverse phase C18 column (150 mmx4.6 mm, 5μm; Fortis), in
gradient solvent systems A (2% acetic acid in water) and solvent B (70:30, acetonitrile/water),
which was sonicated before stirring and continuously degassed by the built-in HPLC system
[12, 13]. The flow rate was kept constant at 1 mL/min using gradient programming, starting
the flow of the mobile phase as B (5%) to 3 minutes, gradually increasing (up to 15, 20, 25,
40 and 80% at 8, 10, 18, 25 and 35 minutes, respectively) and decreasing to 5% at 40 minutes,
before being left for 10 minutes to equilibrate in the column. The standard phenolic
substances chromatogram is given in Figure 1.
Molecular Docking
In the study, some flavonoids detected in the ethanolic propolis extracts and they used
as ligand (see in Supplementary File) for ACE II receptors. The crystal structure of a ACE II
protein was downloaded from protein data bank web site (http://www.rcsb.org/pdb) (PDB ID:
1R4L: Resolution 3.00 Å). This crystal structure contains the inhibitory bound state of the
extracellular metallopeptidase domain of ACE II with MLN-4760 compound. Small
compounds of flavonoids used in docking studies were obtained from PubChem as SDF form
and were drawn in the Hyperchem software [14] then subjected to conformational search with
geometric optimization. Possible docking modes between compounds and the ACE II enzyme
were studied using the Autodock 4.2 [15] and Lamarckian genetic algorithm was employed
for docking simulations. The selected cavity is the binding site of reference inhibitor MLN-
4760 ((S,S)-2-{1-Carboxy-2-[3-(3,5-dichloro-benzyl)-3H-imidazol-4-YL]-ethylamino}-4-
methyl-pentanoic acid). A grid box dimensions of 52, 34, and 47 points in x, y, and z
directions was set with a grid spacing of 0.375 Å. The program was run for a total number of
100 Genetic algorithm runs. The default settings were applied for all other parameters. Results
of the molecular docking described the affinity represented by docking score and binding
interaction of each ligand on the interested protein target. The visualization of results was
performed with the help of the BIOVIA Discovery Studio 2018 [16].
Results and Discussion
Phenolic composition of propolis extract
In this study, a standard HPLC-UV chromatogram prepared with nineteen phenolic
standards including some phenolic acids and flavonoids is given in Fig 1. The analysis data
of the ethanolic propolis extract carried out according to this chromatogram are summarized
in Table 1. Although the hydroxybenzoic acids and catechin derivatives of the propolis
sample were found below determination limits, it was found to be rich in hydroxycinnamic
acids and flavanoids. Among the hydroxycinnamic acid derivatives, the caffeic acid phenyl
ester is the highest amount of phenolic component in the sample and followed it caffeic acid
and cinnamic acid. Ferulic acid could not be detected in the sample. Among the flavonoids
subclass of flavonoids, the highest amount of myrisetin was detected and rutin followed it.
Among these three flavanons studied, chrysin is the most abundant compounds
pinosebrin and hesperetin followed. A smaller amount of flavone derivative of luteolin, was
detected, while daidzein is not detected. Of all the studied compounds, chyrisin and
pinosembrin were detected as major flavonoids in the propolis sample.
Although composition of propolis varies according to the flora of the region where it is
produced, these flavonoids were also reported in propolis samples of different countries [17,
18, 19]. There are many scientific studies showing that propolis, a natural bee product, is a
very rich mixture of flavonoids and is an important agent of apitherapy. Polyphenolic profile
of propolis varies according to the flora of the region where it is collected, caffeic acid,
CAPE, rutin, quercetin, polyphenols such as myricetin, kampherol, hesperetin, galangin are
the active substances of Anatolian propolis [3, 4, 5, 20, 21]. Barbarić et al. (2011) studied
chemical composition of the ethanolic propolis extracts and determined ferulic acid, p-
coumaric acid, caffeic acid, tectochrysin, galangin, pinocembrin, chrysin, apigenin,
kaempferol, quercetin as phenolic compound in Croatia, Bosnia and Hercegovina and
Macedonia propolis [22]. Major compounds of red propolis samples from Brasilia were found
as luteolin (1.75 mg/g), naringenin (0.96 mg/g), kaempferol (0.59 mg/g), pinocembrin (0.41
mg/g) and biochanin A (0.39 mg/g) [23]. There are some differences between the findings
because the chemical composition of propolis varies according to the geographical region,
climate, environmental conditions and collection seasons [23, 24, 25]. The findings show that
propolis are a good source of phenolic substances. The literature states that propolis samples
from different geographical origins have a good antioxidant antimicrobial, antifungal and
antiviral (Avian influenza virus) activity [26, 27, 28, 29, 30].
Binding affinity analysis for proteins and ligands with molecular docking
We focus here on the Anatolian propolis compounds used by people to treat infections
against ACE II with molecular docking methods. For this purpose, we made docking analysis
with the compounds and found that quercetin, rutin, myrisetin and hesperetin have a better
affinity against ACE II enzyme than natural inhibitor MLN-4760 with low µM Ki values
among the evaluated compounds (Table 2).
Furthermore, these compounds interacted with Arg273, Thr371, His345, Pro346,
Tyr515, Glu402 and Glu375 in ACE II binding site. Especially, our in silico study showed
that, rutin has the best binding affinity to the ACE II enzyme (Binding energy: -8.98 kcal/mol,
Ki 0.261 M). This compound was observed to bind to the residues Asn149, His345, Asp269,
Glu375, Glu406, Thr371, Tyr127 and Asp368 of ACE II protein with the stronger hydrogen
bond (Figure 2). It can be suggested that these residues can contribute to the enhancement of
ligand affinity for ACE II enzyme. In addition, this compound has the pi-cation interaction
with Arg273, pi-pi T shape interaction with His374, alkyl interaction with Cys344 and pi-
alkyl interaction with Tyr 127 residues (Figure 2).
Therefore, in this study, in silico effects of Anatolian propolis on ACE II enzyme
inhibition was investigated with the ten flavonoids as major substances. The results of this
study showed that quercetin, rutin, myricetin and hesperetin compounds effectively inhibit the
ACE II enzyme. These compounds can be clinically tested and used for the treatment disease
role of ACE II. Furthermore, Arg273, Thr371, His345, Pro346, Tyr515, Glu402 and Glu375
are potential inhibitor targeting sites for the ACE II enzyme. Based on this information, we
propose guidelines to develop novel and specific inhibitors that target ACE II enzyme.
Guerrero et al. (2012) experimentally demonstrated that some flavonoids have a
relatively high inhibition potential for ACE-I [31]. With the molecular docking studies, we
have shown that some of these flavonoids inhibit ACE-II. ACE-I and ACE-II enzymes are
metalloproteases, both of which contain similar zinc fingers (HEXXH) in their active sites.
Molecular docking studies indicated that there are bond interactions between rutin and zinc
finger residues of ACE II. Because of similar active sites of ACE I and II, rutin may
functionally bind both ACE I and II similar way.
It is revealed that Covid-19 binds to human angiotensin-converting enzyme 2 (ACE2) to
enter the host cells. Rutin may compete with Covid-19 for ACE II and may prevent or delay
the entry of Covid-19 into the cell.
In recent years, flavonoids have gained a great amount of interest with regards to their
potential for cardiovascular protection. In fact, many epidemiological studies associate an
increased consumption of foods and beverages rich in flavonoids with a reduced risk of CVD
death [32, 33, 34]. Additionally, several of these flavonoids or their derivatives (i.e., diosmin,
rutin and quercetin) are widely used as pharmaceutical agents for their vasoprotective
properties (i.e., Daflon 500, cantaining flavonoid derivatives hesperedin and diosmin) [35].
Therefore, rutin and other flavonoids used in this study can be used for prophylactic purposes
as ACE II inhibitors and competitor [36, 37].
In conclusion, in silico study is shown that the high binding constants for the ACE II
receptors of flavanones in the ethanolic propolis extract make it a good competitive inhibitor
and protective natural agents for the treatment of Covid-19. However, this study should be
supported with further in vivo studies.
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Figure 1. Chromatogram of nineteen phenolic compounds of HPLC-UV; (1): Gallic acid,
(2): Protocathequic acid, (3): p-OH benzoic acid, (4):catechin, (5): caffeic acid, (6): syringic
acid, (7): epicatechin, (8): p-coumaric acid, (9): ferulic acid, (10): rutin, (11): myricetin, (12):
resveratrol, (13).daidzein, (14); luteolin, (15): t-cinnamic acid, (16): hesperetin, (17): chrysin,
(18):pinocembrin, (19): Caffeic acid phenethyl ester (CAPE).
Figure 2. The two-dimension (2D) and three-dimension (3D) interaction analysis of
ACE II with rutin
Table 1. Phenolic composition of propolis
Group name
Compound name
mg/100g
Hydroxybenzoic acids
Gallic acid
n.d.
Protocateuic acid
n.d.
p-OH Benzoic acid
n.d.
Syringic acid
n.d.
Catechin
Catechin
n.d.
Epicatechin
n.d.
Hydroxycinnamic acids
Caffeic acid
254.501
p-Coumaric acid
63.871
Ferulic acid
n.d.
t-Cinnamic acid
145.455
CAPE
541.213
Flavanons
Rutin
770.970
Myricetin
1567.750
Flavones
Hesperetin
258.010
Chrysin
4678.423
Pinocembrin
1467.260
Isoflavons
Luteolin
684.752
Stilbands and Lignans
Daidzein
n.d
Resveratrol
2.372
n.d: not detected
Table 2: Summary of reference and flavonoids compounds aganist ACE II with binding energy,
Ki and interacted residues in the ACE II binding site.
Ligand Name
Binding
Energy
(kcal/mol)
Ki
(uM)
ACE II residues interacting with ligands
MLN-4760 ((S,S)-2-{1-Carboxy-2-[3-
(3,5-Dıchloro-Benzyl)-3h-Imıdazol-4-
Yl]-Ethylamıno}-4-Methyl-Pentanoic
Acid)*
-7.28
4.65
Tyr127, Arg273, Phe274, Trp271, Arg273,
Phe274, His345, Pro346,Cys361, Thr371,
His374, Glu375, His378,Glu406, Phe504,
His505, Tyr515, Arg518
Caffeic acid (3,4-dihyroxycinnamic
acid)
-5.53
89.08
Arg273, His345, Pro346, Thr347, Ala348,
His374, Glu375, His378, Phe504, His505,
Tyr515
Caffeic acid phenethyl ester (Caffeic
acid 2-phenylethyl ester; β-Phenylethyl
caffeate) (2-Phenylethyl (2E)-3-(3,4-
dihydroxyphenyl)acrylate)
-7.76
2.04
Tyr127, Ser128, Leu144, Glu145, Asn149,
Trp271, Val343, Cys344, His345, Pro346,
Met360, Cys361, Thr362, Lys363, Asp368,
Phe504
Chrysin (5,7-Dihydroxyflavone)
-7.08
6.41
Tyr127, Ser128, Glu145, Asn149, Cys344,
His345, Pro346, Met360, Cys361, Thr362,
Lys363, Asp368, Phe504
Galangin ( 3,5,7-Trihydroxyflavone)
-7.18
5.41
Arg273, Phe274, His345, Pro346, Thr347,
Ala348,Thr371, His374, Glu375, His378,
Glu406, Phe504, His505, Tyr515, Arg518
Myricetin (3,3′,4′,5,5′,7-
Hexahydroxyflavone)
-7.70
2.28
Arg273, Phe274, His345, Pro346, Thr347,
Ala348, Thr371, His374, Glu375, His378,
Glu406, Phe504, His505, Tyr515, Arg518,
Rutin (Quercetin-3-rutinoside hydrate)
-8.98
0.261
Tyr127, Ser128, Leu144, Glu145, Asn149,
Asp269, Met270, Trp271, Arg273, Phe274,
Val343, Cys344, His345, Pro346, Met360,
Cys361, Lys363, Asp367, Asp368, Thr371,
His374, Glu375, Glu406, Phe504,Arg518
Hesperetin (3',5,7-Trihydroxy-4'-
methoxyflavanone)
-7.40
3.79
Arg273, His345, Pro346, Thr347, Ala348,
Trp349, Thr371, His374, Glu375, His378,
Glu406, Phe504, His505, Tyr510, Tyr515,
Arg518
Pinocembrin (5,7-Dihydroxy-2-phenyl-
2,3-dihydro-4H-chromen-4-one)
-7.46
3.38
Tyr127, Ser128, Leu144, Glu145, Asn149,
Trp271, Val343, Cys344, His345, Pro346,
Met360, Cys361, Thr362, Lys363, Asp368
Luteolin (2-(3,4-Dihydroxyphenyl)- 5,7-
dihydroxy-4-chromenone)
-6.93
8.36
Arg273, Phe274, His345, Pro346, Thr347,
Ala348, Trp349, His374, Glu375, His378,
Asp382, Glu402, Phe504, His505, Tyr510,
Tyr515, Arg518
Ouercetin
-7.62
2.62
Arg273, Phe274, His345, Pro346, Thr347,
Ala348, Thr371, Glu375, His374, His378,
Glu406, Phe504, His505, Tyr515, Arg518
*Reference compund
Supplementary Table: Chemical compounds used for the molecular docking screening
Chemical compound
2D-Structure
Caffeic acid (3,4-
dihyroxycinnamic acid)
Caffeic acid phenethyl ester
(Caffeic acid 2-phenylethyl ester;
β-Phenylethyl caffeate) (2-
Phenylethyl (2E)-3-(3,4-
dihydroxyphenyl)acrylate)
Chrysin (5,7-Dihydroxyflavone)
Galangin ( 3,5,7-
Trihydroxyflavone)
Myricetin (3,3′,4′,5,5′,7-
Hexahydroxyflavone)
Rutin (Quercetin-3-rutinoside
hydrate)
Hesperetin (3',5,7-Trihydroxy-4'-
methoxyflavanone)
Pinocembrin (5,7-Dihydroxy-2-
phenyl-2,3-dihydro-4H-chromen-
4-one)
Luteolin (2-(3,4-
Dihydroxyphenyl)- 5,7-
dihydroxy-4-chromenone)
... Thus, even though the redocking process was carried out by these papers, the RMSD was not described, beyond others evaluation methods, such as roc curve or molecular dynamics simulations. Güler et al. (2020) also evaluated the ability of flavonoids present in propolis to bind to ACE2 receptors. According to the docking analysis, it was demonstrated that rutin, myricetin, CAPE, hesperetin and pinocembrin showed the best potential for inhibition compared to the natural inhibitor (MLN-4760). ...
... • More detailed studies are needed. Güler et al. (2020) ...
... for the binding site of ACE2 and can prevent or delay the entry of SARS-CoV-2 into the cell. Thus, rutin and other flavonoids have prophylactic capacity as inhibitors and competitors of ACE2 (Güler et al., 2020). ...
Article
Full-text available
Despite the advancement of vaccination and the reduction in the number of deaths, there is still the emergence of new variants, such as the omicron of SARS-CoV-2 (COVID-19). In this sense, new natural antiviral therapies are highly explored. One of these products, propolis, have shown promising results against COVID-19, including the inhibition of the binding between the coronavirus and ACE2. This systematic review aimed to gather a summary of scientific evidence existing on the effective of the therapeutic use of propolis and their components in the treatment of COVID-19. The protocol for the present systematic review was registered on the PROSPERO (CRD42021267016). In this study, we analyzed 185 articles, selecting 13 of them. Some phenolic compounds and flavonoids, such as artepillin C, hesperetin, CAPE and rutin, were widely cited, as they have great potential for binding with the molecular targets of SARS-CoV-2. Some clinical studies that evaluated the effects of propolis against COVID-19 were included, and confirmed the effectiveness of propolis and its components. The results of this review demonstrate the effectiveness of using propolis and their components in the treatment of COVID-19 due to its antiviral activities. Additionally, the anti-inflammatory and immunomodulatory properties can help to patients with COVID-19.
... Reports have been published about anti-SARS-CoV-2 activity based on inhibition of the angiotensin-converting enzyme 2 (ACE2), to which SARS-CoV-2 strongly binds for invasion and replication inside host human cells [136,137]. The binding energy to ACE2 of several flavonoids and other propolis components has been evaluated [138]. Rutin has the highest binding energy, followed by myricetin, CAPE (Figure 2, I), hesperetin, and pinocembrin. ...
... The COVID-19 pandemic encouraged some medical teams to test propolis or honey as adjunct treatments. A detailed review has been published about the prospects of honey and propolis for the treatment of COVID-19 based on in vitro, in silico and clinical studies [138]. The study focuses on known properties of phenolic components of propolis, including CAPE ( Figure 2, I), artepillin C (Figure 2, III), rutin, naringin, and luteolin. ...
Article
Full-text available
Propolis has gained wide popularity over the last decades in several parts of the world. In parallel, the literature about propolis composition and biological properties increased markedly. A great number of papers have demonstrated that propolis from different parts of the world is composed mainly of phenolic substances, frequently flavonoids, derived from plant resins. Propolis has a relevant role in increasing the social immunity of bee hives. Experimental evidence indicates that propolis and its components have activity against bacteria, fungi, and viruses. Mechanisms of action on bacteria, fungi, and viruses are known for several propolis components. Experiments have shown that propolis may act synergistically with antibiotics, antifungals, and antivirus drugs, permitting the administration of lower doses of drugs and higher antimicrobial effects. The current trend of growing resistance of microbial pathogens to the available drugs has encouraged the introduction of propolis in therapy against infectious diseases. Because propolis composition is widely variable, standardized propolis extracts have been produced. Successful clinical trials have included propolis extracts as medicine in dentistry and as an adjuvant in the treatment of patients against COVID-19. Present world health conditions encourage initiatives toward the spread of the niche of propolis, not only as traditional and alternative medicine but also as a relevant protagonist in anti-infectious therapy. Production of propolis and other apiary products is environmentally friendly and may contribute to alleviating the current crisis of the decline of bee populations. Propolis production has had social-economic relevance in Brazil, providing benefits to underprivileged people.
... Mohamed (2020) observed that propolis shows an antiviral activity against SARS-CoV-2, reducing its replication. Güler et al. (2020) demonstrated that flavonoids in ethanolic propolis extracts have high activity in binding, and thus blocking the angiotensin-converting enzyme 2 (ACE-2) receptors; this activity indicates that natural bee propolis can have a strong potential for COVID-19 therapy. SARS-CoV-2 utilizes ACE-2 receptors to enter into the cells (Hoffmann et al. 2020;Zhou et al. 2020). ...
... In literature, there are several studies on the application of bee pollen for COVID-19 therapy. Güler et al. (2020) tested the active compounds of the bee pollen obtained from Cistus L. (Cisteceae). They observed that caffeic acid phenethyl ester compounds, pinocembrin, and chrysin effectively inhibit the SARS-CoV-2 spike glycoprotein-human ACE-2 complex. ...
Article
Full-text available
COVID-19 pandemic has passed to the front all the contradictions of the beekeeping sector: the valuable role of bee products as immune enhancers and antiviral agents and the impact that unsustainability of human activities has on bees’ health and survival. The COVID-19 emergency led several countries to adopt severe restriction measures to contrast the infection. The lowering of industrial and commercial activities, transports, and the general lockdown had immediate consequences on the air quality, significantly improving environmental conditions. This had a positive impact on honeybees’ life’s quality. On the other hand, the bee and beehive transportation limitations threaten to hit food production by affecting the pollinator service, and this is particularly true in large, food-exporting countries like the USA and China where due to the few numbers of local bees, beekeepers import them by other countries and convey by truck hives for thousands of kilometers to pollinate crops. Furthermore, honeybee products, focusing on their natural pharmacological properties, can play an essential role as a potential natural contrast to the virus by enhancing the immunity defenses of both humans and animals, and their demand by consumers is expected to increase. Several researchers in the last months focused their attention on bee products to evaluate their effect in the cure of COVID-19 patients to ameliorate the symptoms or to contrast the coronavirus directly. This review reports these preliminary results.
... In previous in vitro and in vivo studies, it was shown that flavonoids could inhibit the activity of ACE. RecentlyGuler et al. (2021) used ten flavonoids (Caffeic acid, CAPE, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin, and quercetin) for detecting their binding ability to ACE-2 receptors and it was shown that rutin has the best inhibition potentials for ACE-2 receptors and then followed by myricetin, CAPE, hesperetin, and pinocembrin. It was concluded that flavonoids in ethanolic propolis extracts have a high potential for COVID-19 treatment by inhibition of ACE-2 receptors and preventing entry of virus to host cells(Guler et al., 2021). ...
... RecentlyGuler et al. (2021) used ten flavonoids (Caffeic acid, CAPE, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin, and quercetin) for detecting their binding ability to ACE-2 receptors and it was shown that rutin has the best inhibition potentials for ACE-2 receptors and then followed by myricetin, CAPE, hesperetin, and pinocembrin. It was concluded that flavonoids in ethanolic propolis extracts have a high potential for COVID-19 treatment by inhibition of ACE-2 receptors and preventing entry of virus to host cells(Guler et al., 2021). Also,Refaat et al. (2021) andVijayakumar et al. (2020) established that rutin, luteolin, and CAPE inhibit ACE 2 receptors too.Kumara et al. (2020), showed that CAPE inhibits the TMPRSS2 and block the entry of SARS-CoV-2 into the cell.Refaat et al. (2020) andJain et al. (2021) detected that naringin, rutin, and quercetin have the binding activity to S protein and inhibit viral fusion in the host cell membrane.Harisna et al. (2021) suggested that propolis components genistin, methylophopogonone A and 3'methoxydaidzin inhibit main protease and spike protein and these compounds could be used as antiviral agents. ...
... Further, macrophage and monocyte activation occurs, as well as production of additional cytokines, including TNF and IL-6. Compounds derived from green propolis negatively regulate the expression of TMPRSS2 and the anchoring of ACE2, which limits entry of the virus [10,11]. Additionally, these compounds promote the immunomodulation of NF-κB, the NLRP3 in ammasome and monocytes/macrophages, reducing the overproduction of proin ammatory cytokines [1,6,7]. ...
... Several experimental studies have already demonstrated the effects of substances present in green propolis against pathways used by the coronavirus to enter cells, trigger exaggerated in ammatory mechanisms and promote immune responses with disordered orchestration [1,[7][8][9][10][11][12]. ...
Preprint
Full-text available
Background The 2019 coronavirus disease (COVID-19) pandemic continues to spread and affects large numbers of people with unprecedented impacts. To date, there is no consensus on a specific treatment. Experimental evidence has already been obtained for use of the standardized extract of Brazilian green propolis (EPP-AF) against viral targets, and clinical rationality has been demonstrated for testing this extract as an adjunct to treatment in patients affected by COVID-19. The BeeCovid2 study is once again assessing EPP-AF in hospitalized patients with coronavirus infection. Methods BeeCovid2 is a randomized, double-blinded, placebo-controlled clinical study being conducted in Brazil to provide further evidence on the effectiveness of standardized green propolis extract as an adjunctive treatment for adults hospitalized with COVID-19. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days who are not on invasive oxygen therapy are eligible. Enrolled patients are randomized at a 1:1 ratio to receive placebo or standardized propolis extract (900 mg/day) for 10 days. The study treatments are administered in a double-blinded manner, and patients are followed for 28 days. The primary outcome is the length of hospital stay. Secondary outcomes include the need for mechanical ventilation, the rate of acute kidney injury, the need for renal replacement therapy, the requirement for vasoactive drugs, the use of an intra-aortic balloon pump (IABP), and the use of extracorporeal membrane oxygenation (ECMO). Discussion This trial is very useful and will provide more data on the effectiveness of using the standardized Brazilian green propolis extract as an adjunctive treatment in association with standard care in adults hospitalized with moderate to severe acute COVID-19. Trial registration ClinicalTrials.gov NCT04800224. Registered on March 16, 2021.
... SARS-CoV-2 is known to bind strongly to angiotensin-converting enzyme 2 (ACE2), using this enzyme as a receptor for host cell invasion and replication (59,60), causing damage and increasing interpersonal transmission (61). Consequently, ACE inhibitors have been considered as useful pharmacological alternatives. ...
... Further, macrophage and monocyte activation occurs, as well as production of additional cytokines, including TNF and IL-6 [1]. Compounds derived from green propolis negatively regulate the expression of TMPRSS2 and the anchoring of ACE2, which limits entry of the virus [4][5][6]8]. Experimental evidence also points to propolis substances capable of reducing activation of the PAK1 pathway, an important target used by the virus to shield itself from adaptive immunity [7]. ...
Article
Full-text available
Background The 2019 coronavirus disease (COVID-19) pandemic continues to spread and affects large numbers of people with unprecedented impacts. Experimental evidence has already been obtained for use of the standardized extract of Brazilian green propolis (EPP-AF) against viral targets, and clinical rationality has been demonstrated for testing this extract as an adjunct to treatment in patients affected by COVID-19. The BeeCovid2 study aims to assess whether EPP-AF has an impact on the improvement of patients hospitalized with COVID-19 by reducing the length of hospital stay. Methods BeeCovid2 is a randomized, double-blinded, placebo-controlled clinical study being conducted in Brazil to provide further evidence on the effectiveness of standardized green propolis extract as an adjunctive treatment for adults hospitalized with COVID-19. Hospitalized patients over 18 years of age with a confirmed diagnosis of COVID-19 and up to 14 days of symptoms were included. Patients under mechanical ventilation at randomization, pregnant women, cancer patients, transplanted or using immunosuppression, HIV patients, patients who used propolis in the last 30 days, bacterial or fungal infection at randomization, impossibility of using medication orally or enterally, and advanced chronic diseases (e.g., advanced heart failure, severe liver disease, and end-stage chronic kidney disease). Enrolled patients are randomized at a 1:1 ratio to receive placebo or standardized propolis extract (900 mg/day) for 10 days. The study treatments are administered in a double-blinded manner, and patients are followed for 28 days. The primary outcome is the difference in length of hospital stay in days between groups. Secondary outcomes include the need for mechanical ventilation, the rate of secondary infection, rate of acute kidney injury, the need for renal replacement therapy, the requirement for vasoactive drugs, the use of an intra-aortic balloon pump (IABP), and the use of extracorporeal membrane oxygenation (ECMO). Discussion This trial is very useful and will provide more data on the effectiveness of using the standardized Brazilian green propolis extract as an adjunctive treatment in association with standard care in adults hospitalized with moderate to severe acute COVID-19. Trial registration ClinicalTrials.gov NCT04800224 . Registered on March 16, 2021.
... Kaempferol Memblokir saluran 3a yang dikodekan oleh ORF 3a dari SARS-COV (in vitro)114 Potensi penghambatan dengan energi ikat tinggi ke ACE2 (-8.97 kcal/mol) (in silico)115 ...
... Currently, probiotic metabolites are undergone extensive research to determine their possible anti-SARS-CoV-2 properties [47]. Propolis studies are also focused on the metabolomics side in order to provide sufficient data to the structural bioinformatics research, especially to determine the inhibitory activities against the SARS-CoV-2 virus [48][49][50][51]. Up to today, there are still limited number of the approved natural product based drugs, such as aspirin, penicillin, and taxol [52]. ...
Article
Full-text available
Background: Chronic kidney disease (CKD) is a public health problem worldwide, and proteinuria is a well-established marker of disease progression in CKD patients. Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory, immunomodulatory, and anti-oxidant properties, as well as having been shown to have an antiproteinuric effect in experimental CKD. The aim of this study was to evaluate the impact of Brazilian green propolis extract on proteinuria reduction and the changes in the estimated glomerular filtration rate (eGFR). Methods: This was a randomized, double-blind, placebo-controlled study including patients with CKD caused by diabetes or of another etiology, 18-90 years of age, with an eGFR of 25-70 ml/min per 1.73 m2 and proteinuria (urinary protein excretion > 300 mg/day) or micro- or macro-albuminuria (urinary albumin-to-creatinine ratio > 30 mg/g or > 300 mg/g, respectively). We screened 148 patients and selected 32, randomly assigning them to receive 12 months of Brazilian green propolis extract at a dose of 500 mg/day (n = 18) or 12 months of a placebo (n = 14). Results: At the end of treatment, proteinuria was significantly lower in the propolis group than in the placebo group-695 mg/24 h (95% CI, 483 to 999) vs. 1403 mg/24 h (95% CI, 1031 to 1909); P = 0.004-independent of variations in eGFR and blood pressure, which did not differ between the groups during follow-up. Urinary monocyte chemoattractant protein-1 was also significantly lower in the propolis group than in the placebo group-58 pg/mg creatinine (95% CI, 36 to 95) vs. 98 pg/mg creatinine (95% CI, 62 to 155); P = 0.038. Conclusions: Brazilian green propolis extract was found to be safe and well tolerated, as well as to reduce proteinuria significantly in patients with diabetic and non-diabetic CKD. Trial registration: ( ClinicalTrials.gov number NCT02766036. Registered: May 9, 2016).
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The aim of this study was to identify and characterize the bioactive compounds of Coriandrum sativum responsible for the treatment of hypertension and to explore their mechanism of action as angiotensin-converting enzyme (ACE) inhibitors. Bioactive fractions like alkaloids, flavonoids, steroids, and tannins were extracted and evaluated for their ACE inhibition potential. Among them, only flavonoid-rich fraction showed high ACE inhibition potential with IC 50 value of 28.91 ± 13.42 μ g/mL. The flavonoids were characterized through LC-ESI-MS/MS. Seventeen flavonoids were identified in this fraction of Coriandrum sativum in negative ionization mode which includes pinocembrin, apigenin, pseudobaptigenin, galangin-5-methyl ether, quercetin, baicalein trimethyl ether, kaempferol dimethyl ether, pinobanksin-5-methylether-3-O-acetate, pinobanksin-3-O-pentenoate, pinobanksin-3-O-phenylpropionate, pinobanksin-3-O-pentanoate, apigenin-7-O-glucuronoide, quercetin-3-O-glucoside, apigenin-3-O-rutinoside, rutin, isorhamnetin-3-O-rutinoside, and quercetin dimethyl ether-3-O-rutinoside, while six flavonoids including daidzein, luteolin, pectolinarigenin, apigenin-C-glucoside, kaempferol-3-7-dimethyl ether-3-O-glucoside, and apigenin-7-O-(6-methyl-beta-D-glucoside) were identified in positive ionization mode. The results of this study revealed that Coriandrum sativum is a valuable functional food that possesses a number of therapeutic flavonoids with ACE inhibition potential that can manage blood pressure very efficiently.
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Propolis is a natural substance collected by honey bees from various plants such as, poplar, palm, pine, conifer secretions, gums, resins, mucilage and leaf buds. It is collected and brought very painstakingly by honey bees to be used for sealing cracks and crevices occurring in their hives. Originally, it as an antiseptic meant for preventing beehive from microbial infections along with preventing decomposition of intruders. Additionally, propolis has been used in folk medicine for centuries. The biological characteristics of propolis depend upon its chemical composition, plant sources, geographical zone and seasons. More than 300 compounds have been identified in propolis such as, phenolic compounds, aromatic acids, essential oils, waxes and amino acids. Many scientific articles are published every year in different international journals, and several groups of researchers have focused their attention on the chemical compounds and biological activity of propolis.
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The flavonoid extract from propolis (FP) has been shown to protect against heart injury induced by isoproterenol. However, the effect of FP on cardiac fibrosis after myocardial infarction (MI) as well as the underlying mechanisms is not known. In the present study, we used biochemical and histological approaches to examine the effects of FP on MI-induced cardiac fibrosis and the related mechanisms in a rat MI model and in angiotensin II- (Ang II-) treated rat cardiac fibroblasts (CFs). In vivo, MI was generated by ligation of the left anterior descending coronary artery of rats, which remained for 4 weeks. Rats were randomly divided into the sham, MI, FP (12.5 mg/kg/d), and MI+FP groups. We found that FP treatment improved heart function, reduced cardiac fibrosis, and downregulated the expression of fibrosis-related factors including collagen I, collagen III, matrix metalloproteinase-2 (MMP-2), MMP-9, transforming growth factor- β 1 (TGF- β 1), and p-Smad2/3, which coincided with the upregulated expression of silent information regulator 1 (SIRT1) in the hearts of MI rats. Our in vitro experiments showed that FP inhibited the proliferation and migration of primary cultured rat CFs and downregulated the expression of the above-mentioned fibrosis-related factors in Ang II-stimulated CFs. In addition, FP can decrease ROS production induced by MI and Ang II in vivo and vitro . Notably, silencing SIRT1 counteracted the FP-induced effects on CFs treated with Ang II. We conclude that FP inhibits MI-induced cardiac fibrosis through SIRT1 activation and that FP represents a potential promising drug for the treatment of MI patients in the clinic.
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In this study, a simple and a fast method were developed using RP-HPLC-UV for the separation and quantitative determination of phenolic compounds in various bee products. Fourteen phenolic compounds were identified using 70% acetonitrile in water, and 2% acetic acid in water as a mobile phase with a gradient elution mode. The validation method exhibited linearity (R2>0.994), limits of detection (0.022-0.062 mg/L) and quantification (0.030-0.187mg/L). Under the optimized conditions, 14 commercially available phenolic compounds were analyzed in less than 50 min. This method was successfully employed to study the phenolic profiles of bee products as well as other natural samples.
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The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
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Background: As a natural bioproduct obtained from beekeeping, propolis – with its antimicrobial and antioxidative properties – can be used in food production. Scope and approach: This review discusses methods for obtaining propolis extracts (EP), application of propolis in antimicrobial and antioxidative protection of food, and the influence of propolis on the physical, chemical, and sensory properties of food. In addition, the allergenic potential of propolis is presented, together with the legal status of propolis application in food production. Key findings and conclusions: In food production, EP are used primarily in ethanol, or water/ethanol, because of its low wax content and high content of bioactive compound. The addition of EP enhances the microbial durability and quality of foods during storage. EP are added directly to foods, or are administered superficially through immersing foods in EP or by applying special EP coats. These procedures reduce pathogen counts or completely eliminate pathogens that are transferred by foods and the saprophytic microbiota of meat, fishes, fruits, vegetables, fruit juices, and milk. Propolis can be used as an antioxidant, particularly in meat and fish products, and can confer protection of the antioxidative properties of fruits and juices during storage. Moreover, it contributes to the physical and chemical properties of food, thereby maintaining the quality of food during storage. A disadvantage of propolis is its unique flavor and aroma, which may negatively alter the sensory properties of foods to which it is added.
Article
New Zealand propolis resin and tinctures are rich in compounds that have in vitro anti-gastrointestinal cancer activity. However, propolis tincture has restricted acceptability for human consumption due to pungency in taste and aroma. We have formulated New Zealand propolis into cyclodextrin complexes (CD) that resolve these acceptability issues, and carried out in vitro bioactivity testing of these complexes using human anti-gastrointestinal cancer, anti-inflammatory and anti-oxidant assays. Demonstration of encapsulation was performed by physical, enzymic and chemical measurements. The New Zealand propolis γCD, αCD, and βCD complexes inhibited the proliferation of 4 human gastro-intestinal cancer cell lines, with the extent of inhibition increasing with increasing exposure time. The complexes were also strongly anti-inflammatory in vitro with respect to the cytokine TNF-α, and showed strong lipid anti-oxidant activity. The bioassay results give a strong first indication of beneficial gastro-intestinal health potential of New Zealand propolis – cyclodextrin complexes.